Journal articles: 'Adenosine mediated cardioprotection'

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McIntosh, Victoria J., and Robert D. Lasley. "Adenosine Receptor-Mediated Cardioprotection." Journal of Cardiovascular Pharmacology and Therapeutics 17, no. 1 (February 18, 2011): 21–33. http://dx.doi.org/10.1177/1074248410396877.

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Zhan, Enbo, Victoria J. McIntosh, and Robert D. Lasley. "Adenosine A2A and A2B receptors are both required for adenosine A1 receptor-mediated cardioprotection." American Journal of Physiology-Heart and Circulatory Physiology 301, no. 3 (September 2011): H1183—H1189. http://dx.doi.org/10.1152/ajpheart.00264.2011.

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All four adenosine receptor subtypes have been shown to play a role in cardioprotection, and there is evidence that all four subtypes may be expressed in cardiomyocytes. There is also increasing evidence that optimal adenosine cardioprotection requires the activation of more than one receptor subtype. The purpose of this study was to determine whether adenosine A2A and/or A2B receptors modulate adenosine A1 receptor-mediated cardioprotection. Isolated perfused hearts of wild-type (WT), A2A knockout (KO), and A2BKO mice, perfused at constant pressure and constant heart rate, underwent 30 min of global ischemia and 60 min of reperfusion. The adenosine A1 receptor agonist N6-cyclohexyladenosine (CHA; 200 nM) was administrated 10 min before ischemia and for the first 10 min of reperfusion. Treatment with CHA significantly improved postischemic left ventricular developed pressure (74 ± 4% vs. 44 ± 4% of preischemic left ventricular developed pressure at 60 min of reperfusion) and reduced infarct size (30 ± 2% with CHA vs. 52 ± 5% in control) in WT hearts, effects that were blocked by the A1 antagonist 8-cyclopentyl-1,3-dipropylxanthine (100 nM). Treatments with the A2A receptor agonist CGS-21680 (200 nM) and the A2B agonist BAY 60-6583 (200 nM) did not exert any beneficial effects. Deletion of adenosine A2A or A2B receptor subtypes did not alter ischemia-reperfusion injury, but CHA failed to exert a cardioprotective effect in hearts of mice from either KO group. These findings indicate that both adenosine A2A and A2B receptors are required for adenosine A1 receptor-mediated cardioprotection, implicating a role for interactions among receptor subtypes.

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LIANG, Bruce T. "Protein kinase C-dependent activation of KATP channel enhances adenosine-induced cardioprotection." Biochemical Journal 336, no. 2 (December 1, 1998): 337–43. http://dx.doi.org/10.1042/bj3360337.

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Prior activation of protein kinase C (PKC) can precondition the cardiac cell against injury during subsequent ischaemia. By using cultured chick ventricular cell model for simulated ischaemia and preconditioning, the present study investigated the biochemical mechanism underlying the PKC-mediated preconditioning. A 5 min exposure to PMA enhanced the ability of pinacidil to mediate cardioprotection during a subsequent 90 min period of ischaemia, which is consistent with a sustained activation of the KATP channel initiated by PKC. The brief prior exposure to PMA was also associated with an enhanced ability of the adenosine A1 or A3 receptor agonist 2-chloro-N6-cyclopentyladenosine or N6-(3-iodobenzyl)adenosine-5´-N-methyluronamide to elicit a cardioprotective response during the subsequent ischaemia. In myocytes pretreated with PMA, the cardioprotection mediated by receptor agonist was blocked by the concomitant presence of KATP-channel antagonists glibenclamide or 5-hydroxydecanoic acid during the ischaemia. Thus the KATP channel acts downstream of the adenosine A1 and A3 receptors in mediating the protective effect due to prior PMA exposure. KATP channel activation is responsible for the adenosine receptor-mediated effect. PMA treatment had no effect on other A1 or A3 receptor-mediated effects such as the inhibition of adenylate cyclase, ruling out a direct stimulation of the receptor or G-protein by PMA. The present results indicate that prior stimulation of PKC causes a sustained KATP channel activation, which in turn renders the myocyte more responsive to the protective action of adenosine A1 and A3 receptor agonists during the subsequent ischaemia.

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WILLEMS, L., K. ASHTON, and J. HEADRICK. "Adenosine-mediated cardioprotection in the aging myocardium." Cardiovascular Research 66, no. 2 (May 1, 2005): 245–55. http://dx.doi.org/10.1016/j.cardiores.2004.11.008.

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Peart, Jason, Amanda Flood, Joel Linden, G. Paul Matherne, and John P. Headrick. "Adenosine-Mediated Cardioprotection in Ischemic-Reperfused Mouse Heart." Journal of Cardiovascular Pharmacology 39, no. 1 (January 2002): 117–29. http://dx.doi.org/10.1097/00005344-200201000-00013.

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Kurz, Michael A., David A. Bullough, Christopher J. L. Buggé, Kevin M. Mullane, and Mark A. Young. "Cardioprotection with a novel adenosine regulating agent mediated by intravascular adenosine." European Journal of Pharmacology 322, no. 2-3 (March 1997): 211–20. http://dx.doi.org/10.1016/s0014-2999(97)00011-3.

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Peart, Jason, and John Headrick. "Mechanisms of adenosine-mediated cardioprotection in the murine heart." Journal of Molecular and Cellular Cardiology 33, no. 6 (June 2001): A91. http://dx.doi.org/10.1016/s0022-2828(01)90363-3.

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Peart, Jason, Laura Willems, and John P. Headrick. "Receptor and non-receptor-dependent mechanisms of cardioprotection with adenosine." American Journal of Physiology-Heart and Circulatory Physiology 284, no. 2 (February 1, 2003): H519—H527. http://dx.doi.org/10.1152/ajpheart.00717.2002.

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The relative roles of mitochondrial (mito) ATP-sensitive K+ (mitoKATP) channels, protein kinase C (PKC), and adenosine kinase (AK) in adenosine-mediated protection were assessed in Langendorff-perfused mouse hearts subjected to 20-min ischemia and 45-min reperfusion. Control hearts recovered 72 ± 3 mmHg of ventricular pressure (50% preischemia) and released 23 ± 2 IU/g lactate dehydrogenase (LDH). Adenosine (50 μM) during ischemia-reperfusion improved recovery (149 ± 8 mmHg) and reduced LDH efflux (5 ± 1 IU/g). Treatment during ischemia alone was less effective. Treatment with 50 μM diazoxide (mitoKATP opener) during ischemia and reperfusion enhanced recovery and was equally effective during ischemia alone. A3 agonism [100 nM 2-chloro- N 6-(3-iodobenzyl)-adenosine-5′- N-methyluronamide], A1 agonism ( N 6-cyclohexyladenosine), and AK inhibition (10 μM iodotubercidin) all reduced necrosis to the same extent as adenosine, but less effectively reduced contractile dysfunction. These responses were abolished by 100 μM 5-hydroxydecanoate (5-HD, mitoKATP channel blocker) or 3 μM chelerythrine (PKC inhibitor). However, the protective effects of adenosine during ischemia-reperfusion were resistant to 5-HD and chelerythrine and only abolished when inhibitors were coinfused with iodotubercidin. Data indicate adenosine-mediated protection via A1/A3 adenosine receptors is mitoKATP channel and PKC dependent, with evidence for a downstream location of PKC. Adenosine provides additional and substantial protection via phosphorylation to 5′-AMP, primarily during reperfusion.

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Caricati-Neto, Afonso, Paolo Ruggero Errante, and Francisco Sandro Menezes-Rodrigues. "Recent Advances in Pharmacological and Non-Pharmacological Strategies of Cardioprotection." International Journal of Molecular Sciences 20, no. 16 (August 16, 2019): 4002. http://dx.doi.org/10.3390/ijms20164002.

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Ischemic heart diseases (IHD) are the leading cause of death worldwide. Although the principal form of treatment of IHD is myocardial reperfusion, the recovery of coronary blood flow after ischemia can cause severe and fatal cardiac dysfunctions, mainly due to the abrupt entry of oxygen and ionic deregulation in cardiac cells. The ability of these cells to protect themselves against injury including ischemia and reperfusion (I/R), has been termed “cardioprotection”. This protective response can be stimulated by pharmacological agents (adenosine, catecholamines and others) and non-pharmacological procedures (conditioning, hypoxia and others). Several intracellular signaling pathways mediated by chemical messengers (enzymes, protein kinases, transcription factors and others) and cytoplasmic organelles (mitochondria, sarcoplasmic reticulum, nucleus and sarcolemma) are involved in cardioprotective responses. Therefore, advancement in understanding the cellular and molecular mechanisms involved in the cardioprotective response can lead to the development of new pharmacological and non-pharmacological strategies for cardioprotection, thus contributing to increasing the efficacy of IHD treatment. In this work, we analyze the recent advances in pharmacological and non-pharmacological strategies of cardioprotection.

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Wakeno-Takahashi, Mayu, Hajime Otani, Shinichi Nakao, Yuka Uchiyama, Hiroji Imamura, and Koh Shingu. "Adenosine and a Nitric Oxide Donor Enhances Cardioprotection by Preconditioning with Isoflurane through Mitochondrial Adenosine Triphosphate-sensitive K+Channel-dependent and -independent Mechanisms." Anesthesiology 100, no. 3 (March 1, 2004): 515–24. http://dx.doi.org/10.1097/00000542-200403000-00009.

