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Journal articles on the topic 'N-Acetyl-Seryl-Aspartyl-Lysyl-Proline (Ac-SDKP)'

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Published: 9 March 2023
Last updated: 10 March 2023

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1

Wang, Dahai, Oscar A. Carretero, Xiao-Yi Yang, Nour-Eddine Rhaleb, Yun-He Liu, Tang-Dong Liao, and Xiao-Ping Yang. "N-acetyl-seryl-aspartyl-lysyl-proline stimulates angiogenesis in vitro and in vivo." American Journal of Physiology-Heart and Circulatory Physiology 287, no. 5 (November 2004): H2099—H2105. http://dx.doi.org/10.1152/ajpheart.00592.2004.

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N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP), a natural inhibitor of pluripotent hematopoietic stem cell proliferation, has been suggested as capable of promoting an angiogenic response. We studied whether Ac-SDKP stimulates endothelial cell proliferation, migration, and tube formation; enhances angiogenic response in the rat cornea after implantation of a tumor spheroid; and increases capillary density in rat hearts with myocardial infarction (MI). In vitro, an immortal BALB/c mouse aortic endothelial 22106 cell line was used to determine the effects of Ac-SDKP on endothelial cell proliferation and migration and tube formation. In vivo, a 9L-gliosarcoma cell spheroid (250–300 μm in diameter) was implanted in the rat cornea and vehicle or Ac-SDKP (800 μg·kg−1·day−1ip) infused via osmotic minipump. Myocardial capillary density was studied in rats with MI given either vehicle or Ac-SDKP. We found that Ac-SDKP 1) stimulated endothelial cell proliferation and migration and tube formation in a dose-dependent manner, 2) enhanced corneal neovascularization, and 3) increased myocardial capillary density. Endothelial cell proliferation and angiogenesis stimulated by Ac-SDKP could be beneficial in cardiovascular diseases such as hypertension and MI. Furthermore, because Ac-SDKP is mainly cleaved by ACE, it may partially mediate the cardioprotective effect of ACE inhibitors.
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2

Nakagawa, Pablo, Yunhe Liu, Tang-Dong Liao, Xiaojuan Chen, Germán E. González, Kevin R. Bobbitt, Derek Smolarek, et al. "Treatment with N-acetyl-seryl-aspartyl-lysyl-proline prevents experimental autoimmune myocarditis in rats." American Journal of Physiology-Heart and Circulatory Physiology 303, no. 9 (November 1, 2012): H1114—H1127. http://dx.doi.org/10.1152/ajpheart.00300.2011.

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Myocarditis is commonly associated with cardiotropic infections and has been linked to development of autoimmunity. N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) is a naturally occurring tetrapeptide that prevents inflammation and fibrosis in hypertension and other cardiovascular diseases; however, its effect on autoimmune-mediated cardiac diseases remains unknown. We studied the effects of Ac-SDKP in experimental autoimmune myocarditis (EAM), a model of T cell-mediated autoimmune disease. This study was conducted to test the hypothesis that Ac-SDKP prevents autoimmune myocardial injury by modulating the immune responses. Lewis rats were immunized with porcine cardiac myosin and treated with Ac-SDKP or vehicle. In EAM, Ac-SDKP prevented both systolic and diastolic cardiac dysfunction, remodeling as shown by hypertrophy and fibrosis, and cell-mediated immune responses without affecting myosin-specific autoantibodies or antigen-specific T cell responses. In addition, Ac-SDKP reduced cardiac infiltration by macrophages, dendritic cells, and T cells, pro-inflammatory cytokines [interleukin (IL)-1α, tumor necrosis factor-α, IL-2, IL-17] and chemokines (cytokine-induced neutrophil chemoattractant-1, interferon-γ-induced protein 10), cell adhesion molecules (intercellular adhesion molecule-1, L-selectin), and matrix metalloproteinases (MMP). Ac-SDKP prevents autoimmune cardiac dysfunction and remodeling without reducing the production of autoantibodies or T cell responses to cardiac myosin. The protective effects of Ac-SDKP in autoimmune myocardial injury are most likely mediated by inhibition of 1) innate and adaptive immune cell infiltration and 2) expression of proinflammatory mediators such as cytokines, chemokines, adhesion molecules, and MMPs.
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3

Castoldi, Giovanna, Cira R. T. Di Gioia, Camila Bombardi, Carla Perego, Lucia Perego, Massimiliano Mancini, Martina Leopizzi, et al. "Prevention of myocardial fibrosis by N-acetyl-seryl-aspartyl-lysyl-proline in diabetic rats." Clinical Science 118, no. 3 (February 1, 2010): 211–20. http://dx.doi.org/10.1042/cs20090234.

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Ac-SDKP (N-acetyl-seryl-aspartyl-lysyl-proline) is a physiological tetrapeptide hydrolysed by ACE (angiotensin-converting enzyme). In experimental models of hypertension, Ac-SDKP has antifibrotic effects in the heart; however, the role of Ac-SDKP in diabetic cardiomyopathy is currently unknown. The aim of the present study was to evaluate the effect of Ac-SDKP on cardiac systolic and diastolic function, and interstitial and perivascular fibrosis in the heart of diabetic rats. Diabetes was induced in 55 Sprague–Dawley rats by streptozotocin injection. Control rats (n=18) underwent only buffer injection. Out of the 55 diabetic rats, 19 were chronically treated with insulin and 13 with the ACEI (ACE inhibitor) ramipril (3 mg·kg−1 of body weight·day−1). At 2 months after the onset of diabetes, Ac-SDKP (1 mg·kg−1 of body weight·day−1) was administered by osmotic minipumps for 8 weeks to eight control rats, 13 diabetic rats, seven diabetic rats treated with ramipril and nine insulin-treated diabetic rats. Diabetic rats had a significant increase in blood glucose levels. Left ventricular interstitial and perivascular fibrosis, and TGF-β1 (transforming growth factor-β1) protein levels were increased in diabetic rats, but not in insulin-treated diabetic rats and ramipril-treated diabetic rats, compared with control rats. Ac-SDKP administration significantly reduced left ventricular interstitial and perivascular fibrosis in diabetic rats and in diabetic rats treated with ramipril. This was accompanied by a significant reduction in active TGF-β1 and phospho-Smad2/3 protein levels in myocardial tissue of diabetic rats. Echocardiography showed that diabetes was associated with increased end-systolic diameters, and depressed global systolic function and diastolic dysfunction, as assessed by transmitral Doppler velocity profile. These changes were completely reversed by insulin or ramipril treatment. Ac-SDKP treatment partially restored diastolic function in diabetic rats. In conclusion, Ac-SDKP administration in diabetic rats reduces left ventricular interstitial and perivascular fibrosis, active TGF-β1 and phospho-Smad2/3 levels, and improves diastolic function. Taken together, these findings suggest that, by inhibiting the TGF-β/Smad pathway, Ac-SDKP protects against the development of diabetic cardiomyopathy.
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4

Lin, Chun-Xia, Nour-Eddine Rhaleb, Xiao-Ping Yang, Tang-Dong Liao, Martin A. D'Ambrosio, and Oscar A. Carretero. "Prevention of aortic fibrosis by N-acetyl-seryl-aspartyl-lysyl-proline in angiotensin II-induced hypertension." American Journal of Physiology-Heart and Circulatory Physiology 295, no. 3 (September 2008): H1253—H1261. http://dx.doi.org/10.1152/ajpheart.00481.2008.

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Fibrosis is an important component of large conduit artery disease in hypertension. The endogenous tetrapeptide N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) has anti-inflammatory and antifibrotic effects in the heart and kidney. However, it is not known whether Ac-SDKP has an anti-inflammatory and antifibrotic effect on conduit arteries such as the aorta. We hypothesize that in ANG II-induced hypertension Ac-SDKP prevents aortic fibrosis and that this effect is associated with decreased protein kinase C (PKC) activation, leading to reduced oxidative stress and inflammation and a decrease in the profibrotic cytokine transforming growth factor-β1 (TGF-β1) and phosphorylation of its second messenger Smad2. To test this hypothesis we used rats with ANG II-induced hypertension and treated them with either vehicle or Ac-SDKP. In this hypertensive model we found an increased collagen deposition and collagen type I and III mRNA expression in the aorta. These changes were associated with increased PKC activation, oxidative stress, intercellular adhesion molecule (ICAM)-1 mRNA expression, and macrophage infiltration. TGF-β1 expression and Smad2 phosphorylation also increased. Ac-SDKP prevented these effects without decreasing blood pressure or aortic hypertrophy. Ac-SDKP also enhanced expression of inhibitory Smad7. These data indicate that in ANG II-induced hypertension Ac-SDKP has an aortic antifibrotic effect. This effect may be due in part to inhibition of PKC activation, which in turn could reduce oxidative stress, ICAM-1 expression, and macrophage infiltration. Part of the effect of Ac-SDKP could also be due to reduced expression of the profibrotic cytokine TGF-β1 and inhibition of Smad2 phosphorylation.
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5

Liao, Tang-Dong, Pablo Nakagawa, Branislava Janic, Martin D'Ambrosio, Morel E. Worou, Edward L. Peterson, Nour-Eddine Rhaleb, Xiao-Ping Yang, and Oscar A. Carretero. "N-Acetyl-Seryl-Aspartyl-Lysyl-Proline: mechanisms of renal protection in mouse model of systemic lupus erythematosus." American Journal of Physiology-Renal Physiology 308, no. 10 (May 15, 2015): F1146—F1154. http://dx.doi.org/10.1152/ajprenal.00039.2015.

