Abstract
Ischemia/reperfusion (I/R) injury is the central cause of global death in cardiovascular diseases, which is characterized by disorders such as angina, stroke, and peripheral vascular disease, finally causing severe debilitating diseases and death. The increased rates of morbidity and mortality caused by I/R are parallel with aging. Aging-associated cardiac physiological structural and functional deterioration were found to contribute to abnormal reactive oxygen species (ROS) production during I/R stress. Disturbed redox homeostasis could further trigger the related signaling pathways that lead to cardiac irreversible damages with mitochondria dysfunction and cell death. It is notable that sirtuin proteins are impaired in aged hearts and are critical to maintaining redox homeostasis via regulating substrate metabolism and inflammation and thus preserving cardiac function under stress. This review discussed the cellular and functional alterations upon I/R especially in aging hearts. We propose that mitochondria are the primary source of reactive oxygen species (ROS) that contribute to I/R injury in aged hearts. Then, we highlight the cardiomyocyte protection of the age-related proteins Sirtuin1 (SIRT1) and Sirtuin1 (SIRT3) in response to I/R injury, and we discuss their modulation of cardiac metabolism and the inflammatory reaction that is involved in ROS formation.
Highlights
Ischemic heart disease, symbolized by the constriction in the coronary blood vessel, is one of the most significant cardiac problems with a higher death rate among the elderly population [1]
We found that the deletion of SIRT1 in cardiomyocytes caused the hyperacetylation of liver kinase B1 (LKB1) and impaired the phosphorylation of adenosine monophosphate protein kinase (AMPK) during ischemia [36]
These findings suggest that the impaired SIRT1 in aged hearts causes the hyperactivation of NF-κB in response to I/R stress, leading to an excessive production of cytoplasmic reactive oxygen species (ROS) mediated by NOX and inducible nitric oxide synthase (iNOS)
Summary
Ischemic heart disease, symbolized by the constriction in the coronary blood vessel, is one of the most significant cardiac problems with a higher death rate among the elderly population [1]. Uncontrolled cardiac ROS generation caused by pathological alterations involved in myocardial I/R injury can promote oxidative damage to cellular proteins and other biomolecules, as well as mitochondrial dysfunction and cell death [6] These discoveries advance the understanding of the mechanisms of abnormal redox homeostasis in order to develop potentially effective approaches to protect hearts from I/R injury, especially in the older population. Recent research revealed the three ways that SIRT3 regulates cardiac autophagy during I/R stress, which are autophagosome formation-related AMPK/mTOR activation, the Foxo3a-mediated Pink1/Parkin pathway, and mitochondrial ROS homeostasis via superoxide dismutase 2 (SOD2) [41,42] In this way, SIRT1 and SIRT3 have multiple beneficial effects on protecting hearts against I/R injury and suggest the significance of them as potential targets for cardioprotection, especially in the elder population. Considering the importance of ROS, which are primary toxic by-products of aerobic metabolism that lead to macromolecular damage in cardiovascular disease [6], this review focuses on summarizing the latest evidence regarding the role of SIRT1 and SIRT3 in redox homeostasis during cardiac I/R stress
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