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Background Preconditioning with isoflurane has been shown to confer cardioprotection via activation of mitochondrial adenosine triphosphate-sensitive K+ (mito K(ATP)) channels. However, the relative contribution of mito K(ATP) channel and non-mito K(ATP) channel mechanisms to isoflurane-mediated cardioprotection has not been investigated. Methods Isolated and buffer-perfused rat hearts were used. Flavoprotein fluorescence was monitored as an index for mito K(ATP) channel activity. Isovolumic left ventricular function and infarct size were measured as indices for cardioprotection. Results Flavoprotein fluorescence, which was monitored as an index for mito K(ATP) channel activity, was increased by isoflurane and a known mito K(ATP) channel opener, diazoxide, in a 5-hydroxydecanoate-sensitive manner. Although flavoprotein oxidation induced by diazoxide was dissipated soon after its removal from the buffer, flavoprotein oxidation induced by isoflurane was sustained after cessation of the treatment. The sustained increase in flavoprotein oxidation was associated with a significant reduction in infarct size after 30 min of ischemia followed by 120 min of reperfusion. Although adenosine and S-nitroso-N-acetyl-penicillamine each alone did not increase flavoprotein fluorescence, nor did they confer significant cardioprotection, coadministration of adenosine and S-nitroso-N-acetyl-penicillamine with isoflurane conferred a highly significant reduction of infarct size and improvement of left ventricular function without increasing flavoprotein oxidation over isoflurane alone. The early treatment with 5-hydroxydecanoate before and during preconditioning completely reversed flavoprotein oxidation and inhibited the infarct-sparing effect of isoflurane and combined preconditioning with isoflurane, adenosine, and S-nitroso-N-acetyl-penicillamine. The late treatment with 5-hydroxydecanoate after preconditioning abolished flavoprotein oxidation and the infarct-sparing effect of isoflurane but only partially inhibited cardioprotection conferred by the combined preconditioning, despite complete abrogation of flavoprotein oxidation. Conclusions Mito K(ATP) channel activation is the essential trigger of both preconditioning with isoflurane and combined preconditioning with isoflurane, adenosine, and S-nitroso-N-acetyl-penicillamine. Mito K(ATP) channel activation is also a crucial mediator of cardioprotection afforded by preconditioning with isoflurane. However, enhanced cardioprotection conferred by combined preconditioning is mediated through both mito K(ATP) channel-dependent and -independent mechanisms.

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Tracey, W. Ross, William P. Magee, Joseph J. Oleynek, Roger J. Hill, Andrew H. Smith, David M. Flynn, and Delvin R. Knight. "NovelN6-substituted adenosine 5′-N-methyluronamides with high selectivity for human adenosine A3receptors reduce ischemic myocardial injury." American Journal of Physiology-Heart and Circulatory Physiology 285, no. 6 (December 2003): H2780—H2787. http://dx.doi.org/10.1152/ajpheart.00411.2003.

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We recently reported the identification of a novel human adenosine A3receptor-selective agonist, (2 S,3 S,4 R,5 R)-3-amino-5-{6-[5-chloro-2-(3-methylisoxazol-5-ylmethoxy)benzylamino]purin-9-yl}-4-hydroxytetrahydrofuran-2-carboxylic acid methylamide (CP-608,039), with 1,260-fold selectivity for the human A3versus human A1receptor (DeNinno et al., J Med Chem 46: 353–355, 2003). However, because the modest (20-fold) rabbit A3receptor selectivity of CP-608,039 precludes demonstration of A3-mediated cardioprotection in rabbit models, we identified another member of this class, (2 S,3 S,4 R,5 R)-3-amino-5-[6-(2,5-dichlorobenzylamino)purin-9-yl]-4-hydroxytetrahydrofuran-2-carboxylic acid methylamide (CP-532,903), which both retained human A3receptor selectivity (210-fold; human A3/human A1Ki: 23/4,800 nM) and had improved rabbit A3receptor selectivity (90-fold; rabbit A3/rabbit A1Ki: 23/2,000 nM). Infarct size was measured in Langendorff hearts or in vivo after 30 min of regional ischemia and 120 min of reperfusion. Five-minute perfusion with CP-532,903 before ischemia-reperfusion elicited a concentration-dependent reduction in infarct size in isolated hearts (EC50: 0.97 nM; maximum reduction in infarct size: 77%, P < 0.05 vs. control). Furthermore, administration of CP-532,903 (150 nM) at reperfusion also significantly reduced infarct size by 64% ( P < 0.05 vs. control), which was not different ( P ≥ 0.05) from the cardioprotection provided by the same concentration of drug given before ischemia. The selective rabbit A1receptor antagonist BWA1433 did not affect CP-532,903-dependent cardioprotection. In vivo, CP-532,903 (1 mg/kg) reduced infarct size by 50% in the absence of significant hemodynamic effects (mean arterial pressure, heart rate, rate-pressure product). CP-532,903 and CP-608,039 represent a novel class of human A3receptor-selective agonists that may prove suitable for investigation of the clinical cardioprotective efficacy of A3receptor activation.

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Emanuelov, Avishag K., Asher Shainberg, Yelena Chepurko, Doron Kaplan, Alex Sagie, Eyal Porat, Michael Arad, and Edith Hochhauser. "Adenosine A3 receptor-mediated cardioprotection against doxorubicin-induced mitochondrial damage." Biochemical Pharmacology 79, no. 2 (January 2010): 180–87. http://dx.doi.org/10.1016/j.bcp.2009.08.010.

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Miyamae, Masami, S. Albert Camacho, Hui-Zhong Zhou, Ivan Diamond, and Vincent M. Figueredo. "Alcohol consumption reduces ischemia-reperfusion injury by species-specific signaling in guinea pigs and rats." American Journal of Physiology-Heart and Circulatory Physiology 275, no. 1 (July 1, 1998): H50—H56. http://dx.doi.org/10.1152/ajpheart.1998.275.1.h50.

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We recently discovered that regular alcohol consumption reduces ischemia-reperfusion injury to the same degree as ischemic preconditioning in guinea pig hearts. Ischemic preconditioning, like this cardioprotective effect of alcohol, is mediated by adenosine signaling in guinea pigs. In rats, ischemic preconditioning may be mediated predominantly by α1-adrenergic signaling. To be certain that this protective effect of alcohol is a general biological response, we searched for alcohol’s cardioprotection in rat and identified a potential signaling mechanism. Hearts isolated from alcohol-fed guinea pigs and rats were subjected to ischemia-reperfusion. Hearts from alcohol-fed animals showed greater recovery of left ventricular developed pressure than controls (guinea pigs, 46 vs. 29%; rats, 50 vs. 31%) and decreased myocyte necrosis assessed by creatine kinase release (guinea pigs, 204 ± 42 vs. 440 ± 70 U ⋅ ml−1 ⋅ g dry wt−1; rats 158 ± 13 vs. 328 ± 31 U ⋅ ml−1 ⋅ g dry wt−1). Adenosine receptor blockade [8-( p-sulfophenyl)theophylline] abolished alcohol’s protection in guinea pig but not rat hearts. By contrast, α1-adrenergic blockade (prazosin) abolished alcohol’s protection in rat but not guinea pig hearts. We conclude that regular alcohol consumption reduces ischemia-reperfusion injury and is mediated by species-specific signaling mechanisms. A major goal of cardiovascular research is to find a pharmacologically induced chronic state of preconditioning. Understanding the mechanisms of alcohol’s cardioprotection against ischemia-reperfusion injury may aid in reaching this goal.

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Kersten, Judy R., Karl G. Orth, Paul S. Pagel, David A. Mei, Garrett J. Gross, and David C. Warltier. "Role of Adenosine in Isoflurane-induced Cardioprotection." Anesthesiology 86, no. 5 (May 1, 1997): 1128–39. http://dx.doi.org/10.1097/00000542-199705000-00017.

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Background This investigation tested the hypothesis that adenosine (A1) receptor blockade modulates the cardioprotective effects of isoflurane. Methods Hemodynamics and percentage segment shortening (%SS) in the left anterior descending coronary artery (LAD) perfusion territory were evaluated in barbiturate-anesthetized dogs (n = 31) at selected intervals after pretreatment with the selective A1 receptor antagonist (8-cyclopentyl-1,3,dipropyl-xanthine; DPCPX 0.8 mg/kg, intravenously) or drug vehicle in the presence or absence of 1 minimum alveolar concentration (MAC) isoflurane. Dogs were subjected to five 5-min occlusions and reperfusions of the LAD, followed by 180 min of final reperfusion. Isoflurane was administered for 30 min before and during LAD occlusions and reperfusions and was discontinued at the onset of final reperfusion. Two other groups of dogs (n = 17) were used to measure interstitial concentrations of purines in the LAD region using a microdialysis technique in the presence and absence of isoflurane. Results Dogs receiving drug vehicle or DPCPX exhibited no recovery of %SS after 180 min of reperfusion (-5 +/- 7 and 5 +/- 11% of baseline, respectively, +/- SEM). In contrast, dogs receiving isoflurane alone demonstrated complete recovery of %SS at 60 min after reperfusion. DPCPX pretreatment partially attenuated isoflurane-induced enhancement of recovery of %SS (34 +/- 11% of baseline 180 min after reperfusion; P < 0.05). Interstitial purine concentrations were increased during multiple occlusions and reperfusions of the LAD in dogs not receiving isoflurane, but they were unchanged by coronary artery occlusion and reperfusion in dogs receiving isoflurane. Conclusions The results indicate that isoflurane-induced cardioprotection in stunned myocardium is partially mediated by adenosine type 1 receptor activation and is accompanied by decreases in endogenous adenosine release.