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Systemic lupus erythematosus is an autoimmune disease characterized by the development of auto antibodies against a variety of self-antigens and deposition of immune complexes that lead to inflammation, fibrosis, and end-organ damage. Up to 60% of lupus patients develop nephritis and renal dysfunction leading to kidney failure. N-acetyl-seryl-aspartyl-lysyl-proline, i.e., Ac-SDKP, is a natural tetrapeptide that in hypertension prevents inflammation and fibrosis in heart, kidney, and vasculature. In experimental autoimmune myocarditis, Ac-SDKP prevents cardiac dysfunction by decreasing innate and adaptive immunity. It has also been reported that Ac-SDKP ameliorates lupus nephritis in mice. We hypothesize that Ac-SDKP prevents lupus nephritis in mice by decreasing complement C5-9, proinflammatory cytokines, and immune cell infiltration. Lupus mice treated with Ac-SDKP for 20 wk had significantly lower renal levels of macrophage and T cell infiltration and proinflammatory chemokine/cytokines. In addition, our data demonstrate for the first time that in lupus mouse Ac-SDKP prevented the increase in complement C5-9, RANTES, MCP-5, and ICAM-1 kidney expression and it prevented the decline of glomerular filtration rate. Ac-SDKP-treated lupus mice had a significant improvement in renal function and lower levels of glomerular damage. Ac-SDKP had no effect on the production of autoantibodies. The protective Ac-SDKP effect is most likely achieved by targeting the expression of proinflammatory chemokines/cytokines, ICAM-1, and immune cell infiltration in the kidney, either directly or via C5-9 proinflammatory arm of complement system.
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6

Romero, Cesar A., Nitin Kumar, Pablo Nakagawa, Morel E. Worou, Tang-Dong Liao, Edward L. Peterson, and Oscar A. Carretero. "Renal release of N-acetyl-seryl-aspartyl-lysyl-proline is part of an antifibrotic peptidergic system in the kidney." American Journal of Physiology-Renal Physiology 316, no. 1 (January 1, 2019): F195—F203. http://dx.doi.org/10.1152/ajprenal.00270.2018.

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The antifibrotic peptide N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) is released from thymosin-β4 (Tβ4) by the meprin-α and prolyl oligopeptidase (POP) enzymes and is hydrolyzed by angiotensin-converting enzyme (ACE). Ac-SDKP is present in urine; however, it is not clear whether de novo tubular release occurs or if glomerular filtration is the main source. We hypothesized that Ac-SDKP is released into the lumen of the nephrons and that it exerts an antifibrotic effect. We determined the presence of Tβ4, meprin-α, and POP in the kidneys of Sprague-Dawley rats. The stop-flow technique was used to evaluate Ac-SDKP formation in different nephron segments. Finally, we decreased Ac-SDKP formation by inhibiting the POP enzyme and evaluated the long-term effect in renal fibrosis. The Tβ4 precursor and the releasing enzymes meprin-α and POP were expressed in the kidneys. POP enzyme activity was almost double that in the renal medulla compared with the renal cortex. With the use of the stop-flow technique, we detected the highest Ac-SDKP concentrations in the distal nephron. The infusion of a POP inhibitor into the kidney decreased the amount of Ac-SDKP in distal nephron segments and in the proximal nephron to a minor extent. An ACE inhibitor increased the Ac-SDKP content in all nephron segments, but the increase was highest in the distal portion. The chronic infusion of a POP inhibitor increased kidney medullary fibrosis, which was prevented by Ac-SDKP. We conclude that Ac-SDKP is released by the nephron and is part of an important antifibrotic system in the kidney.
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7

Peng, Hongmei, Jiang Xu, Xiao-Ping Yang, Kamal M. Kassem, Imane A. Rhaleb, Ed Peterson, and Nour-Eddine Rhaleb. "N-acetyl-seryl-aspartyl-lysyl-proline treatment protects heart against excessive myocardial injury and heart failure in mice." Canadian Journal of Physiology and Pharmacology 97, no. 8 (August 2019): 753–65. http://dx.doi.org/10.1139/cjpp-2019-0047.

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Myocardial infarction (MI) in mice results in cardiac rupture at 4–7 days after MI, whereas cardiac fibrosis and dysfunction occur later. N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) has anti-inflammatory, anti-fibrotic, and pro-angiogenic properties. We hypothesized that Ac-SDKP reduces cardiac rupture and adverse cardiac remodeling, and improves function by promoting angiogenesis and inhibiting detrimental reactive fibrosis and inflammation after MI. C57BL/6J mice were subjected to MI and treated with Ac-SDKP (1.6 mg/kg per day) for 1 or 5 weeks. We analyzed (1) intercellular adhesion molecule-1 (ICAM-1) expression; (2) inflammatory cell infiltration and angiogenesis; (3) gelatinolytic activity; (4) incidence of cardiac rupture; (5) p53, the endoplasmic reticulum stress marker CCAAT/enhancer binding protein homology protein (CHOP), and cardiomyocyte apoptosis; (6) sarcoplasmic reticulum Ca2+ ATPase (SERCA2) expression; (7) interstitial collagen fraction and capillary density; and (8) cardiac remodeling and function. Acutely, Ac-SDKP reduced cardiac rupture, decreased ICAM-1 expression and the number of infiltrating macrophages, decreased gelatinolytic activity, p53 expression, and myocyte apoptosis, but increased capillary density in the infarction border. Chronically, Ac-SDKP improved cardiac structures and function, reduced CHOP expression and interstitial collagen fraction, and preserved myocardium SERCA2 expression. Thus, Ac-SDKP decreased cardiac rupture, ameliorated adverse cardiac remodeling, and improved cardiac function after MI, likely through preserved SERCA2 expression and inhibition of endoplasmic reticulum stress.
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8

González, Germán E., Nour-Eddine Rhaleb, Pablo Nakagawa, Tang-Dong Liao, Yunhe Liu, Pablo Leung, Xiangguo Dai, Xiao-Ping Yang, and Oscar A. Carretero. "N-acetyl-seryl-aspartyl-lysyl-proline reduces cardiac collagen cross-linking and inflammation in angiotensin II-induced hypertensive rats." Clinical Science 126, no. 1 (September 9, 2013): 85–94. http://dx.doi.org/10.1042/cs20120619.

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We have reported previously that Ac-SDKP (N-acetyl-seryl-aspartyl-lysyl-proline) reduces fibrosis and inflammation (in macrophages and mast cells). However, it is not known whether Ac-SDKP decreases collagen cross-linking and lymphocyte infiltration; lymphocytes modulate both collagen cross-linking and ECM (extracellular matrix) formation in hypertension. Thus we hypothesized that (i) in AngII (angiotensin II)-induced hypertension, Ac-SDKP prevents increases in cross-linked and total collagen by down-regulating LOX (lysyl oxidase), the enzyme responsible for cross-linking, and (ii) these effects are associated with decreased pro-fibrotic cytokine TGFβ (transforming growth factor β) and the pro-inflammatory transcription factor NF-κB (nuclear factor κB) and CD4+/CD8+ lymphocyte infiltration. We induced hypertension in rats by infusing AngII either alone or combined with Ac-SDKP for 3 weeks. Whereas Ac-SDKP failed to lower BP (blood pressure) or LV (left ventricular) hypertrophy, it did prevent AngII-induced increases in (i) cross-linked and total collagen, (ii) LOX mRNA expression and LOXL1 (LOX-like 1) protein, (iii) TGFβ expression, (iv) nuclear translocation of NF-κB, (v) CD4+/CD8+ lymphocyte infiltration, and (vi) CD68+ macrophages infiltration. In addition, we found a positive correlation between CD4+ infiltration and LOXL1 expression. In conclusion, the effect of Ac-SDKP on collagen cross-linking and total collagen may be due to reduced TGFβ1, LOXL1, and lymphocyte and macrophage infiltration, and its effect on inflammation could be due to lower NF-κB.
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9

Chan, Gary C. W., Wai Han Yiu, Hao Jia Wu, Dickson W. L. Wong, Miao Lin, Xiao Ru Huang, Hui Yao Lan, and Sydney C. W. Tang. "N-Acetyl-seryl-aspartyl-lysyl-proline Alleviates Renal Fibrosis Induced by Unilateral Ureteric Obstruction in BALB/C Mice." Mediators of Inflammation 2015 (2015): 1–10. http://dx.doi.org/10.1155/2015/283123.

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To expand the armamentarium of treatment for chronic kidney disease (CKD), we explored the utility of boosting endogenously synthesized N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP), which is augmented by inhibition of the angiotensin converting enzyme. Male BALB/c mice underwent unilateral ureteral ligation (UUO) or sham operation and received exogenously administered Ac-SDKP delivered via a subcutaneous osmotic minipump or Captopril treatment by oral gavage. Seven days after UUO, there were significant reductions in the expression of both collagen 1 and collagen 3 in kidneys treated with Ac-SDKP or Captopril, and there was a trend towards reductions in collagen IV,α-SMA, and MCP-1 versus control. However, no significant attenuation of interstitial injury or macrophage infiltration was observed. These findings are in contrary to observations in other models and underscore the fact that a longer treatment time frame may be required to yield anti-inflammatory effects in BALB/c mice treated with Ac-SDKP compared to untreated mice. Finding an effective treatment regimen for CKD requires fine-tuning of pharmacologic protocols.
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10

Liu, Yun-He, Martin D'Ambrosio, Tang-dong Liao, Hongmei Peng, Nour-Eddine Rhaleb, Umesh Sharma, Sabine André, Hans-J. Gabius, and Oscar A. Carretero. "N-acetyl-seryl-aspartyl-lysyl-proline prevents cardiac remodeling and dysfunction induced by galectin-3, a mammalian adhesion/growth-regulatory lectin." American Journal of Physiology-Heart and Circulatory Physiology 296, no. 2 (February 2009): H404—H412. http://dx.doi.org/10.1152/ajpheart.00747.2008.

