Protective Effects of Isorhamnetin on Cardiomyocytes Against Anoxia/Reoxygenation-induced Injury Is Mediated by SIRT1

Abstract

It has been reported that apoptosis plays a very important role on anoxia/reoxygenation (A/R)-induced injury, and human silent information regulator type 1 (SIRT1) can inhibit the apoptosis of cardiomyocytes. It has been proved that isorhamnetin (IsoRN), 3'-O-methyl-quecetin, can protect the cardiomyocytes, but the mechanism is still not clear. The aim of the study was to explore whether the protective effects of IsoRN on the cardiomyocytes against the A/R-induced injury are mediated by SIRT1. The effects of IsoRN on cardioprotection against A/R injury in neonatal rat cardiomyocytes were monitored by cell viability, the levels of mitochondrial membrane potential (Δψm), apoptosis, and intracellular reactive oxygen species (ROS), the levels of lactate dehydrogenase (LDH), creatine phosphokinase (CPK) and mitochondrial permeability transition pores (mPTP). The effects on protein expression were measured by western blot assay. The results showed that IsoRN can reduce A/R-induced injury by decreasing the level of lactate dehydrogenase and creatine phosphokinase release from the cardiomyocytes, increasing cell viability and expression of SIRT1, reducing the generation of reactive oxygen species, inhibiting opening of mitochondrial permeability transition pores and loss of Δψm and activation of caspase-3, and decreasing the release of cytochrome c, and reducing apoptosis. In addition, sirtinol, a SIRT1 inhibitor, drastically reduced the protective effects of IsoRN on cardioprotective effects in cardiomocytes. In conclusion, we firstly demonstrated that SIRT1 may be involved in the protective effects of IsoRN on cardiomocytes against the A/R-induced injury.

Activators of Sirtuin-1 and their Involvement in Cardioprotection

“…Isorhamnetin increased cell viability, reduced ROS production, lactate dehydrogenase (LDH) and creatine phosphokinase (CPK) release from cardiomyocytes, apoptosis and preserved the mitochondrial membrane potential. The involvement of SIRT1 was confirmed by the administration of sirtinol, which abolished the protective effects of isorhamnetin [104]. n-Tyrosol 59 [2-(4-hydroxyphenyl)ethanol, Figure 9] is a natural compound found in olive and argan oil and in white wine.…”

“…Chikusetsu saponin IVa (53) protects against hyperglycemia-induced myocardial injury in vivo and in vitro [94] Sulforaphane (54) prevents myocardial hypoxia/reoxygenation injury in cardiomyocytes [97] Curcumin (55) attenuates injury of post-ischemic hearts, decreases infarct size and decreases mitochondrial oxidative damage in both hearts and cardiomyocytes [98] alleviates hydrogen peroxide-induced endothelial cells premature senescence by reducing oxidative stress and apoptosis [99] Melatonin (56) attenuates myocardial ischemia/reperfusion injury by reducing oxidative stress damage in vivo [101] ameliorates reperfusion-induced oxidative stress in a type 2 diabetic animal model [102] Isorhamnetin (58) reduces anoxia/reoxygenation-induced injury in cardiomyocytes [104] n-Tyrosol (59) induces myocardial protection against ischemia related stress in a in vivo model of myocardial infarction [105] Sesamin (60) exerts cardioprotective effects in animal and cell models of Doxorubicininduced cardiac injury [106]…”

Dietary Isorhamnetin Intake Is Inversely Associated with Coronary Artery Disease Occurrence in Polish Adults

“…However, it is worth noting that the studies regarding flavonols supplementation were based on much higher doses of the selected flavonols than occur in the everyday diet. Cardioprotective effects of isorhamnetin were reported only in in vitro and animal model studies [40][41][42]. There have not been any studies regarding isorhamnetin's role in cardiovascular protection in humans yet.…”

NOX4 stimulates ANF secretion via activation of the Sirt1/Nrf2/ATF3/4 axis in hypoxic beating rat atria

“…Acute ischemic preconditioning, pressure overload, nutrient starvation and exercise, can also upregulate Sirt1 expression in the heart ( 12 , 13 ). Furthermore, Sirt1 prevents apoptosis of cardiomyocytes and protects the heart from ischemia/reperfusion-induced damage ( 20 , 21 ). Sirt1 acts as an upstream signaling molecule for the transcription factor Nrf2, which serves a role in resisting ischemia/reperfusion injury via activation of Nrf2 and its downstream signaling pathway ( 22 , 23 ).…”