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Kristo, G., Y. Yoshimura, B. J. Keith, R. M. Mentzer, and R. D. Lasley. "Aged Rat Myocardium Exhibits Normal Adenosine Receptor-Mediated Bradycardia and Coronary Vasodilation But Increased Adenosine Agonist-Mediated Cardioprotection." Journals of Gerontology Series A: Biological Sciences and Medical Sciences 60, no. 11 (November 1, 2005): 1399–404. http://dx.doi.org/10.1093/gerona/60.11.1399.

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Thai, B., L. Chia, A. Nguyen, D. Hutchinson, A. Kompa, P. White, and L. May. "Adenosine Receptor-Mediated Cardioprotection Post-Myocardial Infarction Associated With Advanced Age." Heart, Lung and Circulation 31 (2022): S68. http://dx.doi.org/10.1016/j.hlc.2022.06.057.

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Hussain, A., P. Karjian, and H. Maddock. "The role of nitric oxide in A3 adenosine receptor-mediated cardioprotection." Autonomic and Autacoid Pharmacology 29, no. 3 (July 2009): 97–104. http://dx.doi.org/10.1111/j.1474-8673.2009.00438.x.

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Yao, Z., and G. J. Gross. "Glibenclamide antagonizes adenosine A1 receptor-mediated cardioprotection in stunned canine myocardium." Circulation 88, no. 1 (July 1993): 235–44. http://dx.doi.org/10.1161/01.cir.88.1.235.

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Torregroza, Carolin, Chiara O. Glashoerster, Katharina Feige, Martin Stroethoff, Annika Raupach, André Heinen, Markus W. Hollmann, and Ragnar Huhn. "Mediation of the Cardioprotective Effects of Mannitol Discovered, with Refutation of Common Protein Kinases." International Journal of Molecular Sciences 22, no. 22 (November 19, 2021): 12471. http://dx.doi.org/10.3390/ijms222212471.

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The osmodiuretic agent Mannitol exerts cardioprotection against ischemia and reperfusion (I/R) injury when applied as a pre- and/or postconditioning stimulus. Previously, we demonstrated that these properties are mediated via the activation of mitochondrial ATP-sensitive potassium (mKATP) channels. However, considering Mannitol remains in the extracellular compartment, the question arises as to which receptor and intracellular signaling cascades are involved in myocardial protection by the osmodiuretic substance. Protein kinase B (Akt) and G (PKG), as part of the reperfusion injury salvage kinase (RISK) and/or endothelial nitric oxide (eNOS)/PKG pathway, are two well-investigated intracellular targets conferring myocardial protection upstream of mitochondrial potassium channels. Adenosine receptor subtypes have been shown to trigger different cardioprotective pathways, for example, the reperfusion injury. Further, Mannitol induces an increased activation of the adenosine 1 receptor (A1R) in renal cells conferring its nephroprotective properties. Therefore, we investigated whether (1) Akt and PKG are possible signaling targets involved in Mannitol-induced conditioning upstream of the mKATP channel and/or whether (2) cardioprotection by Mannitol is mediated via activation of the A1R. All experiments were performed on male Wistar rats in vitro employing the Langendorff isolated heart perfusion technique with infarct size determination as the primary endpoint. To unravel possible protein kinase activation, Mannitol was applied in combination with the Akt (MK2206) or PKG (KT5823) inhibitor. In further groups, an A1R blocker (DPCPX) was given with or without Mannitol. Preconditioning with Mannitol (Man) significantly reduced the infarct size compared to the control group. Co-administration of the A1R blocker DPXPC fully abolished myocardial protection of Mannitol. Interestingly and in contrast to the initial hypothesis, neither administration of the Akt nor the PKG blocker had any impact on the cardioprotective properties of Mannitol-induced preconditioning. These results are quite unexpected and show that the protein kinases Akt and PKG—as possible targets of known protective signaling cascades—are not involved in Mannitol-induced preconditioning. However, the cardioprotective effects of Mannitol are mediated via the A1R.

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Vecchio, E., A. TN Nguyen, C. Tan, P. White, and L. May. "A tale of two receptors - Investigating how adenosine A2 receptors modulate adenosine A1 receptor-mediated cardioprotection." Heart, Lung and Circulation 24 (2015): S134. http://dx.doi.org/10.1016/j.hlc.2015.06.050.

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Peart, Jason N., Garrett J. Gross, and John P. Headrick. "15 Ageing impairs ischemic tolerance and adenosine-mediated cardioprotection in murine myocardium." Journal of Molecular and Cellular Cardiology 34, no. 7 (July 2002): A36. http://dx.doi.org/10.1016/s0022-2828(02)90199-9.

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Ashton, Kevin, Kirsty Holmgren, Jason Peart, Sean Grimmon, Paul Matherne, and John Headrick. "16 Gene expression profiles involved in ischemic tolerance and adenosine-mediated cardioprotection." Journal of Molecular and Cellular Cardiology 34, no. 7 (July 2002): A36. http://dx.doi.org/10.1016/s0022-2828(02)90200-2.

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Peart, Jason N., and Garrett J. Gross. "Adenosine and opioid receptor-mediated cardioprotection in the rat: evidence for cross-talk between receptors." American Journal of Physiology-Heart and Circulatory Physiology 285, no. 1 (July 2003): H81—H89. http://dx.doi.org/10.1152/ajpheart.00985.2002.

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The relative roles of free-radical production, mitochondrial ATP-sensitive K+ (mitoKATP) channels and possible receptor cross-talk in both opioid and adenosine A1 receptor (A1AR) mediated protection were assessed in a rat model of myocardial infarction. Sprague-Dawley rats were subjected to 30 min of occlusion and 90 min of reperfusion. The untreated rats exhibited an infarct of 58.8 ± 2.9% [infarct size (IS)/area at risk (AAR), %] at the end of reperfusion. Pretreatment with either the nonselective opioid receptor agonist morphine or the selective A1AR agonist 2-chloro-cyclopentyladenosine (CCPA) dramatically reduced IS/AAR to 41.1 ± 2.2% and 37.9 ± 5.5%, respectively ( P < 0.05). Protection afforded by either morphine or CCPA was abolished by the reactive oxygen species scavenger N-(2-mercaptopropionyl)glycine or the mitoKATP channel blocker 5-hydroxydecanoate. Both morphine- and CCPA-mediated protection were attenuated by the selective A1AR antagonist 1,3-dipropyl-8-cyclopentylxanthine and the selective δ1-opioid receptor (DOR) antagonist 7-benzylidenealtrexone. Simultaneous administration of morphine and CCPA failed to enhance the infarct-sparing effect of either agonist alone. These data suggest that both DOR and A1AR-mediated cardioprotection are mitoKATP and reactive oxygen species dependent. Furthermore, these data suggest that there are converging pathways and/or receptor cross-talk between A1AR- and DOR-mediated cardioprotection.

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Hack, Ben D., and John P. Headrick. "Adenosine-mediated cardioprotection is carbon substrate-dependent in the isolated perfused murine heart." Journal of Molecular and Cellular Cardiology 33, no. 6 (June 2001): A43. http://dx.doi.org/10.1016/s0022-2828(01)90169-5.

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Zhou, Bin, Shaoqing Lei, Rui Xue, Yan Leng, Zhengyuan Xia, and Zhong-Yuan Xia. "DJ-1 overexpression restores ischaemic post-conditioning-mediated cardioprotection in diabetic rats: role of autophagy." Clinical Science 131, no. 11 (May 22, 2017): 1161–78. http://dx.doi.org/10.1042/cs20170052.

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IPO (ischaemic post-conditioning) is a promising method of alleviating myocardial IR (ischaemia-reperfusion) injury; however, IPO-mediated cardioprotection is lost in diabetic hearts via mechanisms that remain largely unclear. We hypothesized that decreased cardiac expression of DJ-1, a positive modulator of autophagy, compromises the effectiveness of IPO-induced cardioprotection in diabetic rats. Diabetic rats subjected to myocardial IR (30 min of coronary artery occlusion followed by 120 min of reperfusion) exhibited more severe myocardial injury, less cardiac autophagy, lower DJ-1 expression and AMPK (adenosine monophosphate-activated protein kinase)/mTOR (mammalian target of rapamycin) pathway activity than non-diabetic rats. IPO significantly attenuated myocardial injury and up-regulated cardiac DJ-1 expression, AMPK/mTOR activity and autophagy in non-diabetic rats but not in diabetic rats. AAV9 (adeno-associated virus 9)-mediated cardiac DJ-1 overexpression as well as pretreatment with the autophagy inducer rapamycin restored IPO-induced cardioprotection in diabetic rats, an effect accompanied by AMPK/mTOR activation and autophagy up-regulation. Combining HPO (hypoxic post-conditioning) with DJ-1 overexpression markedly attenuated HR (hypoxia-reoxygenation) injury in H9c2 cells with high glucose (HG, 30 mM) exposure, accompanied by AMPK/mTOR signalling activation and autophagy up-regulation. The DJ-1 overexpression-mediated preservation of HPO-induced cardioprotection was completely inhibited by the AMPK inhibitor compound C (CC) and the autophagy inhibitor 3-MA (3-methyladenine). Thus, decreased cardiac DJ-1 expression, which results in impaired AMPK/mTOR signalling and decreased autophagy, could be a major mechanism underlying the loss of IPO-induced cardioprotection in diabetes.