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Galectin-3 (Gal-3) is secreted by activated macrophages. In hypertension, Gal-3 is a marker for hypertrophic hearts prone to develop heart failure. Gal-3 infused in pericardial sac leads to cardiac inflammation, remodeling, and dysfunction. N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP), a naturally occurring tetrapeptide, prevents and reverses inflammation and collagen deposition in the heart in hypertension and heart failure postmyocardial infarction. In the present study, we hypothesize that Ac-SDKP prevents Gal-3-induced cardiac inflammation, remodeling, and dysfunction, and these effects are mediated by the transforming growth factor (TGF)-β/Smad3 signaling pathway. Adult male rats were divided into four groups and received the following intrapericardial infusion for 4 wk: 1) vehicle (saline, n = 8); 2) Ac-SDKP (800 μg·kg−1·day−1, n = 8); 3) Gal-3 (12 μg/day, n = 7); and 4) Ac-SDKP + Gal-3 ( n = 7). Left ventricular ejection fraction, cardiac output, and transmitral velocity were measured by echocardiography; inflammatory cell infiltration, cardiomyocyte hypertrophy, and collagen deposition in the heart by histological and immunohistochemical staining; and TGF-β expression and Smad3 phosphorylation by Western blot. We found that, in the left ventricle, Gal-3 1) enhanced macrophage and mast cell infiltration, increased cardiac interstitial and perivascular fibrosis, and causes cardiac hypertrophy; 2) increased TGF-β expression and Smad3 phosphorylation; and 3) decreased negative change in pressure over time response to isoproterenol challenge, ratio of early left ventricular filling phase to atrial contraction phase, and left ventricular ejection fraction. Ac-SDKP partially or completely prevented these effects. We conclude that Ac-SDKP prevents Gal-3-induced cardiac inflammation, fibrosis, hypertrophy, and dysfunction, possibly via inhibition of the TGF-β/Smad3 signaling pathway.
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11

Kassem, Kamal M., Sonal Vaid, Hongmei Peng, Sarah Sarkar, and Nour-Eddine Rhaleb. "Tβ4–Ac-SDKP pathway: Any relevance for the cardiovascular system?" Canadian Journal of Physiology and Pharmacology 97, no. 7 (July 2019): 589–99. http://dx.doi.org/10.1139/cjpp-2018-0570.

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The last 20 years witnessed the emergence of the thymosin β4 (Tβ4)–N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) pathway as a new source of future therapeutic tools to treat cardiovascular and renal diseases. In this review article, we attempted to shed light on the numerous experimental findings pertaining to the many promising cardiovascular therapeutic avenues for Tβ4 and (or) its N-terminal derivative, Ac-SDKP. Specifically, Ac-SDKP is endogenously produced from the 43-amino acid Tβ4 by 2 successive enzymes, meprin α and prolyl oligopeptidase. We also discussed the possible mechanisms involved in the Tβ4–Ac-SDKP-associated cardiovascular biological effects. In infarcted myocardium, Tβ4 and Ac-SDKP facilitate cardiac repair after infarction by promoting endothelial cell migration and myocyte survival. Additionally, Tβ4 and Ac-SDKP have antifibrotic and anti-inflammatory properties in the arteries, heart, lungs, and kidneys, and stimulate both in vitro and in vivo angiogenesis. The effects of Tβ4 can be mediated directly through a putative receptor (Ku80) or via its enzymatically released N-terminal derivative Ac-SDKP. Despite the localization and characterization of Ac-SDKP binding sites in myocardium, more studies are needed to fully identify and clone Ac-SDKP receptors. It remains promising that Ac-SDKP or its degradation-resistant analogs could serve as new therapeutic tools to treat cardiac, vascular, and renal injury and dysfunction to be used alone or in combination with the already established pharmacotherapy for cardiovascular diseases.
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12

Wang, Wei, Wenning Jia, and Chunping Zhang. "The Role of Tβ4-POP-Ac-SDKP Axis in Organ Fibrosis." International Journal of Molecular Sciences 23, no. 21 (October 31, 2022): 13282. http://dx.doi.org/10.3390/ijms232113282.

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Fibrosis is a pathological process in which parenchymal cells are necrotic and excess extracellular matrix (ECM) is accumulated due to dysregulation of tissue injury repair. Thymosin β4 (Tβ4) is a 43 amino acid multifunctional polypeptide that is involved in wound healing. Prolyl oligopeptidase (POP) is the main enzyme that hydrolyzes Tβ4 to produce its derivative N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) which is found to play a role in the regulation of fibrosis. Accumulating evidence suggests that the Tβ4-POP-Ac-SDKP axis widely exists in various tissues and organs including the liver, kidney, heart, and lung, and participates in the process of fibrogenesis. Herein, we aim to elucidate the role of Tβ4-POP-Ac-SDKP axis in hepatic fibrosis, renal fibrosis, cardiac fibrosis, and pulmonary fibrosis, as well as the underlying mechanisms. Based on this, we attempted to provide novel therapeutic strategies for the regulation of tissue damage repair and anti-fibrosis therapy. The Tβ4-POP-Ac-SDKP axis exerts protective effects against organ fibrosis. It is promising that appropriate dosing regimens that rely on this axis could serve as a new therapeutic strategy for alleviating organ fibrosis in the early and late stages.
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13

Magalhães, Flávio de Castro, Tiago Fernandes, Vinícius Bassaneze, Katt Coelho Mattos, Isolmar Schettert, Fabio Luiz Navarro Marques, José Eduardo Krieger, Roberto Nava, Valério Garrone Barauna, and Oliveira Edilamar Menezes. "High-volume endurance exercise training stimulates hematopoiesis by increasing ACE NH2-terminal activity." Clinical Science 135, no. 20 (October 2021): 2377–91. http://dx.doi.org/10.1042/cs20210739.

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Abstract One of the health benefits of endurance exercise training (ET) is the stimulation of hematopoiesis. However, the mechanisms underlying ET-induced hematopoietic adaptations are understudied. N–Acetyl–Seryl–Aspartyl–Lysyl–Proline (Ac-SDKP) inhibits proliferation of early hematopoietic progenitor cells. The angiotensin I-converting enzyme (ACE) NH2-terminal promotes hematopoiesis by inhibiting the anti-hematopoietic effect of Ac-SDKP. Here we demonstrate for the first time the role of ACE NH2-terminal in ET-induced hematopoietic adaptations. Wistar rats were subjected to 10 weeks of moderate-(T1) and high-(T2) volume swimming-training. Although both protocols induced classical ET-associated adaptations, only T2 increased plasma ACE NH2-domain activity (by 40%, P=0.0003) and reduced Ac-SDKP levels (by 50%, P<0.0001). T2 increased the number of hematopoietic stem cells (HSCs; ∼200%, P=0.0008), early erythroid progenitor colonies (∼300%, P<0.0001) and reticulocytes (∼500%, P=0.0007), and reduced erythrocyte lifespan (∼50%, P=0.022). Following, Wistar rats were subjected to T2 or T2 combined with ACE NH2-terminal inhibition (captopril (Cap) treatment: 10 mg.kg−1.day−1). T2 combined with ACE NH2-terminal inhibition prevented Ac-SDKP decrease and attenuated ET-induced hematopoietic adaptations. Altogether, our findings show that ET-induced hematopoiesis was at least partially associated with increased ACE NH2-terminal activity and reduction in the hematopoietic inhibitor Ac-SDKP.
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Zhu, Liping, Xiao-Ping Yang, Branislava Janic, Nour-Eddine Rhaleb, Pamela Harding, Pablo Nakagawa, Edward L. Peterson, and Oscar A. Carretero. "Ac-SDKP suppresses TNF-α-induced ICAM-1 expression in endothelial cells via inhibition of IκB kinase and NF-κB activation." American Journal of Physiology-Heart and Circulatory Physiology 310, no. 9 (May 1, 2016): H1176—H1183. http://dx.doi.org/10.1152/ajpheart.00252.2015.

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N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) is a naturally occurring tetrapeptide that prevents inflammation and fibrosis in hypertension and other cardiovascular diseases. We previously showed that, in angiotensin II-induced hypertension, Ac-SDKP decreased the activation of nuclear transcription factor NF-κB, whereas, in experimental autoimmune myocarditis and hypertension animal models, it also reduced the expression of endothelial leukocyte adhesion molecule ICAM-1. However, the mechanisms by which Ac-SDKP downregulated ICAM-1 expression are still unclear. TNF-α is a proinflammatory cytokine that induces ICAM-1 expression in various cell types via TNF receptor 1 and activation of the classical NF-κB pathway. We hypothesized that in endothelial cells Ac-SDKP suppresses TNF-α-induced ICAM-1 expression by decreasing IKK phosphorylation that as a consequence leads to a decrease of IκB phosphorylation and NF-κB activation. To test this hypothesis, human coronary artery endothelial cells were treated with Ac-SDKP and then stimulated with TNF-α. We found that TNF-α-induced ICAM-1 expression was significantly decreased by Ac-SDKP in a dose-dependent manner. Ac-SDKP also decreased TNF-α-induced NF-κB translocation from cytosol to nucleus, as assessed by electrophoretic mobility shift assay, which correlated with a decrease in IκB phosphorylation. In addition, we found that Ac-SDKP decreased TNF-α-induced IKK phosphorylation and IKK-β expression. However, Ac-SDKP had no effect on TNF-α-induced phosphorylation of p38 MAP kinase or ERK. Thus we conclude that Ac-SDKP inhibition of TNF-α activation of canonical, i.e., IKK-β-dependent, NF-κB pathway and subsequent decrease in ICAM-1 expression is achieved via inhibition of IKK-β.
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15

Kumar, Nitin, Pablo Nakagawa, Branislava Janic, Cesar A. Romero, Morel E. Worou, Sumit R. Monu, Edward L. Peterson, et al. "The anti-inflammatory peptide Ac-SDKP is released from thymosin-β4 by renal meprin-α and prolyl oligopeptidase." American Journal of Physiology-Renal Physiology 310, no. 10 (May 15, 2016): F1026—F1034. http://dx.doi.org/10.1152/ajprenal.00562.2015.

