Background and Purpose: Myocardial infarction (MI) is an irreversible damage caused by ischemia and hypoxia in coronary arteries accompanied with elevated levels of catecholamine, leading to the accumulation of free radicals. Our previous study discovered coumarin-derived imino sulfonates as a novel class of potential cardioprotective agents possessing strong anti-oxidative effect in cardimyocytes. Therefore, the identification of the compound with the highest cardioprotective activity, 5h, and the mechanism involved was necessary. Experimental Approach: As a kind of catecholamine, isoproterenol induces MI injury mimicking symptoms of MI patients in clinic. Cardiac function, nfarct area, histopathological changes were evaluated. The potential mechanism underlying such action of compound 5h was explored via transfection with adenovirus to downregulate Sirt1 in vitro, and by administration of Ex527, the specific inhibitor for Sirt1, in vivo. Key Results: Compound 5h exhibited strong cardioprotective actions in vivo and in vitro via improving cell survival, cardiac function and decreasing the cellular oxidative stress and cardiac infarct size against MI. Furthermore, compound 5h significantly enhanced cardiac expression of Sirt1, subsequently activating the Nrf2/NQO1 signaling pathway. However, adenovirus induced Sirt1 downregulation or Sirt1 specific inhibitor largely blocked such beneficial effects of 5h in vitro and in vivo, respectively. Conclusions and Implications: Our results demonstrated, for the first time, that the cardioprotective action of 5h against MI was mediated by reducing oxidative stress and apoptosis through the Sirt1/Nrf2 signaling pathway. Our findings proposed novel insights in the development and evaluation of coumarin-derived imino sulfonate compounds as epigenetics-targeted drug therapy for MI.
Background and Purpose Myocardial ischemia/reperfusion (MI/R) injury is the main clinical problem of coronary heart disease. Higenamine (HG), a cardiotonic active component isolated from aconiti tuber, exhibits cardioprotective effects. However, its exact mechanism in MI/R is limited. Experimental Approach The oxidative stress induced by H2O2 in H9c2 and MI/R rat model was established. Metprolol, evidenced to ameliorate MI/R injury, was used as the positive control. Cardiac impairment indexes, were detected in vitro and in vivo. Changes of peroxiredoxins (Prxs), important anti-oxidative stress proteins in MI/R were also evaluated. Adenovirus induced Prx2 down-regulation and specific inhibitor of Prx2 was employed to determine the exact mechanism of HG in vitro and in vivo. Metabolomic analysis of MI/R rats with or without HG administration based on UPLC-MS/MS was further performed. Key Results HG significantly reduced the oxidative stress, improve cardiac dysfunction and decrease cardiac infarct size against MI/R via Prx2 activation, which was stronger than those in positive control treated rats. Additionally, HG altered metabolism of arginine and proline and biosynthesis of arginine during MI/R. Mechanically, HG increased the levels of Prx2, accompanied with decreased apoptotic protein, in vitro and in vivo expressions. However, down-regulation of Prx2 markedly blocked all the cardioprotective effect of HG. Conclusion and Implications Our work systematicly demonstrated that HG possessed a strong cardioprotective effect against MI/R by up-regulating cardiac expression of Prx2 and modulating disordered metabolism of arginine and glutamine in heart. We provided HG as the potential to further explore therapeutic strategy for MI/R.
Myocardial infarction (MI) is an irreversible damage caused by ischemia and hypoxia in coronary arteries accompanied with elevated levels of catecholamine, leading to the accumulation of free radicals. Our previous study discovered coumarin-derived imino sulfonates as a novel class of potential cardioprotective agents possessing strong anti-oxidative effect in cardimyocytes. Therefore, the identification of the compound with the highest cardioprotective activity, 5h, and the mechanism involved was necessary. As a kind of catecholamine, isoproterenol can clinically induce myocardial infarction injury similar to the symptoms of myocardial infarction patients. Our experiments explored the underlying mechanism of this effect of compound 5h by assessing cardiac function, infarct size, histopathological changes, and downregulation of Sirt1 by transfection of adenovirus in vitro and by administering Ex527, a specific inhibitor of Sirt1, in vivo. Compound 5h exhibited strong cardioprotective actions in vivo and in vitro via improving cell survival, cardiac function and decreasing the cellular oxidative stress and cardiac infarct size against MI. Furthermore, compound 5h significantly enhanced cardiac expression of Sirt1, subsequently activating the Nrf2/NQO1 signaling pathway. However, adenovirus induced Sirt1 downregulation or Sirt1 specific inhibitor largely blocked such beneficial effects of 5h in vitro and in vivo, respectively. Taken together our results demonstrated, for the first time, that the cardioprotective action of 5h against MI was mediated by reducing oxidative stress and apoptosis through the Sirt1/Nrf2 signaling pathway. Our findings proposed novel insights in the development and evaluation of coumarin-derived imino sulfonate compounds as epigenetics-targeted drug therapy for MI.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.