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Lankford, Amy R., Anne M. Byford, Kevin J. Ashton, Brent A. French, Jae K. Lee, John P. Headrick, and G. Paul Matherne. "Gene expression profile of mouse myocardium with transgenic overexpression of A1adenosine receptors." Physiological Genomics 11, no. 2 (October 29, 2002): 81–89. http://dx.doi.org/10.1152/physiolgenomics.00008.2002.

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Transgenic mice with cardiac-specific overexpression of adenosine A1receptors (A1AR) have demonstrated metabolic and functional tolerance to myocardial ischemia. We utilized cDNA microarrays to test the hypothesis that the cardioprotective mechanism(s) of A1overexpression involves altered gene expression. Total RNA extracted from the left ventricles from A1transgenic ( n = 4) and wild-type ( n = 6) mice was hybridized to Affymetrix mgU74A chips. Comparison of RNA expression levels in transgenic to wild-type myocardium revealed ∼636 known genes with expression significantly altered by greater than 25%. We observed increased expressions of genes including NADH dehydrogenase, the GLUT4 glucose transporter, Na-K-ATPase, sarcolemmal KATPchannels, and Bcl-xl in A1AR-overexpressing hearts. We also observed decreased expression of pro-apoptotic genes including a 50% reduction in message level of caspase-8. Protein expression of GLUT4 and caspase-8 was also altered comparable to the differences in gene expression. These data illustrate genes with chronically altered patterns of expression in A1transgenic mouse myocardium that may be related to adenosine receptor overexpression-mediated cardioprotection.

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Zhao, Ting C., Denise S. Hines, and Rakesh C. Kukreja. "Adenosine-induced late preconditioning in mouse hearts: role of p38 MAP kinase and mitochondrial KATP channels." American Journal of Physiology-Heart and Circulatory Physiology 280, no. 3 (March 1, 2001): H1278—H1285. http://dx.doi.org/10.1152/ajpheart.2001.280.3.h1278.

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We investigated the role of p38 mitogen-activated protein kinase (MAPK) phosphorylation and opening of the mitochondrial ATP-sensitive K+[(KATP)mito] channel in the adenosine A1 receptor (A1AR)-induced delayed cardioprotective effect in the mouse heart. Adult male mice were treated with vehicle (5% DMSO) or the A1AR agonist 2-chloro- N 6-cyclopentyladenosine (CCPA; 0.1 mg/kg ip). Twenty-four hours later, hearts were subjected to 30 min of global ischemia and 30 min of reperfusion in the Langendorff mode. Genistein or SB-203580 (1 mg/kg ip) given 30 min before CCPA treatment was used to block receptor tyrosine kinase or p38 MAPK phosphorylation, respectively. 5-Hydroxydecanoate (5-HD; 200 μM) was used to block (KATP)mito channels. CCPA produced marked improvement in left ventricular function, which was partially blocked by SB-203580 and 5-HD and completely abolished with genistein. CCPA caused a reduction in infarct size (12.0 ± 2.0 vs. 30.3 ± 3.0% in vehicle), which was blocked by genistein (29.4 ± 2.3%), SB-203580 (28.3 ± 2.6%), and 5-HD (33.9 ± 2.4%). CCPA treatment also caused increased phosphorylation of p38 MAPK during ischemia, which was blocked by genistein, SB-203580, and 5-HD. The results suggest that A1AR-triggered delayed cardioprotection is mediated by p38 MAPK phosphorylation. Blockade of cardioprotection with 5-HD concomitant with decrease in p38 MAPK phosphorylation suggests a potential role of (KATP)mito channel opening in phosphorylation and ensuing the late preconditioning effect of A1AR.

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Okada, Takayuki, Hajime Otani, Yue Wu, Takamichi Uchiyama, Shiori Kyoi, Reiji Hattori, Tomohiko Sumida, Hiroyoshi Fujiwara, and Hiroji Imamura. "Integrated pharmacological preconditioning and memory of cardioprotection: role of protein kinase C and phosphatidylinositol 3-kinase." American Journal of Physiology-Heart and Circulatory Physiology 289, no. 2 (August 2005): H761—H767. http://dx.doi.org/10.1152/ajpheart.00012.2005.

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Although protein kinase C (PKC) and phosphatidylinositol 3 (PI3)-kinase are implicated in cardioprotective signal transduction mediated by ischemic preconditioning, their role in pharmacological preconditioning (PPC) has not been determined. Cultured neonatal rat cardiomyocytes (CMCs) were subjected to simulated ischemia for 2 h followed by 15 min of reoxygenation. PPC of CMCs consisted of administration of 50 μM adenosine, 50 μM diazoxide, and 50 μM S-nitroso- N-acetylpenicillamine (SNAP), each alone or in combination, for 15 min followed by 30 min of washout before simulated ischemia. Although PKC-ε and PI3-kinase were significantly activated during treatment with adenosine, activation of these kinases dissipated after washout. In contrast, PPC combined with adenosine, diazoxide, and SNAP elicited sustained activation of PKC-ε and PI-3 kinase after washout. The combined-PPC, but not the single-PPC, protocol conferred antiapoptotic and antinecrotic effects after reoxygenation. The PKC inhibitor chelerythrine (5 μM) or the PI3-kinase inhibitor LY-294002 (10 μM) given during the washout period partially blocked the activation of PKC-ε and PI3-kinase mediated by the combined-PPC protocol, whereas combined addition of chelerythrine and LY-294002 completely inhibited activation of PKC-ε and PI3-kinase. Chelerythrine or LY-294002 partially blocked antiapoptotic and antinecrotic effects mediated by the combined-PPC protocol, whereas combined addition of chelerythrine and LY-294002 completely abrogated antiapoptotic and antinecrotic effects. These results suggest that the combined-PPC protocol confers cardioprotective memory through sustained and interdependent activation of PKC and PI3-kinase.

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Zaugg, Michael, Eliana Lucchinetti, Donat R. Spahn, Thomas Pasch, and Marcus C. Schaub. "Volatile Anesthetics Mimic Cardiac Preconditioning by Priming the Activation of Mitochondrial KATPChannels via Multiple Signaling Pathways." Anesthesiology 97, no. 1 (July 1, 2002): 4–14. http://dx.doi.org/10.1097/00000542-200207000-00003.

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Background Volatile anesthetics induce pharmacological preconditioning in cardiac tissue. The purpose of this study was to test whether volatile anesthetics mediate this effect by activation of the mitochondrial adenosine triphosphate-sensitive potassium (mitoK(ATP)) or sarcolemmal K(ATP) (sarcK(ATP)) channel in rat ventricular myocytes and to evaluate the signaling pathways involved. Methods A cellular model of ischemia with subsequent hypoosmolar trypan blue staining served to determine the effects of 5-hydroxydecanoate, a selective mitoK(ATP) channel blocker, HMR-1098, a selective sarcK(ATP) channel blocker, diazoxide, a preconditioning mimicking agent, and various modulators of putative signaling pathways on cardioprotection elicited by sevoflurane and isoflurane. Microscopy was used to visualize and measure autofluorescence of flavoproteins, a direct index of mitoK(ATP) channel activity. Results Volatile anesthetics significantly enhanced diazoxide-mediated activation of mitoK(ATP) channels as assessed by autofluorescence of myocytes. Conversely, volatile anesthetics alone did not alter mitoK(ATP) channel activity, implying a priming effect of volatile anesthetics on mitoK(ATP) channels. Administration of the protein kinase C inhibitor chelerythrine completely blocked this effect. Also, pretreatment with volatile anesthetics potentiated diazoxide-mediated protection against ischemia, as indicated by a reduction in trypan blue-positive myocytes. Importantly, cardioprotection afforded by volatile anesthetics was unaffected by the sarcK(ATP) channel blocker HMR-1098 but sensitive to modulations of nitric oxide and adenosine-G(i) signaling pathways. Conclusions Using autofluorescence in live cell imaging microscopy and a simulated model of ischemia, the authors present evidence that volatile anesthetics mediate their protection in cardiomyocytes by selectively priming mitoK(ATP) channels through multiple triggering protein kinase C-coupled signaling pathways. These observations provide important new insight into the mechanisms of anesthetic-induced preconditioning.

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Ihara, Madoka, Hiroshi Asanuma, Satoru Yamazaki, Hisakazu Kato, Yoshihiro Asano, Yoshihiro Shinozaki, Hidezo Mori, et al. "An interaction between glucagon-like peptide-1 and adenosine contributes to cardioprotection of a dipeptidyl peptidase 4 inhibitor from myocardial ischemia-reperfusion injury." American Journal of Physiology-Heart and Circulatory Physiology 308, no. 10 (May 15, 2015): H1287—H1297. http://dx.doi.org/10.1152/ajpheart.00835.2014.