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N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) is a natural tetrapeptide with anti-inflammatory and antifibrotic properties. Previously, we have shown that prolyl oligopeptidase (POP) is involved in the Ac-SDKP release from thymosin-β4 (Tβ4). However, POP can only hydrolyze peptides shorter than 30 amino acids, and Tβ4 is 43 amino acids long. This indicates that before POP hydrolysis takes place, Tβ4 is hydrolyzed by another peptidase that releases NH2-terminal intermediate peptide(s) with fewer than 30 amino acids. Our peptidase database search pointed out meprin-α metalloprotease as a potential candidate. Therefore, we hypothesized that, prior to POP hydrolysis, Tβ4 is hydrolyzed by meprin-α. In vitro, we found that the incubation of Tβ4 with both meprin-α and POP released Ac-SDKP, whereas no Ac-SDKP was released when Tβ4 was incubated with either meprin-α or POP alone. Incubation of Tβ4 with rat kidney homogenates significantly released Ac-SDKP, which was blocked by the meprin-α inhibitor actinonin. In addition, kidneys from meprin-α knockout (KO) mice showed significantly lower basal Ac-SDKP amount, compared with wild-type mice. Kidney homogenates from meprin-α KO mice failed to release Ac-SDKP from Tβ4. In vivo, we observed that rats treated with the ACE inhibitor captopril increased plasma concentrations of Ac-SDKP, which was inhibited by the coadministration of actinonin (vehicle, 3.1 ± 0.2 nmol/l; captopril, 15.1 ± 0.7 nmol/l; captopril + actinonin, 6.1 ± 0.3 nmol/l; P < 0.005). Similar results were obtained with urinary Ac-SDKP after actinonin treatment. We conclude that release of Ac-SDKP from Tβ4 is mediated by successive hydrolysis involving meprin-α and POP.
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Yang, Fang, Xiao-Ping Yang, Yun-He Liu, Jiang Xu, Nour-Eddine Rhaleb, Hong-Mei Peng, and Oscar A. Carretero. "Effects of Ac-Sdkp, a Natural Inhibitor of Hematopoietic Stem Cell Proliferation, on Cardiac Collagen Deposition in Rats with Myocardial Infarction." Hypertension 36, suppl_1 (October 2000): 703. http://dx.doi.org/10.1161/hyp.36.suppl_1.703-a.

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P56 N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) is a potent natural inhibitor of hematopoietic stem cell proliferation. Recently, it has been shown to inhibit collagen production by cardiac fibroblasts in vitro and collagen content in the left ventricle (LV) of 2K1C hypertensive rats in vivo . We hypothesized that Ac-SDKP may decrease myocardial collagen deposition in rats with myocardial infarction (MI), thereby reducing interstitial fibrosis and improving cardiac function. Lewis inbred rats were subjected to MI by ligating the left anterior descending coronary artery. Either vehicle or Ac-SDKP (400 mg/kg/day, i.p. by osmotic mini-pump) was given 2 months after MI and continued for another 2 months. Systolic blood pressure (SBP) was measured once a month by tail cuff. LV diastolic dimension (LVDd), mass, ejection fraction (EF) and cardiac output (CO) were measured monthly by echocardiography. At the end of the experiment, mean blood pressure (MBP), LV end-diastolic pressure (LVEDP) and dP/dt were determined. Collagen content in the non-infarcted area of the LV was measured by hydroxyproline assay. We found that Ac-SDKP had no effect on most hemodynamic and cardiac functional parameters. However, it significantly decreased collagen content from 26.1 ±2.2 (vehicle) to 14.7 ±4.8 mg/mg dry weight (Ac-SDKP); P < 0.001, associated with an increase in negative dP/dt from 5451.8 ±1240.9 (vehicle) to 7030.3 ±763.2 mm Hg/sec (Ac-SDKP); P < 0.01. These results suggest that Ac-SDKP could be a potent tool to slow down the process of myocardial interstitial fibrosis and improve post-MI diastolic function.
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Hrenak, Jaroslav, Ludovit Paulis, and Fedor Simko. "N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP): Potential target molecule in research of heart, kidney and brain." Current Pharmaceutical Design 21, no. 35 (October 30, 2015): 5135–43. http://dx.doi.org/10.2174/1381612821666150909093927.

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18

Zhuo, Jia L., Oscar A. Carretero, Hongmei Peng, Xiao C. Li, Domenico Regoli, Witold Neugebauer, and Nour-Eddine Rhaleb. "Characterization and localization of Ac-SDKP receptor binding sites using125I-labeled Hpp-Aca-SDKP in rat cardiac fibroblasts." American Journal of Physiology-Heart and Circulatory Physiology 292, no. 2 (February 2007): H984—H993. http://dx.doi.org/10.1152/ajpheart.00776.2006.

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We have shown that the tetrapeptide N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) inhibited endothelin-1 (ET-1)-induced cell proliferation and collagen synthesis in cultured rat cardiac fibroblasts (CFs) and reduced left ventricle collagen deposition in rats with aldosterone (salt)- and ANG II-induced hypertension. However, it is not known whether these effects are mediated by receptor binding sites specific for Ac-SDKP. We hypothesized that Ac-SDKP exerts antifibrotic effects by binding to specific receptor sites in cultured rat CFs, which mediate the inhibitory effects of Ac-SDKP on ET-1-stimulated collagen synthesis. Ac-SDKP binding sites in rat CFs and hearts were characterized by a specific radioligand,125I-labeled 3-( p-hydroxyphenyl)-propionic acid (or desaminotyrosine) (Hpp)-Aca-SDKP, a biologically active analog of Ac-SDKP.125I-labeled Hpp-Aca-SDKP bound to rat CFs and fractionated membranes with similar affinities and specificity in a concentration- and time-dependent fashion. Scatchard plot analyses revealed a single class of high-affinity Hpp-Aca-SDKP binding sites (maximal binding: 1,704 ± 198 fmol/mg protein; dissociation constant: 3.3 ± 0.6 nM).125I-labeled Hpp-Aca-SDKP binding in CFs was displaced by unlabeled native peptide Ac-SDKP (inhibition constant: 0.69 ± 0.15 nM) and the analog Hpp-Aca-SDKP (inhibition constant: 10.4 ± 0.2 nM) but not the unrelated peptide ANG II or ET-1 (10 μM). In vitro, both Ac-SDKP and Hpp-Aca-SDKP inhibited ET-1-stimulated collagen synthesis in CFs in a dose-dependent fashion, reaching a maximal effect at 1 nM (control: 7.5 ± 0.4, ET-1: 19.9 ± 1.2, ET-1+SDKP: 7.7 ± 0.4, ET-1+Hpp-Aca-SDKP: 9.7 ± 0.1 μg/mg protein; P < 0.001). Ac-SDKP also significantly attenuated ET-1-induced increases in intracellular calcium and MAPK ERK1/2 phosphorylation in CFs. In the rat heart, in vitro autoradiography revealed specific125I-labeled Hpp-Aca-SDKP binding throughout the myocardium, primarily interstitially. We believe that these results demonstrate for the first time that Hpp-Aca-SDKP is a functional ligand specific for Ac-SDKP receptor binding sites and that both Ac-SDKP and Hpp-Aca-SDKP exert antifibrotic effects by binding to Ac-SDKP receptors in rat CFs.
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19

Peng, Hongmei, Oscar A. Carretero, Edward L. Peterson, and Nour-Eddine Rhaleb. "Ac-SDKP inhibits transforming growth factor-β1-induced differentiation of human cardiac fibroblasts into myofibroblasts." American Journal of Physiology-Heart and Circulatory Physiology 298, no. 5 (May 2010): H1357—H1364. http://dx.doi.org/10.1152/ajpheart.00464.2009.

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N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) inhibits collagen production and cell proliferation in cultured rat cardiac fibroblasts, but its effect on differentiation of fibroblasts into myofibroblasts is not known. High amounts of transforming growth factor-β1 (TGF-β1) have been found in fibrotic cardiac tissue. TGF-β1 converts fibroblasts into myofibroblasts, which produce more extracellular matrix proteins than fibroblasts. We hypothesized that 1) Ac-SDKP inhibits TGF-β1-induced differentiation of fibroblasts into myofibroblasts; and 2) this effect is mediated in part by blocking phosphorylation of small-mothers-against-decapentaplegic (Smad) 2 and extracellular signal-regulated kinase (ERK) 1/2. For this study, we used human fetal cardiac fibroblasts (HCFs), which do not spontaneously become myofibroblasts when cultured at low passages. We investigated the effect of Ac-SDKP on TGF-β1-induced HCF transformation into myofibroblasts, Smad2 and ERK1/2 phosphorylation, Smad7 expression, cell proliferation, and collagen production. We also investigated TGF-β1 production by HCFs stimulated with endothelin-1 (ET-1). As expected, HCFs treated with TGF-β1 transformed into myofibroblasts as indicated by increased expression of α-smooth muscle actin and a higher proportion of the embryonic isoform of smooth muscle myosin compared with untreated cells. TGF-β1 also increased Smad2 and ERK1/2 phosphorylation but did not affect Smad7 expression. In addition, TGF-β1 stimulated HCF proliferation as indicated by an increase in mitochondrial dehydrogenase activity and collagen production (hydroxyproline assay). Ac-SDKP significantly inhibited all of the effects of TGF-β1. It also inhibited ET-1-stimulated TGF-β1 production. We concluded that Ac-SDKP markedly suppresses differentiation of human cardiac fibroblasts into myofibroblasts, probably by inhibiting the TGF-β/Smad/ERK1/2 signaling pathway, and thus mediating its anti-fibrotic effects.
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20

Maheshwari, Mani, Cesar A. Romero, Sumit R. Monu, Nitin Kumar, Tang-Dong Liao, Edward L. Peterson, and Oscar A. Carretero. "Renal Protective Effects of N-Acetyl-Seryl-Aspartyl-Lysyl-Proline (Ac-SDKP) in Obese Rats on a High-Salt Diet." American Journal of Hypertension 31, no. 8 (May 2, 2018): 902–9. http://dx.doi.org/10.1093/ajh/hpy052.

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21

Cavasin, Maria A. "Therapeutic Potential of Thymosin-??4 and its Derivative N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) in Cardiac Healing After Infarction." American Journal of Cardiovascular Drugs 6, no. 5 (2006): 305–11. http://dx.doi.org/10.2165/00129784-200606050-00003.

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22

Okwan-Duodu, Derick, Jerome Landry, Xiao Z. Shen, and Roberto Diaz. "Angiotensin-converting enzyme and the tumor microenvironment: mechanisms beyond angiogenesis." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 305, no. 3 (August 1, 2013): R205—R215. http://dx.doi.org/10.1152/ajpregu.00544.2012.