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Dipeptidyl peptidase 4 (DPP4) inhibitors suppress the metabolism of the potent antihyperglycemic hormone glucagon-like peptide-1 (GLP-1). DPP4 was recently shown to provide cardioprotection through a reduction of infarct size, but the mechanism for this remains elusive. Known interactions between DPP4 and adenosine deaminase (ADA) suggest an involvement of adenosine signaling in DPP4 inhibitor-mediated cardioprotection. We tested whether the protective mechanism of the DPP4 inhibitor alogliptin against myocardial ischemia-reperfusion injury involves GLP-1- and/or adenosine-dependent signaling in canine hearts. In anesthetized dogs, the coronary artery was occluded for 90 min followed by reperfusion for 6 h. A 4-day pretreatment with alogliptin reduced the infarct size from 43.1 ± 2.5% to 17.1 ± 5.0% without affecting collateral flow and hemodynamic parameters, indicating a potent antinecrotic effect. Alogliptin also suppressed apoptosis as demonstrated by the following analysis: 1) reduction in the Bax-to-Bcl2 ratio; 2) cytochrome c release, 3) an increase in Bad phosphorylation in the cytosolic fraction; and 4) terminal deoxynucleotidyl transferase dUTP nick end labeling assay. This DPP4 inhibitor did not affect blood ADA activity or adenosine concentrations. In contrast, the nonselective adenosine receptor blocker 8-( p-sulfophenyl)theophylline (8SPT) completely blunted the effect of alogliptin. Alogliptin did not affect Erk1/2 phosphorylation, but it did stimulate phosphorylation of Akt, glycogen synthase kinase-3β, and cAMP response element-binding protein (CREB). Only 8SPT prevented alogliptin-induced CREB phosphorylation. In conclusion, the DPP4 inhibitor alogliptin suppresses ischemia-reperfusion injury via adenosine receptor- and CREB-dependent signaling pathways.

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Ye, Yumei, Yu Lin, Regino Perez-Polo, Ming-He Huang, Michael G. Hughes, David J. McAdoo, Saraswathy Manickavasagam, Barry F. Uretsky, and Yochai Birnbaum. "Enhanced cardioprotection against ischemia-reperfusion injury with a dipyridamole and low-dose atorvastatin combination." American Journal of Physiology-Heart and Circulatory Physiology 293, no. 1 (July 2007): H813—H818. http://dx.doi.org/10.1152/ajpheart.00210.2007.

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Atorvastatin (ATV) limits infarct size (IS) by activating Akt and ecto-5-nucleotidase, which generates adenosine. Activated Akt and adenosine activate endothelial nitric oxide synthase (eNOS). When given orally, high doses (10 mg/kg) are needed to achieve full protection. We determined whether dipyridamole (DIP), by preventing the reuptake of adenosine, has a synergistic effect with ATV in reducing myocardial IS. In this study, rats received 3-days of the following: water, ATV (2 mg·kg−1·day−1), DIP (6 mg·kg−1·day−1), or ATV + DIP. In addition, rats received 3-days of the following: aminophylline (Ami; 10 mg·kg−1·day−1) or Ami + ATV + DIP. Rats underwent 30 min of myocardial ischemia followed by 4 h of reperfusion (IS protocol), or hearts were explanted for immunoblotting. As a result, IS in the controls was 34.0 ± 2.8% of the area at risk. ATV (33.1 ± 2.1%) and DIP (30.5 ± 1.5%) did not affect IS, whereas ATV + DIP reduced IS (12.2 ± 0.5%; P < 0.001 vs. each of the other groups). There was no difference in IS between the Ami alone (48.1 ± 0.8%) and the Ami + ATV + DIP (45.8 ± 2.9%) group ( P = 0.422), suggesting that Ami completely blocked the protective effect. Myocardial adenosine level in the controls was 30.6 ± 3.6 pg/μl. ATV (51.0 ± 4.9 pg/μl) and DIP (51.5 ± 6.8 pg/μl) caused a small increase in adenosine levels, whereas ATV + DIP caused a greater increase in adenosine levels (66.4 ± 3.1 pg/μl). ATV and DIP alone did not affect myocardial Ser473 phosphorylated-Akt and Ser1177 phosphorylated-eNOS levels, whereas ATV + DIP significantly increased them. In conclusion, low-dose ATV and DIP had synergistic effects in reducing myocardial IS and activation of Akt and eNOS. This combination may have a potential benefit in augmenting the eNOS-mediated pleiotropic effects of statins.

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Haessler, Reinhard, Koh Kuzume, Roger A. Wolff, Kazuyo Kuzume, Grace L. Chien, Richard F. Davis, and Donna M. Van Winkle. "Adrenergic activation confers cardioprotection mediated by adenosine, but is not required for ischemic preconditioning." Coronary Artery Disease 7, no. 4 (April 1996): 305–14. http://dx.doi.org/10.1097/00019501-199604000-00007.

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Ding, Mingge, Yin Wang, Di Sun, Zhenhua Liu, Jie Wang, Xing Li, Cong Huo, et al. "Punicalagin Pretreatment Attenuates Myocardial Ischemia-Reperfusion Injury via Activation of AMPK." American Journal of Chinese Medicine 45, no. 01 (January 2017): 53–66. http://dx.doi.org/10.1142/s0192415x17500057.

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Punicalagin (PUN), a major bioactive component in pomegranate juice, has been proven to exert neuroprotective effects against cerebral ischemia/reperfusion (I/R) insult via anti-oxidant properties. This study aims to investigate whether PUN provides cardioprotection against myocardial I/R (MI/R) injury and the underlying mechanisms. PUN (30[Formula: see text]mg/kg/d) or vehicle was intragastrically administered to Sprague-Dawley rats for one week before the operation. MI/R was induced by ligating the left anterior descending coronary artery for 30[Formula: see text]min and subsequent reperfusion for 3[Formula: see text]h. PUN pretreatment conferred cardioprotective effects against MI/R injury by improving cardiac function, limiting infarct size, reducing serum creatine kinase-MB and lactate dehydrogenase activities, and suppressing cardiomyocyte apoptosis. Moreover, PUN pretreatment inhibited I/R-induced myocardial oxidative stress as evidenced by decreased generation of superoxide content and malonaldialdehyde formation and increased antioxidant capability. Furthermore, PUN pretreatment increased adenosine monophosphate-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC) phosphorylation in I/R hearts. AMPK inhibitor compound c inhibited PUN-enhanced AMPK phosphorylation, and blunted PUN-mediated anti-oxidative effects and cardioprotection. These results indicate for the first time that PUN pretreatment protect against I/R-induced oxidative stress and myocardial injury via activation of AMPK.

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Williams-Pritchard, Grant, Matthew Knight, Louise See Hoe, John P. Headrick, and Jason N. Peart. "Essential role of EGFR in cardioprotection and signaling responses to A1 adenosine receptors and ischemic preconditioning." American Journal of Physiology-Heart and Circulatory Physiology 300, no. 6 (June 2011): H2161—H2168. http://dx.doi.org/10.1152/ajpheart.00639.2010.

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Transactivation of epidermal growth factor receptor (EGFR) may contribute to specific protective responses (e.g. mediated by δ-opioid, bradykinin, or muscarinic receptors). No studies have assessed EGFR involvement in cardioprotection mediated by adenosine receptors (ARs), and the role of EGFR in ischemic preconditioning (IPC) is unclear. We tested EGFR, matrix metalloproteinase (MMP), and heparin-binding EGF (HB-EGF) dependencies of functional protection via A1AR agonism or IPC. Pretreatment of mouse hearts with 100 nM of A1AR agonist 2-chloro- N6-cyclopentyladenosine (CCPA) or IPC (3 × 1.5-min ischemia/2-min reperfusion) substantially improved recovery from 25-min ischemia, reducing left ventricular diastolic dysfunction up to 50% and nearly doubling pressure development and positive change in pressure over time (+dP/d t). Benefit with both CCPA and IPC was eliminated by inhibitors of EGFR tyrosine kinase (0.3 μM AG1478), MMP (0.3 μM GM6001), or HB-EGF ligand (0.3 ng/ml CRM197), none of which independently altered postischemic outcome. Phosphorylation of myocardial EGFR, Erk1/2, and Akt increased two- to threefold during A1AR agonism, with responses blocked by AG1478, GM6001, and CRM197. Studies in HL-1 myocytes confirm A1AR-dependent Erk1/2 phosphorylation is negated by AG1478 or GM6001, and reduced with CRM197 (as was Akt activation). These data collectively reveal that A1AR- and IPC-mediated functional protection is entirely EGFR and MMP dependent, potentially involving the HB-EGF ligand. Myocardial survival kinase activation (Erk1/2, Akt) by A1AR agonism is similarly MMP/HB-EGF/EGFR dependent. Thus MMP-mediated EGFR activation appears essential to cardiac protection and signaling via A1ARs and preconditioning.

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Bradamante, Silvia, Livia Barenghi, Franco Piccinini, Alberto A. E. Bertelli, Robert De Jonge, Patricia Beemster, and Jan Willem De Jong. "Resveratrol provides late-phase cardioprotection by means of a nitric oxide- and adenosine-mediated mechanism." European Journal of Pharmacology 465, no. 1-2 (March 2003): 115–23. http://dx.doi.org/10.1016/s0014-2999(03)01441-9.

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Del Pozzo, Jaclyn, Puja Mehta, Fei Cai, Cairong Li, Satoru Kobayashi, and Qiangrong Liang. "Unexpected Role of Adenosine-Monophosphate Activated Protein Kinase in Doxorubicin Cardiotoxicity and Metformin-Mediated Cardioprotection." Journal of Cardiac Failure 25, no. 8 (August 2019): S2. http://dx.doi.org/10.1016/j.cardfail.2019.07.015.

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Ballard-Croft, Cherry, Gentian Kristo, Yukihiro Yoshimura, Easton Reid, Byron J. Keith, Robert M. Mentzer, and Robert D. Lasley. "Acute adenosine preconditioning is mediated by p38 MAPK activation in discrete subcellular compartments." American Journal of Physiology-Heart and Circulatory Physiology 288, no. 3 (March 2005): H1359—H1366. http://dx.doi.org/10.1152/ajpheart.01006.2004.