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The renin angiotensin system (RAS) is a network of enzymes and peptides that coalesce primarily on the angiotensin II type 1 receptor (AT1R) to induce cell proliferation, angiogenesis, fibrosis, and blood pressure control. Angiotensin-converting enzyme (ACE), the key peptidase of the RAS, is promiscuous in that it cleaves other substrates such as substance P and bradykinin. Accumulating evidence implicates ACE in the pathophysiology of carcinogenesis. While the role of ACE and its peptide network in modulating angiogenesis via the AT1R is well documented, its involvement in shaping other aspects of the tumor microenvironment remains largely unknown. Here, we review the role of ACE in modulating the immune compartment of the tumor microenvironment, which encompasses the immunosuppressive, cancer-promoting myeloid-derived suppressor cells, alternatively activated tumor-associated macrophages, and T regulatory cells. We also discuss the potential roles of peptides that accumulate in the setting of chronic ACE inhibitor use, such as bradykinin, substance P, and N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP), and how they may undercut the gains of anti-angiogenesis from ACE inhibition. These emerging mechanisms may harmonize the often-conflicting results on the role of ACE inhibitors and ACE polymorphisms in various cancers and call for further investigations into the potential benefit of ACE inhibitors in some neoplasms.
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23

Mnguni, Ayanda Trevor, Mark E. Engel, Megan S. Borkum, and Bongani M. Mayosi. "The Effects of Angiotensin Converting Enzyme Inhibitors (ACE-I) on Human N-Acetyl-Seryl-Aspartyl-Lysyl-Proline (Ac-SDKP) Levels: A Systematic Review and Meta-Analysis." PLOS ONE 10, no. 12 (December 11, 2015): e0143338. http://dx.doi.org/10.1371/journal.pone.0143338.

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24

Ntsekhe, Mpiko, Kerryn Matthews, Janine Wolske, Motasim Badri, Katalin A. Wilkinson, Robert J. Wilkinson, Edward D. Sturrock, and Bongani M. Mayosi. "Scientific letter: Ac-SDKP (N-acetyl-seryl-aspartyl-lysyl-proline) and Galectin-3 levels in tuberculous pericardial effusion: implications for pathogenesis and prevention of pericardial constriction." Heart 98, no. 17 (July 26, 2012): 1326.1–1328. http://dx.doi.org/10.1136/heartjnl-2012-302196.

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25

Zhang, Lijuan, Dingjie Xu, Qian Li, Yi Yang, Hong Xu, Zhongqiu Wei, Ruimin Wang, et al. "N -acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) attenuates silicotic fibrosis by suppressing apoptosis of alveolar type II epithelial cells via mediation of endoplasmic reticulum stress." Toxicology and Applied Pharmacology 350 (July 2018): 1–10. http://dx.doi.org/10.1016/j.taap.2018.04.025.

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26

Nakagawa, Pablo, and Pablo Nakagawa. "Abstract 178: Effects of N-Acetyl-Seryl-Aspartyl-Lysyl-Proline in Experimental Autoimmune Mocarditis." Hypertension 60, suppl_1 (September 2012). http://dx.doi.org/10.1161/hyp.60.suppl_1.a178.

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Background: Acetyl-Ser-Asp-Lys-Pro (Ac-SDKP), a naturally occurring tetrapeptide, prevents autoimmune cardiac dysfunction and remodeling. The mechanism by which this occurs remains unknown. Experimental autoimmune myocarditis (EAM), a T cell-mediated autoimmune disease, is a model of autoimmune cardiac injury. Cytokines and adhesion molecules are necessary for the development of EAM. We hypothesized that Ac-SDKP prevents autoimmune cardiac injury by reducing T cell response, pro-inflammatory cytokines and adhesion molecules. Methods and results: EAM was induced by immunization of rats with porcine cardiac myosin, followed by s.c. infusion of vehicle or Ac-SDKP (800 μg.kg-1.d-1) via osmotic minipumps. By 3 weeks post-immunization, we evaluated cell-mediated immunity by delayed-type hypersensitivity, myocardial T helper infiltration by immunohistochemistry and both cytokines and adhesion molecules were measured with a proteomic array kit. Ac-SDKP prevented increases in 1) Delayed-type sensitivity (EAM, 0.35±0.06 vs EAM + Ac-SDKP, 0.16±0.01** mm), 2) infiltration by T helper cells (148±20 vs 97±17*** CD4 cells/mm2), 3) pro-inflammatory cytokines [Tumor necrosis factor-α (0.98±0.20 vs 0.17±0.03** A.U.); Interleukin (IL)-1β (13.7±2.9 vs 0.29±0.07*** A.U.); IP-10, a T helper type 1 chemokine (1.54±0.23 vs 0.30±0.08*); IL-17, a T helper type 17 cytokine (1.9±0.3 vs 0.8±0.3* A.U.)] and 4) Cell adhesion molecules [L-selectin (42.4±4.8 vs 9.1±1.9***) and Intercellular adhesion molecule 1 (54.1±3.1 vs 19.1±2.8***)]. Conclusion: Prevention of autoimmune cardiac injury by Ac-SDKP is correlated by decreased cell-mediated immunity. The protective effects of Ac-SDKP are likely mediated by reduction of T cell infiltration, pro-inflammatory cytokines and cell adhesion molecules. *p<0.05, **p<0.005, and ***p<0.001 EAM vs EAM + Ac-SDKP
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Romero, Cesar A., Nitin Kumar, Nour-Eddine Rhaleb, and Oscar A. Carretero. "Abstract P147: Production of Anti-inflammatory Peptide N-Acetyl-Seryl-Aspartyl-Lysyl-Proline (Ac-SDKP) in Kidney." Hypertension 68, suppl_1 (September 2016). http://dx.doi.org/10.1161/hyp.68.suppl_1.p147.

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Ac-SDKP is a natural peptide with anti-fibrotic and anti-inflammatory properties in vascular, myocardial and kidney tissues. It is released from thymosin B4 (TB4) by two step enzymatic reactions by meprin and the prolyl oligopeptidase enzymes (POP) and degraded by angiotensin converting enzyme (ACE). Treatment with ACE inhibitors (ACEi) increases Ac-SDKP plasma concentration. Kidney has been proposed as clearance organ for Ac-SDKP. Thus after Ac-SDKP filtration, 90% is degraded and only 10% is excreting in the urine. However, in rodents the decrease of glomerular filtration rate did not affect the amount of Ac-SDKP in urine and prevention of Ac-SDKP filtration at the glomerular level by using neutralizing antibodies also did no change the urinary Ac-SDKP content; This suggest that mechanisms other than only filtration can be present. We hypothesized that Ac-SDKP is produced in the kidney. We evaluated the presence of TB4 and POP mRNA by analyzing the trascriptome in each segment of the nephron using the public access NHI database ESBL. We confirmed kidney expression of POP enzyme by immunohistochemistry (IHC). Finally the stop flow pressure technique was used to evaluate the Ac-SDKP formation in different segments of the nephron, in normal condition, under POP inhibition (POPi) and ACEi. All experiments were performed in Sprague-Dawley rats.TB4 mRNA was present in all the nephron segments, mainly in the distal parts (1941±949.8 RPKM) in comparison with proximal tubule (101.4±73.7 RPKM) (p<0.05). POP enzyme mRNA was present in proximal tubule, loop of Henle (inner medulla) and distal nephron (distal, connecting and collecting tubules). POP enzyme expression by IHC was observed in the distal convoluted tubule in cortex and mainly in the medullary region. The Stop flow technique showed the high Ac-SDKP/Inulin ratio in the distal nephron: 10.5±0.8 vs. 4.2±0.1 in the proximal segments (p<0.01). POPi infusion into the kidney decreased Ac-SDKP/Inulin in comparison to the vehicle group in distal (10.5±0.8 vs 5.6±0.8, p<0.01) and proximal nephron segments (4.22±0.1 vs. 2.1±0.2, p<0.01). ACEi increased the Ac-SDKP content in all nephron segments, mainly in the distal part. We conclude that Ac-SDKP is synthetized in kidney, predominantly in the distal nephron.
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Bordcoch, Ginette, Pablo Nakagawa, Cesar A. Romero, and Oscar A. Romero. "Abstract P211: N-Acetyl-Seryl-Aspartyl-Lysyl-Proline (Ac-SDKP) Promotes Tube Formation in Human Coronary Artery Endothelial Cells." Hypertension 68, suppl_1 (September 2016). http://dx.doi.org/10.1161/hyp.68.suppl_1.p211.

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Ac-SDKP is an endogenous peptide with anti-inflammation and anti-fibrotic effects in hypertensive and cardiovascular diseases. It is cleaved from Thymosin β4 (Tβ4) and hydrolyzed by angiotensin converting enzyme (ACE). Ac-SDKP plasma concentration increases after treatment with ACE inhibitors (ACEi) and some of the beneficial effects of ACEi treatment has been ascribed to Ac-SDKP. Ac-SDKP is a mediator of angiogenesis in in-vitro and in-vivo animal models. Ac-SDKP stimulates rodents derived immortalized aortic endothelial cells migration and capillary-like structures formation (tube formation). Similarly, Ac-SDKP increases capillary density after myocardial infarction in rats. The mechanism related to angiogenesis induced by Ac-SDKP is not known. Tβ4 (Ac-SDKP precursor) promotes endothelial cell migration and angiogenesis by the activation of the VEGF/AKT pathway. Our objective is to evaluate the Ac-SDKP pro-angiogenic effect in Human Coronary Artery Endothelial Cells (HCAEC) and the mechanism that regulates the angiogenic effect of Ac-SDKP. HCAEC do not produce VEGF, thus we hypothesize that Ac-SDKP increases VEGF expression in fibroblasts and that indirectly could promote capillary tube formation in endothelial cells. We used primary culture of rat cardiac fibroblast (RCF) and we treated these cells with 10nM Ac-SDKP for 24 hours. VEGF concentration in cell supernatant was measured by ELISA. Cells were starved without serum overnight before the Ac-SDKP treatment. For capillary tube formation assay, HCAEC cells were seeded into matrigel and incubated in presence of 10nM Ac-SDKP for 12 hours, pictures were taken by double phase contrast microscope and tube length was quantified with image J software and the results were expressed as percentage of control. After Ac-SDKP treatment, VEGF concentration did not increase in the supernatant of RCF (control: 0.12±0.07 vs. Ac-SDKP: 0.14±0.09 mg/ml; p=0.7). However, Ac-SDKP treatment induced the development of tube formation in HCAECs by 7±2% respect to control (p=0.037). We conclude that Ac-SDKP induces capillary tube formation not only in rodent but also in human derived endothelial cells. The mechanism by which Ac-SDKP promotes tube formation in HCAECs is still unknown.
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Liao, Tang-Dong, Cesar Romero, Nitin Kumar, Nour-Eddine Rhaleb, and Oscar Carretero. "Abstract P299: Thymosin Beta15 is a Novel Precursor of N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP)." Hypertension 68, suppl_1 (September 2016). http://dx.doi.org/10.1161/hyp.68.suppl_1.p299.

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N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) is a natural tetrapeptide with anti-inflammatory and antifibrotic properties that is released from its precursor thymosin β4 (Tβ4). At present, Tβ4 is the only identified Ac-SDKP precursor with no other candidates reported. Our search of National Center for Biotechnology Information (NCBI) database by Basic Local Alignment Search Tool (BLAST) revealed that Tβ15 has similar N-terminal amino acid structure as Tβ4. We hypothesize that in addition to Tβ4, Tβ15 may also be a precursor of Ac-SDKP. To test our hypothesis we used wild-type (WT) and Tβ4 global knockout mice (Tβ4KO). We detected the presence of Ac-SDKP in various organs (pmol/mg protein) in both WT and Tβ4KO mice, including lymph node (459±35 vs 234±37), thymus (241±36 vs 179±24), heart (95±14 vs 71±10), kidney (90±19 vs 56±11), testis (55±16 vs 55±17), spleen (57±10 vs 16±1) and liver (49±16 vs 18±2). We also measured urinary Ac-SDKP execration before and after angiotensin converting enzyme inhibitor (ACEi) treatment. In both group of mice we determined the basal Ac-SDKP excretion (ng/24hrs) and that was significantly increased with ACEi treatment in both WT (36±8 vs 117±17) and Tβ4KO (22±3 vs 36±3), with the increase being lower in Tβ4KO mice. Immunohistochemistry analysis of Tβ15 in the kidney revealed positive cells located in the thick ascending limb, distal tubule, macula densa and collecting duct in both groups of mice. Interestingly, we found that in Tβ4KO mice thymus weight was higher than in WT mice, while there was no difference between the groups with regard to heart and kidney weight. We concluded that Tβ15 is a potential novel precursor of Ac-SDKP.
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Romero, Cesar A., Nitin Kumar, Nour-Eddine Rhaleb, and Oscar A. Carretero. "Abstract P011: Source and Catabolism Sites of the Cardio-renal Protective Peptide N-Acetyl-Seryl-Aspartyl-Lysyl-Proline (Ac-SDKP)." Hypertension 66, suppl_1 (September 2015). http://dx.doi.org/10.1161/hyp.66.suppl_1.p011.

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Ac-SDKP is a natural tetrapeptide with anti-fibrotic and anti-inflammatory properties in vascular, myocardial and kidney tissues. It is degraded by angiotensin converting enzyme (ACE) and treatment with ACE inhibitors increases its plasma levels. However the main sites of Ac-SDKP production and catabolism are unknown. Thus, the aim of this study was to determine the source and catabolism sites of Ac-SDKP. Ac-SDKP was measured in brain, thymus, lungs, heart, spleen, kidney, liver, intestine, and bone marrow from male 200-250 gr Sprague Dawley rats. Samples from arterial blood delivered to and venous blood exiting from kidney, spleen, intestine, liver, and lungs were obtained, and the vein to arterial (V-A) plasma levels differences were calculated as an index of organ production or elimination. Additionally, urinary Ac-SDKP excretion over 24 hrs and Ac-SDKP renal clearance were measured. Inulin clearance was also determined. The Stop Flow technique was performed to evaluate the renal handling of Ac-SDKP in different segments of the nephron. The greatest amounts of Ac-SDKP were found in Thymus, Spleen and Bone marrow (111.3±9; 92.2±24; 70.3±17 pmoles/mg of protein respectively), while the lowest values were found in brain, large intestine and heart (10.7±6; 14.8±6 ;19.8±7; pmoles/mg of protein, respectively). Ac-SDKP is secreted by different organs into the circulating blood. The highest V-A difference was found in the spleen (15.2±7 nM), reflecting its production, while the lowest V-A differences was observed in the lungs (-1.2±3.7 nM), reflecting a high degradation of Ac-SDKP in this tissue. No V-A differences were found in kidney (0.98±7 nM). It was not possible to obtain venous samples from Thymus or Bone marrow. The renal clearance of Ac-SDKP was 0.15 ml/min/100g body weight, equivalent to a fractional excretion of 14.5%. The stop flow technique showed the highest Ac-SDKP levels in the distal part of the nephron, while the proximal segments showed the lowest (11 Vs. 4.2 Ac-SDKP/Inulin ratio). In conclusion, Ac-SDKP production occurs mainly in lymphoid organs. Expectedly, high Ac-SDKP degradation was observed in the lungs. In the kidney Ac-SDKP is filtered, probably degraded in the proximal tubule and secreted in the distal tubule.
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Nakagawa, Pablo, Ginette Bordcoch de Martino, Martin D’Ambrosio, Xu Jiang, and Oscar Carretero. "Abstract 028: Effects of N-acetyl-seryl-aspartyl-lysyl-proline on Inflammatory Cells During the Acute Stage of Myocardial Infarction." Hypertension 68, suppl_1 (September 2016). http://dx.doi.org/10.1161/hyp.68.suppl_1.028.

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Background: The natural peptide N-Acetyl-Seryl-Aspartyl-Lysyl-Proline (Ac-SDKP) decreases inflammation in chronic diseases such as hypertension and heart failure. The effects of Ac-SDKP on acute inflammatory responses during myocardial infarction (MI) are unknown. During the first 72 hours post-MI, neutrophils, M1 macrophages (pro-inflammatory), and M2 macrophages (pro-resolution) and the release of myeloperoxidase (MPO) and matrix metalloproteinases (MMP) play a role in the development of cardiac rupture which is an uncommon, but fatal complication. We hypothesize that in the acute stage of MI, Ac-SDKP decreases the incidence of cardiac rupture and mortality by preventing the infiltration of immune cells and by decreasing the activation of MPO and MMP. Methods: MI was induced by the ligation of the left descending coronary artery in C57 mice. Vehicle or Ac-SDKP (1.6 mg/kg/d) was infused via osmotic minipump. Cardiac immune cell infiltration was assessed by flow cytometry, cardiac MPO and MMP activities were measured at 24-48 hrs post-MI. The incidence of cardiac rupture and mortality was determined at 7 days post-MI. Neutrophil migration was studied in vitro by chemotaxis transwell assay. Results: In infarcted mice, Ac-SDKP decreased the incidence of cardiac rupture from 51.0% (26 of 51 animals) to 27.3% (12/44; p=0.015) and mortality from 56.9% (29/51) to 31.8% (14/44; p=0.019). Ac-SDKP also reduced the cardiac infiltration by the M1 macrophages (veh: 1,495±236 vs Ac-SKDP: 765±69 cells/heart, p=0.027), without affecting M2 macrophages. Ac-SDKP did not affect neutrophil and MPO activity in vivo and neither affected neutrophil chemotaxis in vitro . However, Ac-SDKP prevented the activation of MMP-9 (veh: 3,686±508 vs Ac-SDKP: 1,696±512 optical density units, p=0.029) in infarcted hearts. Conclusion: Ac-SDKP prevents cardiac rupture and mortality in acute MI. These protective effects of Ac-SDKP are associated with a decrease in pro-inflammatory M1 macrophage infiltration and MMP-9 activation. Perspective: Cardiac rupture is an uncommon, but fatal complication of MI that could be prevented by the administration of Ac-SDKP or a peptidase resistant analog.
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Worou, Morel E., Martin D’Ambrosio, Tang-Dong Liao, Pablo Nakagawa, Nour-Eddine Rhaleb, and Oscar A. Carretero. "Abstract 322: Protective effects of N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) on renal damage in Dahl Salt-Sensitive Rats." Hypertension 64, suppl_1 (September 2014). http://dx.doi.org/10.1161/hyp.64.suppl_1.322.