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Although acute adenosine preconditioning (PC) is well established, the signaling pathways mediating this cardioprotection remain unclear. Because adenosine receptor agonists activate p38 MAPK and this kinase has been implicated in ischemic and pharmacological PC, the purpose of this study was to determine the role of p38 MAPK in acute adenosine receptor PC. The role of p38 MAPK activation in discrete subcellular compartments during ischemia-reperfusion was also determined. The following groups were used in an in vivo rat ischemia-reperfusion model: 1) control (10% DMSO iv), 2) the A1/A2a adenosine receptor AMP-579 (50 μg/kg iv), 3) AMP-579 + the A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX, 100 μg/kg iv), 4) AMP-579 + the p38 MAPK inhibitor SB-203580 (1 mg/kg iv), and 5) SB-203580 alone. p38 MAPK activation was measured by Western blot analysis in cytosolic, mitochondrial, membrane, and nuclear/myofilament fractions obtained from hearts at preischemic, ischemic, and reperfusion time points. A significant reduction in infarct size was observed with AMP-579 PC, an effect blocked by DPCPX or SB-203580 pretreatment. AMP-579 treatment was associated with a significant increase in p38 MAPK activation in the nuclear/myofilament fraction before ischemia, whereas no activation of this kinase occurred during ischemia or reperfusion. In contrast, p38 MAPK was activated in the mitochondrial fraction by ischemia and in the cytosolic, mitochondrial, and membrane fractions by reperfusion in the control group. SB-203580 blocked the AMP-579-induced increase in phosphorylation of the downstream p38 substrate activating transcription factor-2. These results suggest a role for p38 MAPK activation in discrete subcellular compartments in acute adenosine A1 receptor PC.

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Drenger, Benjamin, Israel A. Ostrovsky, Michal Barak, Yael Nechemia-Arbely, Ehud Ziv, and Jonathan H. Axelrod. "Diabetes Blockade of Sevoflurane Postconditioning Is Not Restored by Insulin in the Rat Heart." Anesthesiology 114, no. 6 (June 1, 2011): 1364–72. http://dx.doi.org/10.1097/aln.0b013e31820efafd.

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Background The possibility of restoring sevoflurane postconditioning (sevo-postC) cardioprotection in diabetic animals is uncertain. We hypothesized that attenuation of myocardial injury by sevo-postC might be hindered by inhibition of signal transducer and activator of transcription (STAT) 3-regulated activity of phosphatidylinositol 3-kinase (PI3K) in diabetic animals. To determine whether postC cardioprotection can be restored by normoglycemia, we treated rats with insulin. Methods Diabetic or nondiabetic rats were randomly subjected to 30-min ischemia/reperfusion, with ischemic postC or sevo-postC, with and without mitochondrial adenosine triphosphate-dependent potassium channel blocker 5-hydroxy decanoate sodium and PI3K antagonist wortmannin. The infarct area, phosphorylated STAT3, and apoptosis were examined. Studies were repeated after insulin treatment. Results Ischemic postC and sevo-postC significantly reduced infarct size by 50% in the nondiabetic rats (P < 0.002), a phenomenon completely reversed by 5-hydroxy decanoate sodium and wortmannin. Diabetes mellitus blocked the protective effect of postC, and insulin treatment to achieve normoglycemia did not restore cardioprotection. Phosphorylated STAT3 nuclear retention was significantly increased after ischemia-reperfusion and was further enhanced in response to ischemic postC (P < 0.05) but was significantly reduced in diabetic rats (by 43%; P < 0.01). Conclusions The effective reduction in infarct size and apoptosis in the nondiabetic rat heart by postC was completely abrogated in diabetic rats. This inhibition is not relieved by insulin-induced normoglycemia. The PI3K pathway and mitochondrial adenosine triphosphate-dependent potassium channel activation are involved in the mechanism of postC. In diabetic rats, STAT3 activation was strongly reduced, as was postC cardioprotection, suggesting that the inability of insulin to restore postC may be attributed to diabetes-induced STAT3-mediated inhibition of PI3K signaling.

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Tian, Yikui, Bryan A. Piras, Irving L. Kron, Brent A. French, and Zequan Yang. "Adenosine 2B Receptor Activation Reduces Myocardial Reperfusion Injury by Promoting Anti-Inflammatory Macrophages Differentiation via PI3K/Akt Pathway." Oxidative Medicine and Cellular Longevity 2015 (2015): 1–8. http://dx.doi.org/10.1155/2015/585297.

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Background. Activation of the adenosineA2Breceptor (A2BR) can reduce myocardial ischemia/reperfusion (IR) injury. However, the mechanism underlying theA2BR-mediated cardioprotection is less clear. The present study was designed to investigate the potential mechanisms of cardioprotection mediated byA2BR.Methods and Results. C57BL/6 mice underwent 40-minute ischemia and 60-minute reperfusion. ATL-801, a potent selectiveA2BR antagonist, could not block ischemic preconditioning induced protection. BAY 60-6583, a highly selectiveA2BR agonist, significantly reduced myocardial infarct size, and its protective effect could be blocked by either ATL-801 or wortmannin. BAY 60-6583 increased phosphorylated Akt (p-Akt) levels in the heart at 10 min of reperfusion, and this phosphorylation could also be blocked by ATL-801 or wortmannin. Furthermore, BAY 60-6583 significantly increased M2 macrophages and decreased M1 macrophage and neutrophils infiltration in reperfused hearts, which also could be blocked by wortmannin. Meanwhile, confocal imaging studies showed that the majority of Akt phosphorylation in the heart was colocalized to CD206+ cells in both control and BAY 60-6583 pretreated hearts.Conclusion. Our results indicated that pretreatment with BAY 60-6583 protects the heart against myocardial IR injury by its anti-inflammatory effects, probably by modulating macrophages phenotype switching via a PI3K/Akt pathway.

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Goyal, A., BC Semwal, and HN Yadav. "Abrogated cardioprotective effect of ischemic preconditioning in ovariectomized rat heart." Human & Experimental Toxicology 35, no. 6 (August 11, 2015): 644–53. http://dx.doi.org/10.1177/0960327115597980.

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Background: Ischemic heart disease is the leading cause of death in postmenopausal women. The expression of caveolin, a membrane protein and a negative regulator of nitric oxide (NO), increases after menopause. The present study was designed to determine the effect of daidzein (DDZ), a phytoestrogen in attenuated cardioprotective effect of ischemic preconditioning (IPC) in ovariectomized rat heart. Methods: Heart was isolated from ovariectomized rat and mounted on Langendorff’s apparatus, subjected to 30 min ischemia and 120 min reperfusion. IPC was mediated by four cycles of 5 min ischemia and 5 min reperfusion. The infarct size was estimated using triphenyltetrazolium chloride stain, and coronary effluent was analyzed for lactate dehydrogenase and creatine kinase MB (CK-MB) release to assess the degree of myocardial injury. The release of NO was estimated indirectly by measuring the release of nitrite in coronary effluent. Results: IPC-induced cardioprotection was significantly attenuated in ovariectomized rats as compared to normal rats, which was restored by treatment of DDZ, a caveolin inhibitor (0.2 mg/kg subcutaneously) for 1 week. However, this observed cardioprotection was significantly attenuated by perfusion of l-nitroarginine methyl ester, an endothelial nitric oxide synthase (eNOS) inhibitor (100 µM/L) and glibenclamide, an adenosine triphosphate-sensitive potassium ion channel blocker (10 µM/L) alone or in combination, noted in terms of increase in myocardial infarct size, release of LDH and CK-MB, and also decrease in the release of NO. Conclusion: Thus, it is suggested that DDZ restores the attenuated cardioprotective effect in ovariectomized rat heart, which may be due to downregulation of caveolin and subsequent increase in the activity of eNOS.

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Cope, Doris K., Keyser W. Impastato, Michael V. Cohen, and James M. Downey. "Volatile Anesthetics Protect the Ischemic Rabbit Myocardium from Infarction." Anesthesiology 86, no. 3 (March 1, 1997): 699–709. http://dx.doi.org/10.1097/00000542-199703000-00023.

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Background The influence of anesthetic agents on the infarction process in the ischemic myocardium is unclear. This study evaluated the effects of three intravenous and three inhalational anesthetic agents on myocardial infarction within a quantified ischemic risk zone in rabbit hearts subjected to a standardized regional ischemia-reperfusion insult. Methods Both in vitro and in situ rabbit models were used to investigate the effects of anesthetic agents on infarct size. In all rabbits the heart was exposed and a coronary artery surrounded with a suture to form a snare for subsequent occlusion. In in situ preparations, both intravenous and inhalational agents were tested, whereas only the latter were used in isolated hearts. Infarct size was determined by triphenyltetrazolium chloride staining. To determine whether an adenosine-mediated protective mechanism was involved, 8-(p-sulfophenyl)theophylline, an adenosine receptor blocker, was added to halothane-treated isolated hearts. Adenosine concentration in the coronary effluent was also measured in isolated hearts exposed to halothane. In other protocols, chelerythrine, a highly selective protein kinase C inhibitor, was administered to both halothane-treated and untreated isolated hearts. Results Infarcts in the three in situ groups anesthetized with halothane, enflurane, and isoflurane were about one half as large as infarcts in rabbits that underwent anesthesia with pentobarbital, ketamine-xylazine, or propofol. Volatile anesthetics also protected isolated hearts by a similar amount. Both adenosine receptor blockade and chelerythrine abolished cardioprotection from halothane in isolated hearts. Halothane treatment did not increase adenosine release. Conclusions The volatile anesthetics tested protected the ischemic rabbit heart from infarction, in contrast to the three intravenous agents tested. Protection was independent of the hypotensive effect of the inhalational agents because halothane also protected isolated hearts, in which changing vascular tone is not an issue and coronary perfusion pressure is constant. Cardioprotection by volatile anesthetics depended on both adenosine receptors and protein kinase C, and thus is similar to the mechanism of protection seen with ischemic preconditioning.