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N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) is a naturally occurring tetrapeptide hydrolyzed by angiotensin-converting enzyme. We previously reported that Ac-SDKP protects the kidney from inflammation, fibrosis, and dysfunction caused by hypertension. Salt-sensitivity is highly prevalent in African-Americans and elderly patients, and is associated with a high rate of hypertensive renal disease. The effect of Ac-SDKP on Salt-Sensitive (SS) hypertension is unknown; here, we hypothesized that Ac-SDKP prevents renal fibrosis, glomerulosclerosis and albuminuria in Dahl SS rats on high salt diet without affecting blood pressure. Dahl SS rats and their consomic control, SS-13BN were fed either 0.23% NaCl (low salt, LS) or 4% NaCl (high salt, HS) diet and infused with Ac-SDKP (800 μg/kg/day, subcutaneously via osmotic minipump) or vehicle (0.01 N acetic acid) for 6 weeks. Animals were divided into following groups: LS+vehicle, HS+vehicle, and HS+Ac-SDKP. High salt increased systolic blood pressure (SBP) in SS rats (HS+vehicle 186±5 vs. LS+vehicle 141±3 mmHg), but not in SS-13BN (HS+vehicle 140±3 vs. LS+vehicle 140±2 mmHg). Ac-SDKP did not affect SBP. In both SS and SS-13BN, HS induced renal and cardiac hypertrophy, which were not prevented by Ac-SDKP. However, in SS rats, Ac-SDKP prevented HS-induced renal interstitial fibrosis (HS+vehicle 12±0.5 vs. HS+Ac-SDKP 7±1 % of renal interstitial area) and glomeruloslerosis (HS+vehicle 18±1 vs. HS+Ac-SDKP 9±1 % of glomerular tuft area). Compared to LS, HS increased albuminuria in both strains, from 13±1 to 94±10 mg/24h in SS and from 7±1 to 44±8 mg/24h in SS-13BN. HS also decreased nephrin protein expression in both strains. Interestingly, in SS-13BN, Ac-SDKP attenuated albuminuria (24±3.18 mg/24h) and partially attenuated the decrease in nephrin expression, but in SS, Ac-SDKP had no effect on either albuminuria (126±34 mg/24h) or nephrin expression. In summary, Ac-SDKP prevents renal fibrosis, glomerulosclerosis but not albuminuria in Dahl SS rats on high salt diet. On the other hand, the consomic controls fed high salt developed albuminuria and decreased nephrin, and these effects were prevented by Ac-SDKP.
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Worou, Morel E., Nitin Kumar, Nour-Eddine Rhaleb, Edward L. Peterson, and Oscar A. Carretero. "Abstract P208: N-acetyl-seryl-aspartyl-lysyl-proline Prevents Renal Fibrosis in Dahl Salt-sensitive Rats by an Early Upregulation of miR Let-7b." Hypertension 68, suppl_1 (September 2016). http://dx.doi.org/10.1161/hyp.68.suppl_1.p208.

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We recently showed that N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP), a natural tetrapeptide with antifibrotic properties prevented high salt-induced albuminuria and renal damage including fibrosis in Dahl Salt-Sensitive (SS) rats and their consomic SS13BN controls. However, the mechanism of this antifibrotic effect is unknown. MicroRNAs (miRNAs) have been shown to be important endogenous regulators of several physiological and pathophysiological conditions. The miRNA let-7 family has been suggested as a negative regulator of profibrotic processes in many diseases and its downregulation has been associated with renal fibrosis. Here, we hypothesized that in SS rats, the antifibrotic effect of Ac-SDKP on high salt-induced renal fibrosis is due to an upregulation of miRNA let-7b expression. Dahl SS and consomic SS13BN rats were fed either 0.23% NaCl (low salt, LS) or 4% NaCl (high salt, HS) diet and infused with vehicle (Veh) or Ac-SDKP (1.6 mg/kg/day) subcutaneously via osmotic minipump for 1 week. Animals were divided into the following groups: LS + Veh, HS + Veh and HS + Ac-SDKP. HS increased the systolic blood pressure (SBP) in SS rats, but not in SS13BN rats. Ac-SDKP did not affect SBP. In both strains, one week of HS diet increased albuminuria. Ac-SDKP prevented HS-induced albuminuria. In SS rats, HS-induced a significant downregulation of the renal cortex miR-let 7b expression measured by quantitative RT-PCR (HS + Veh 0.27±0.16 vs. LS + Veh 1.00±0.09; P=0.005), whereas a treatment with Ac-SDKP significantly upregulated the miR-let 7b expression (HS + Ac-SDKP 2.80±0.11; P=0.002). No miR-let 7b expression difference was observed in SS13BN rats. The overexpression of miR-let 7b by Ac-SDKP is associated with a significant decrease in collagen1 mRNA expression (HS + Veh 3.89±0.74 vs. HS + Ac-SDKP 1.25±0.13; P=0.005). One week on HS diet was not sufficient to cause measurable changes in renal collagen protein. In summary, Ac-SDKP prevented albuminuria and renal cortex collagen1 mRNA expression in SS rats fed HS diet for 1 week, and this was associated with an upregulation of miRNA let-7b expression. The antifibrotic effect of Ac-SDKP on HS-induced renal fibrosis in SS rats may be in part due to preceded upregulation of miRNA let-7b expression.
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SUHAIL, HAMID, Hongmei Peng, Sarah Sarkar, Jiang Xu, Kenneth E. Bernstein, Tang-Dong Liao, Pablo A. Ortiz, and Nour-Eddine Rhaleb. "Abstract MP43: Knockout Of ACE-N Facilitates Improved Cardiac Function After Myocardial Infarction." Hypertension 78, Suppl_1 (September 2021). http://dx.doi.org/10.1161/hyp.78.suppl_1.mp43.

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Angiotensin-converting enzyme (ACE) hydrolyzes N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) into inactive fragments through its N-terminal domain (ACE-N). We reported that cardioprotective effects of ACE inhibitor in angiotensin II-induced hypertension were partially mediated through increased Ac-SDKP bioavailability. Whether increased endogenous Ac-SDKP by knocking out ACE-N leads to improved cardiac function in myocardial infarction (MI) is unknown. Wild-type (WT) and ACE-N knockout (ACE-N -/- ) mice were subjected to MI induced by ligating the left anterior descending artery and treated with either vehicle or Ac-SDKP (1.6 mg/kg/day, s.c.) for 5 weeks. Echocardiography was performed on awake mice at the end of experiment and left ventricles (LV) were harvested for histology and molecular biology studies. ACE-N-/- mice showed increased plasma Ac-SDKP level in Sham or MI group compared to WT. Exogenous Ac-SDKP further increased Ac-SDKP level in both WT and ACE-N-/-. SF and EF were significantly decreased in both WT and ACE-N-/- mice post-MI, . Exogenous Ac-SDKP further increased EF and SF post-MI only in WT, but not in ACE-N-/- mice. Sarcoendoplasmic reticulum calcium transport ATPase 2 (SERCA2), a marker of cardiac calcium homeostatsis, significantly decreased in WT post-MI was rescued with Ac-SDKP, whereas ACE-N-/- mice displayed less reduction in SERCA2 expression. These results demonstrate that gene deletion of ACE-N improves cardiac function in mice post-MI, which was associated with increased Ac-SDKP level and minimally reduced expression of SERCA2.Therefore,this study illustrates that endogenous Ac-SDKP results in cardioprotective role in MI.
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Peng, Hongmei, Jiang Xu, Xiao-Ping Yang, Xiangguo Dai, Edward Petersion, Oscar Carretero, and Nour-Eddine Rhaleb. "Abstract 99: Ac-SDKP Protects the Heart From Post-myocardial Infarction Remodeling and Dysfunction in Mice." Hypertension 62, suppl_1 (September 2013). http://dx.doi.org/10.1161/hyp.62.suppl_1.a99.

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N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) has anti-inflammatory, anti-fibrotic and pro-angiogenic effects. We previously observed that Ac-SDKP reduces incidence of cardiac rupture in mice with acute myocardial infarction (MI), which is associated with its anti-inflammatory and pro-angiogenic properties. We hypothesized that Ac-SDKP, via its anti-fibrotic and pro-angiogenic actions, ameliorates left ventricular (LV) dilatation and fibrosis, thus improving cardiac function post-MI. C57BL/6J mice were divided into three groups: 1) sham MI, 2) MI + vehicle (VEH), and 3) MI + Ac-SDKP. Ac-SDKP (1.6 mg/kg/day) was given immediately after MI induction ( i.p. via osmotic pump) for 5 weeks. Cardiac remodeling and function were assessed by echocardiography, and interstitial collagen fraction (ICF) and capillary density was determined histologically. We found that Ac-SDKP 1) reduced LV remodeling, evidenced by decreased LV chamber dimensions and areas, and reduced ICF and increased capillary density, with no changes in posterior wall thickness and LV weight (LVW), and 2) improved cardiac function, demonstrated by increased fractional shortening (FS) and ejection fraction (EF) (Table). We conclude that in murine models of MI, Ac-SDKP protects the heart from more severe remodeling and dysfunction, possibly via its anti-fibrotic and pro-angiogenic actions. Thus, the use of Ac-SDKP or its analogues could be a new and effective alternative in restoring cardiac function in patients after MI.
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Worou, Morel, M. D'Ambrosio, T‐D Liao, P. Nakagawa, E. Peterson, B. Janic, N‐E Rhaleb, and Oscar Carretero. "Renoprotective Effects of N‐acetyl‐seryl‐aspartyl‐lysyl‐proline (Ac‐SDKP) in Dahl Salt‐Sensitive Rats." FASEB Journal 29, S1 (April 2015). http://dx.doi.org/10.1096/fasebj.29.1_supplement.960.11.

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Liao, Tang-Dong, Pablo Nakagawa, Branislava Janic, Martin D’Ambrosio, Morel E. Worou, Xiao-Ping Yang, Nour-Eddine Rhaleb, and Oscar A. Carretero. "Abstract 457: N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) Prevents The Development Of Nephritis And Skin Lesions In Mouse Model Of Systemic Lupus Erythematosus (MRL/lpr)." Hypertension 64, suppl_1 (September 2014). http://dx.doi.org/10.1161/hyp.64.suppl_1.457.

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Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by development of auto antibodies against various self-antigens and deposition of immune complexes leading to inflammation, fibrosis and end organ damage. Ac-SDKP is a naturally occurring tetrapeptide that in hypertension and other diseases such as autoimmune myocarditis prevents inflammation and fibrosis in heart, kidney and vasculature. Here we tested the hypothesis that Ac-SDKP in a mouse model of SLE decreases autoimmune responses, thus preventing inflammation and renal damage. To test this, lupus mice were treated with Ac-SDKP for 20 weeks. Ac-SDKP treated lupus mice exhibited significant decrease in 1) macrophage and T cell infiltration, 2) expression of pro-inflammatory cytokines, 3) complement system activation and 4) expression of cell adhesion protein ICAM-1. In addition, the lupus mice had a significant improvement in renal function (GFR), decrease in glomerular damage and interstitial collagen deposition. Ac-SDKP also reduced the facial skin lesion. Ac-SDKP did not decrease the production of autoantibodies nor blood pressure. Therefore the protective effect of Ac-SDKP is most likely achieved by modulation of the activation of the complement system, expression of chemokines and ICAM-1, leading to a reduction of innate and adaptive immunity cell infiltration in the kidney
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Romero, Cesar A., Sonal Vaid, Nitin Kumar, Tang-Dong Liao, and Oscar A. Carretero. "Abstract P289: Cardio-protective Peptide Ac-SDKP is Highly Concentrated in Lymph Nodes." Hypertension 70, suppl_1 (September 2017). http://dx.doi.org/10.1161/hyp.70.suppl_1.p289.

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N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) is a natural peptide released from its precursor Thymosin β4 (Tβ4) by meprin-α and the prolyl oligopeptidase enzymes (POP) in sequential steps. Ac-SDKP is hydrolyzed by the angiotensin converting enzyme (ACE). Ac-SDKP has anti-inflammatory and anti-fibrotic effects in heart, aorta and kidney and part of the beneficial effects of ACE inhibitors has been ascribed to the increased levels of Ac-SDKP. Ac-SDKP is present in spleen and thymus, however, the presence of Ac-SDKP in the lymph node has not been studied. We hypothesized that Tβ4, Ac-SDKP and its releasing enzymes are present in lymph node. Ac-SDKP concentration was evaluated in Sprague-Dawley (SD) rat tissues. Tβ4 as well as Meprin-α and POP enzymes were measured in the lymph node, thymus, spleen and other tissues obtained from SD rats. Additionally, Ac-SDKP content was measured in different cell populations of lymph node obtained through cell sorting. Lymph node showed the highest Ac-SDKP concentration (181±18.3 ng/mg of protein), followed by the testis (104.3±6.5, thymus (54.2±1.8) and spleen (44.9±4.7) in SD rats (P<0.001 lymph node vs. testis, thymus and spleen). Meprin-α and POP activity were present in lymph node, spleen and thymus. Tβ4 and Meprin-α immunostaining were found to be positive in multinucleated giant cells in the cortical region of lymph node and along the septums; it was also found in the follicular region and germinal center. POP staining was found positive in the cortical region. In the lymph node, Ac-SDKP concentration was higher in Macrophages (CD45+CD68+) in comparison with T lymphocytes (CD45+CD3+) (150±110 pmol/100,000 cell vs. 0.3±0.1pmol/100,000cell, respectively). We conclude that in lymph node, Ac-SDKP is highly concentrated and that all the components of Tβ4/Ac-SDKP system are present. Macrophages could be the main source of Ac-SDKP in lymph node. The presence of Ac-SDKP in lymph node may have important implications in understanding inflammation and target organ damage in cardiovascular diseases.
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39

Zhu, Liping, Xiao-Ping Yang, Pablo Nakagawa, Nour-Eddine Rhaleb, Pamela Harding, Jiang Xu, and Oscar A. Carretero. "Abstract 447: Ac-SDKP Suppresses TNFα-induced ICAM-1 Expression In Endothelial Cells Via Inhibition Of IκB Kinase And NF-κB Activation." Hypertension 64, suppl_1 (September 2014). http://dx.doi.org/10.1161/hyp.64.suppl_1.447.

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N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) is a naturally occurring tetrapeptide that prevents inflammation and fibrosis in hypertension and other cardiovascular diseases. We previously showed that Ac-SDKP decreased transcription factor NF-κB activation in angiotensin II-induced hypertension and also reduced intercellular adhesion molecule-1 (ICAM-1) expression in an experimental autoimmune myocarditis and hypertension animal model. However, the mechanisms by which Ac-SDKP down-regulated ICAM-1 expression are unclear. TNFα is a proinflammatory cytokine that induces ICAM-1 expression on different cell types. We hypothesized that Ac-SDKP suppresses TNFα-induced ICAM-1 via inhibition of IκB kinase (IKK) and subsequently by blockade of NF-κB activation. Human coronary artery endothelial cells were treated with Ac-SDKP or vehicle and then stimulated with TNFα (0.5 ng/ml). ICAM-1 protein expression and phosphorylation of IKK (p-IKK), inhibitory κB (p-IκB), p38 (p-p38) and ERK (p-ERK) were measured by Western Blot. Activation of NF-κB was determined by electrophoretic mobility shift assay (EMSA). ICAM-1 expression was virtually undetectable under basal conditions, but greatly increased by TNFα. Ac-SDKP dose-dependently suppressed TNFα-induced ICAM-1 expression (set at a value of 1.0 arbitrary units, AU) to 0.67±0.13 (p<0.05), 0.51±0.12 (p<0.01) and 0.39±0.09 AU (p<0.01) at 0.1 nM, 1 nM and 10 nM, respectively. In addition, Ac-SDKP (10 nM) inhibited TNFα-induced p-IKK from 1.0 to 0.71±0.02 AU (p<0.01). Ac-SDKP also inhibited TNFα-induced IKKβ expression from 1.0 to 0.64±0.12 AU (p<0.05), without affecting IKKα expression. Furthermore, Ac-SDKP inhibited TNFα-induced p-IκB from 1.0 to 0.54±0.03 AU (p<0.01). EMSA results showed that Ac-SDKP inhibited TNFα-mediated activation of NF-κB, which was 0.63±0.04-fold of TNFα-treated cells. However, Ac-SDKP had no effect on TNFα-induced p-p38 and p-ERK. Thus, we conclude that Ac-SDKP inhibits TNFα-induced IKK and subsequent degradation of IκB, thereby preventing NF-κB activation and ICAM-1 expression. These inhibitory effects are independent of p38 and ERK.
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40

Palaniyappan, Arivazhagan, Halliday Idikio, and Bodh I. Jugdutt. "Abstract 5422: Effect of Age on Expression of AT 1 and AT 2 Receptors and ACE-2, Angiotensin (1–7), Ac-SDKP and Smad-2 Proteins After Acute Reperfused ST-Segment Elevation Myocardial Infarction." Circulation 118, suppl_18 (October 28, 2008). http://dx.doi.org/10.1161/circ.118.suppl_18.s_547-c.

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Recent evidence suggests that aging alters the expression of inflammatory cytokines, impairs healing and promotes adverse left ventricular (LV) remodeling after chronic reperfused ST-segment elevation myocardial infarction (RSTEMI). Whether aging alters the expression of angiotensin II type 1 (AT 1 ) and type 2 (AT 2 ) receptors, and angiotensin-converting-enzyme-2 (ACE-2), angiotensin (Ang) (1–7), N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) and Smad-2 proteins early after acute RSTEMI is not known. AT 2 receptors have been implicated in cardioprotection, ACE-2 and Ang (1–7) in the counter-regulatory arm of the renin-angiotensin-system (RAS) and Ac-SDKP in inflammation and collagen synthesis. We hypothesized that aging is associated with downregulation of AT 2 receptors and ACE-2, Ang (1–7), Ac-SDKP and Smad-2 proteins. We compared in-vivo LV remodeling and function (echocardiography/Doppler) and the ex-vivo molecular expression of AT 1 and AT 2 receptors, ACE-2, Ang (1–7) and Ac-SDKP after acute RSTEMI (90 min no-flow ischemia and 120 min reperfusion) in young (group 1, n=12) and old (group 2, n=12) dogs. Compared to group 1 controls, group 2 hearts showed more severe echocardiographic LV remodeling and dysfunction (with lower ejection fraction, larger volumes and more diastolic dysfunction, infarct expansion and thinning). In addition, group 2 hearts showed no change in AT 1 receptor protein and decrease in AT 2 receptor protein and ACE-2, Ang (1–7), Ac-SDKP and Smad-2 proteins in the reperfused ischemic zone. The findings suggest that aging is associated with changes in proteins in the regulatory as well as the counter-regulatory arm of the RAS during acute RSTEMI. The age-related downregulation of AT 2 receptors, ACE-2, Ang (1–7), Ac-SDKP and Smad-2 may contribute to the more severe LV remodeling and dysfunction after acute RSTEMI. Targeting these proteins early during reperfusion may improve outcome in acute RSTEMI.
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41

LIAO, TANG‐DONG, PABLO NAKAGAWA, MARTIN D'AMBROSIO, NOUR‐EDDINE RHALEB, XIAO‐PING YANG, and OSCAR CARRETERO. "N‐Acetyl‐Seryl‐Aspartyl‐Lysyl‐Proline (Ac‐SDKP) Prevents the Progression of Renal Dysfunction in Mice with Lupus (MRL/lpr)." FASEB Journal 27, S1 (April 2013). http://dx.doi.org/10.1096/fasebj.27.1_supplement.1110.7.

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42

Nakagawa, Pablo, T‐D Liao, M. Worou, H. Basha, E. Peterson, B. Janic, X‐P Yang, N‐E Rhaleb, and Oscar Carretero. "N‐Acetyl‐Seryl‐Aspartyl‐Lysyl‐Proline (Ac‐SDKP) Delays the Development of Hypertension and Renal Damage in Systemic Lupus Erythematosus (SLE)." FASEB Journal 29, S1 (April 2015). http://dx.doi.org/10.1096/fasebj.29.1_supplement.667.7.

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43

Xiaojun, Wang, Liu Yan, Xu Hong, Zhang Xianghong, Li Shifeng, Xu Dingjie, Gao Xuemin, et al. "Acetylated α-Tubulin Regulated by N-Acetyl-Seryl-Aspartyl-Lysyl-Proline(Ac-SDKP) Exerts the Anti-fibrotic Effect in Rat Lung Fibrosis Induced by Silica." Scientific Reports 6, no. 1 (August 31, 2016). http://dx.doi.org/10.1038/srep32257.

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44

Nakagawa, Pablo, Nour-Eddine Rhaleb, Xiaojuan Chen, Tang Dong Liao, Derek M. Smolarek, Xiao-Ping Yang, Yun-He Liu, and Oscar A. Carretero. "Effect of N‐Acetyl‐Seryl‐Aspartyl‐Lysyl‐Proline (Ac‐SDKP) on intercellular adhesion molecule 1 (ICAM‐1) and proinflammatory cytokines and chemokines in experimental autoimmune myocarditis (EAM)." FASEB Journal 26, S1 (April 2012). http://dx.doi.org/10.1096/fasebj.26.1_supplement.680.20.

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