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Ke, Jianjuan, Bo Yao, Tao Li, Shanshan Cui, and Huang Ding. "A2 Adenosine Receptor-mediated Cardioprotection Against Reperfusion Injury in Rat Hearts Is Associated With Autophagy Downregulation." Journal of Cardiovascular Pharmacology 66, no. 1 (July 2015): 25–34. http://dx.doi.org/10.1097/fjc.0000000000000239.

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Cappello, Sandra, Tommaso Angelone, Bruno Tota, Pasquale Pagliaro, Claudia Penna, Raffaella Rastaldo, Angelo Corti, Gianni Losano, and Maria Carmela Cerra. "Human recombinant chromogranin A-derived vasostatin-1 mimics preconditioning via an adenosine/nitric oxide signaling mechanism." American Journal of Physiology-Heart and Circulatory Physiology 293, no. 1 (July 2007): H719—H727. http://dx.doi.org/10.1152/ajpheart.01352.2006.

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The acidic protein chromogranin A (CgA) is the precursor of several regulatory peptides generated by specific proteolytic processes. Human recombinant CgA NH2-terminal fragment STA-CgA1-78 (hrSTA-CgA1-78), containing vasostatin-1 (CgA1-76) domain, exerts a negative inotropic effect and counteracts the β-adrenergic positive inotropic effect on the rat heart. We hypothesized an involvement of nitric oxide (NO)-dependent pathway in both cardiodepression and cardioprotection by hrSTA-CgA1-78. We also hypothesized an involvement of adenosine A1 receptor and protein kinase C (PKC) in cardioprotection by hrSTA-CgA1-78. Therefore, we evaluated whether 1) the cardioinhibition mediated by hrSTA-CgA1-78 involves the Gi/o proteins/NO-dependent signal transduction cascade, 2) hrSTA-CgA1-78 induces ischemic preconditioning-like protective effects on the myocardium, and 3) inhibition of NO synthase (NOS), adenosine A1 receptor, or PKC affects hrSTA-CgA1-78 protection. Using the isolated rat heart, we found that the reduction of left ventricular pressure (LVP), rate-pressure product, and maximal values of the first derivative of LVP elicited by hrSTA-CgA1-78 at 33 nM is abolished by blocking Gi/o proteins with pertussis toxin, scavenging NO with hemoglobin, and blocking NOS activity with NG-monomethyl-l-arginine or N5-(iminoethyl)-l-ornithine, soluble guanylate cyclase with 1 H-[1,2,4]oxadiazole-[4,4-a]quinoxalin-1-one, and protein kinase (PKG) with KT5823. Data suggest the involvement of the Gi/o proteins/NO-cGMP-PKG pathway in the hrSTA-CgA1-78-dependent cardioinhibition. When given before 30 min of ischemia, hrSTA-CgA1-78 significantly reduced the size of the infarct from 64 ± 4 to 32 ± 3% of the left ventricular mass. This protective effect was abolished by either NOS inhibition or PKC blockade and was attenuated, but not suppressed, by the blockade of A1 receptors. These results suggest that hrSTA-CgA1-78 activity triggers two different pathways: one of these pathways is mediated by A1 receptors, and the other is mediated by NO release. As with repeated brief preconditioning ischemia, hrSTA-CgA1-78 may be considered a stimulus strong enough to trigger both pathways, which may converge on PKC.

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Ludwig, Lynda M., Hemal H. Patel, Garrett J. Gross, Judy R. Kersten, Paul S. Pagel, and David C. Warltier. "Morphine Enhances Pharmacological Preconditioning by Isoflurane." Anesthesiology 98, no. 3 (March 1, 2003): 705–11. http://dx.doi.org/10.1097/00000542-200303000-00019.

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Background Adenosine triphosphate-regulated potassium channels mediate protection against myocardial infarction produced by volatile anesthetics and opioids. We tested the hypothesis that morphine enhances the protective effect of isoflurane by activating mitochondrial adenosine triphosphate-regulated potassium channels and opioid receptors. Methods Barbiturate-anesthetized rats (n = 131) were instrumented for measurement of hemodynamics and subjected to a 30 min coronary artery occlusion followed by 2 h of reperfusion. Myocardial infarct size was determined using triphenyltetrazolium staining. Rats were randomly assigned to receive 0.9% saline, isoflurane (0.5 and 1.0 minimum alveolar concentration [MAC]), morphine (0.1 and 0.3 mg/kg), or morphine (0.3 mg/kg) plus isoflurane (1.0 MAC). Isoflurane was administered for 30 min and discontinued 15 min before coronary occlusion. In eight additional groups of experiments, rats received 5-hydroxydecanoic acid (5-HD; 10 mg/kg) or naloxone (6 mg/kg) in the presence or absence of isoflurane, morphine, and morphine plus isoflurane. Results Isoflurane (1.0 MAC) and morphine (0.3 mg/kg) reduced infarct size (41 +/- 3%; n = 13 and 38 +/- 2% of the area at risk; n = 10, respectively) as compared to control experiments (59 +/- 2%; n = 10). Morphine plus isoflurane further decreased infarct size to 26 +/- 3% (n = 11). 5-HD and naloxone alone did not affect infarct size, but abolished cardioprotection produced by isoflurane, morphine, and morphine plus isoflurane. Conclusions Combined administration of isoflurane and morphine enhances the protection against myocardial infarction to a greater extent than either drug alone. This beneficial effect is mediated by mitochondrial adenosine triphosphate-regulated potassium channels and opioid receptors in vivo.

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Regan, Sara E., Michael Broad, Anne M. Byford, Amy R. Lankford, Rachael J. Cerniway, Marty W. Mayo, and G. Paul Matherne. "A1 adenosine receptor overexpression attenuates ischemia-reperfusion-induced apoptosis and caspase 3 activity." American Journal of Physiology-Heart and Circulatory Physiology 284, no. 3 (March 1, 2003): H859—H866. http://dx.doi.org/10.1152/ajpheart.00251.2002.

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We tested the hypothesis that myocardial ischemia-reperfusion (I/R)-induced apoptosis is attenuated in transgenic mice overexpressing cardiac A1 adenosine receptors. Isolated hearts from transgenic (TG, n = 19) and wild-type (WT, n = 22) mice underwent 30 min of ischemia and 2 h of reperfusion, with evaluation of apoptosis, caspase 3 activity, function, and necrosis. I/R-induced apoptosis was attenuated in TG hearts. TG hearts had less I/R-induced apoptotic nuclei (0.88 ± 0.10% vs. 4.22 ± 0.24% terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive cells in WT, P < 0.05), less DNA fragmentation (3.30 ± 0.38-fold vs. 4.90 ± 0.39-fold over control in WT, P < 0.05), and less I/R-induced caspase 3 activity (145 ± 25% over nonischemic control vs. 234 ± 31% in WT, P < 0.05). TG hearts also had improved recovery of function and less necrosis than WT hearts. In TG hearts pretreated with LY-294002 (3 μM) to evaluate the role of phosphosinositol-3-kinase in acute signaling, there was no change in the functional protection or apoptotic response to I/R. These data suggest that cardioprotection with transgenic overexpression of A1 adenosine receptors involves attenuation of I/R-induced apoptosis that does not involve acute signaling through phosphoinositol-3-kinase.

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Thourani, Vinod H., Masanori Nakamura, Russell S. Ronson, James E. Jordan, Zhi-Qing Zhao, Jerrold H. Levy, Fania Szlam, Robert A. Guyton, and Jakob Vinten-Johansen. "Adenosine A3-receptor stimulation attenuates postischemic dysfunction through KATP channels." American Journal of Physiology-Heart and Circulatory Physiology 277, no. 1 (July 1, 1999): H228—H235. http://dx.doi.org/10.1152/ajpheart.1999.277.1.h228.

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We tested the hypothesis that selective adenosine A3-receptor stimulation reduces postischemic contractile dysfunction through activation of ATP-sensitive potassium (KATP) channels. Isolated, buffer-perfused rat hearts ( n = 8/group) were not drug pretreated (control) or were pretreated with adenosine (20 μM), 2-chloro- N 6-(3-iodobenzyl)-adenosine-5′- N-methyluronamide (Cl-IB-MECA; A3 agonist, 100 nM), Cl-IB-MECA + 8-(3-noradamantyl)-1,3-dipropylxanthine (KW-3902; A1 antagonist, 5 μM), Cl-IB-MECA + glibenclamide (Glib; KATP-channel blocker, 0.3 μM), or Glib alone for 12 min before 30 min of global normothermic ischemia followed by 2 h of reperfusion. After 2 h of reperfusion, left ventricular developed pressure (LVDP, %baseline) in control hearts was depressed to 34 ± 2%. In hearts pretreated with Cl-IB-MECA, there was a statistically significant increase in LVDP (50 ± 6%), which was reversed with coadministration of Glib (37 ± 1%). Control hearts also showed similar decreases in left ventricular peak positive rate of change in pressure (dP/d t). Therefore, the A3 agonist significantly attenuated postischemic cardiodynamic injury compared with the control, which was reversed by Glib. Cumulative creatine kinase (CK in U/min) activity was most pronounced in the control group (10.4 ± 0.6) and was significantly decreased by Cl-IB-MECA (7.5 ± 0.4), which was reversed by coadministration of Glib (9.4 ± 0.2). Coronary flow was increased during adenosine infusion (160% of baseline) but not during Cl-IB-MECA infusion. Effects of Cl-IB-MECA were not reversed by the specific A1 antagonist KW-3902. We conclude that cardioprotection afforded by A3-receptor stimulation may be mediated in part by KATP channels. Cl-IB-MECA may be an effective pretreatment agent that attenuates postischemic cardiodynamic dysfunction and CK release without the vasodilator liability of other adenosine agonists.

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Xu, Fuqi, Shigang Qiao, Hua Li, Yanjun Deng, Chen Wang, and Jianzhong An. "The Effect of Mitochondrial Complex I-Linked Respiration by Isoflurane Is Independent of Mitochondrial Nitric Oxide Production." Cardiorenal Medicine 8, no. 2 (2018): 113–22. http://dx.doi.org/10.1159/000485936.

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Background: Anesthetic preconditioning (APC) of the myocardium is mediated in part by reversible alteration of mitochondrial function. Nitric oxide (NO) inhibits mitochondrial respiration and may mediate APC-induced cardioprotection. In this study, the effects of isoflurane on different states of mitochondrial respiration during the oxidation of complex I-linked substrates and the role of NO were investigated. Methods: Mitochondria were isolated from Sprague-Dawley rat hearts. Respiration rates were measured polarographically at 28ºC with a computer-controlled Clark-type O2 electrode in the mitochondria (0.5 mg/mL) with complex I substrates glutamate/malate (5 mM). Isoflurane (0.25 mM) was administered before or after adenosine diphosphate (ADP)-initiated state 3 respiration. The NO synthase (NOS) inhibitor L-N5-(1-iminoethyl)-ornithine (L-NIO, 10 μM) and the NO donor S-nitroso-N-acetylpenicillamine (SNAP, 1 μM) were added before or after the addition of ADP. Results: Isoflurane administered in state 2 increased state 2 respiration and decreased state 3 respiration. This attenuation of state 3 respiration by isoflurane was similar when it was given during state 3. L-NIO did not alter mitochondrial respiration or the effect of isoflurane. SNAP only, added in state 3, decreased state 3 respiration and enhanced the isoflurane-induced attenuation of state 3 respiration. Conclusion: Isoflurane has clearly distinguishable effects on different states of mitochondrial respiration during the oxidation of complex I substrates. The uncoupling effect during state 2 respiration and the attenuation of state 3 respiration may contribute to the mechanism of APC-induced cardioprotection. These effects of isoflurane do not depend on endogenous mitochondrial NO, as the NOS inhibitor L-NIO did not alter the effects of isoflurane on mitochondrial respiration.

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Zhang, Ye, Michael G. Irwin, Tak Ming Wong, Mai Chen, and Chun-Mei Cao. "Remifentanil Preconditioning Confers Cardioprotection via Cardiac κ- and δ-Opioid Receptors." Anesthesiology 102, no. 2 (February 1, 2005): 371–78. http://dx.doi.org/10.1097/00000542-200502000-00020.

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Background Remifentanil preconditioning (RPC) reduces the infarct size in anesthetized rat hearts, and this effect seems to be mediated by all three types of opioid receptors (ORs). Because there is evidence of only kappa- and delta- but not mu-ORs in the rat heart, the authors investigated whether RPC confers cardioprotection via cardiac kappa- and delta-OR as well as via extracardiac mu-OR agonist activity. The authors also investigated the involvement of signaling mechanisms, namely protein kinase C and mitochondrial adenosine triphosphate-sensitive potassium (KATP) channels. Methods The hearts of male Sprague-Dawley rats weighing 190-210 g were removed, mounted on a Langendorff apparatus, and perfused retrogradely at 100 cm H2O with Krebs-Ringer's solution. All hearts were subjected to 30 min of ischemia and 2 h of reperfusion. The study consisted of three series of experiments on the effect of ischemic preconditioning or RPC (10, 50, and 100 ng/ml remifentanil) after blockade of OR subtypes (delta-OR antagonist naltrindol, kappa-OR antagonist nor-binaltorphimine, and mu-OR antagonist CTOP). The involvement of protein kinase C or the KATP channel in the cardioprotection of RPC was also investigated using specific blockers in each group. RPC was produced by three cycles of 5-min perfusion of remifentanil in Krebs-Ringer's solution interspersed with a 5-min reperfusion with Krebs solution only. Infarct size, as a percentage of the area at risk, was determined by 2,3,5-triphenyltetrazolium staining. Results Infarct size as a percentage of the area at risk was significantly reduced after RPC from 51.9 +/- 5.0% (control, n = 8) to 36.2 +/- 10.0% (100 ng/ml RPC, n = 8, P < 0.01). This effect was stopped by pretreatment with naltrindol (52.3 +/- 5.2%) and nor-binaltorphimine (43.5 +/- 6.0%) but not CTOP (37.1 +/- 6.0%). Chelerythrine and GF109203X, both protein kinase C inhibitors, abolished the effects of RPC or ischemic preconditioning on infarct size as a percentage of area at risk. 5-Hydroxydecanoate (a selective mitochondrial KATP channel blocker) also abolished the cardioprotection of RPC and IPC, but HMR-1098 (a selective inhibitor of the sarcolemmal KATP channel) did not. Conclusion Cardiac delta- and kappa- but not mu-ORs mediate the cardioprotection produced by RPC. Both protein kinase C and the mitochondrial KATP channel were involved in this effect.

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Kawabata, Ken-Ichi, Thomas Netticadan, Mitsuru Osada, Kohji Tamura, and Naranjan S. Dhalla. "Mechanisms of ischemic preconditioning effects on Ca2+paradox-induced changes in heart." American Journal of Physiology-Heart and Circulatory Physiology 278, no. 3 (March 1, 2000): H1008—H1015. http://dx.doi.org/10.1152/ajpheart.2000.278.3.h1008.

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The effects of ischemic preconditioning (IP) on changes in cardiac performance and sarcoplasmic reticulum (SR) function due to Ca2+ paradox were investigated. Isolated perfused hearts were subjected to IP (three cycles of 3-min ischemia and 3-min reperfusion) followed by Ca2+-free perfusion and reperfusion (Ca2+paradox). Perfusion of hearts with Ca2+-free medium for 5 min followed by reperfusion with Ca2+-containing medium for 30 min resulted in a dramatic decrease in the left ventricular (LV) developed pressure and a marked increase in LV end-diastolic pressure. Alterations in cardiac contractile activity due to Ca2+paradox were associated with depressed SR Ca2+-uptake, Ca2+-pump ATPase, and Ca2+-release activities as well as decreased SR protein contents for Ca2+-pump and Ca2+ channels. All these changes due to Ca2+paradox were significantly prevented in hearts subjected to IP. The protective effects of IP on Ca2+ paradox changes in cardiac contractile activity as well as SR Ca2+-pump and Ca2+-release activities were lost when the hearts were treated with 8-( p-sulfophenyl)-theophylline, an adenosine receptor antagonist; KN-93, a specific Ca2+/calmodulin-dependent protein kinase II (CaMK II) inhibitor; or chelerythrine chloride, a protein kinase C (PKC) inhibitor. These results indicate that IP rendered cardioprotection by preventing a depression in SR function in Ca2+ paradox hearts. Furthermore, these beneficial effects of IP may partly be mediated by adenosine receptors, PKC, and CaMK II.

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Li, Yeli, Linying Feng, Dianyou Xie, Mu Lin, Yiqi Li, Nana Chen, Danli Yang, Jianmei Gao, Yizhun Zhu, and Qihai Gong. "Icariside II, a Naturally Occurring SIRT3 Agonist, Protects against Myocardial Infarction through the AMPK/PGC-1α/Apoptosis Signaling Pathway." Antioxidants 11, no. 8 (July 27, 2022): 1465. http://dx.doi.org/10.3390/antiox11081465.

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Myocardial infarction (MI) refers to the death of cardiomyocytes triggered by a lack of energy due to myocardial ischemia and hypoxia, and silent mating type information regulation 2 homolog 3 (SIRT3) plays an essential role in protecting against myocardial oxidative stress and apoptosis, which are deemed to be the principal causes of MI. Icariside II (ICS II), one of the main active ingredients of Herbal Epimedii, possesses extensive pharmacological activities. However, whether ICS II can protect against MI is still unknown. Therefore, this study was designed to investigate the effect and possible underlying mechanism of ICS II on MI both in vivo and in vitro. The results showed that pretreatment with ICS II not only dramatically mitigated MI-induced myocardial damage in mice but also alleviated H9c2 cardiomyocyte injury elicited by oxygen and glucose deprivation (OGD), which were achieved by suppressing mitochondrial oxidative stress and apoptosis. Furthermore, ICS II elevated the phosphorylation level of adenosine monophosphate-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1α) expression, thereby activating SIRT3. However, these protective effects of ICS II on MI injury were largely abolished in SIRT3-deficient mice, manifesting that ICS II-mediated cardioprotective effects are, at least partly, due to the presence of SIRT3. Most interestingly, ICS II directly bound with SIRT3, as reflected by molecular docking, which indicated that SIRT3 might be a promising therapeutic target for ICS II-elicited cardioprotection in MI. In conclusion, our findings illustrate that ICS II protects against MI-induced oxidative injury and apoptosis by targeting SIRT3 through regulating the AMPK/PGC-1α pathway.

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Journal articles on the topic 'Adenosine mediated cardioprotection'

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