Melatonin attenuates diabetic cardiomyopathy and reduces myocardial vulnerability to ischemia‐reperfusion injury by improving mitochondrial quality control: Role of SIRT6

Abstract

Targeting mitochondrial quality control with melatonin has been found promising for attenuating diabetic cardiomyopathy (DCM), although the underlying mechanisms remain largely undefined. Activation of SIRT6 and melatonin membrane receptors exerts cardioprotective effects while little is known about their roles during DCM. Using high‐fat diet‐streptozotocin‐induced diabetic rat model, we found that prolonged diabetes significantly decreased nocturnal circulatory melatonin and heart melatonin levels, reduced the expressions of cardiac melatonin membrane receptors, and decreased myocardial SIRT6 and AMPK‐PGC‐1α‐AKT signaling. 16 weeks of melatonin treatment inhibited the progression of DCM and the following myocardial ischemia‐reperfusion (MI/R) injury by reducing mitochondrial fission, enhancing mitochondrial biogenesis and mitophagy via re‐activating SIRT6 and AMPK‐PGC‐1α‐AKT signaling. After the induction of diabetes, adeno‐associated virus carrying SIRT6‐specific small hairpin RNA or luzindole was delivered to the animals. We showed that SIRT6 knockdown or antagonizing melatonin receptors abolished the protective effects of melatonin against mitochondrial dysfunction as evidenced by aggravated mitochondrial fission and reduced mitochondrial biogenesis and mitophagy. Additionally, SIRT6 shRNA or luzindole inhibited melatonin‐induced AMPK‐PGC‐1α‐AKT activation as well as its cardioprotective actions. Collectively, we demonstrated that long‐term melatonin treatment attenuated the progression of DCM and reduced myocardial vulnerability to MI/R injury through preserving mitochondrial quality control. Melatonin membrane receptor‐mediated SIRT6‐AMPK‐PGC‐1α‐AKT axis played a key role in this process. Targeting SIRT6 with melatonin treatment may be a promising strategy for attenuating DCM and reducing myocardial vulnerability to ischemia‐reperfusion injury in diabetic patients.

Heat shock protein 22 modulates NRF1/TFAM-dependent mitochondrial biogenesis and DRP1-sparked mitochondrial apoptosis through AMPK-PGC1α signaling pathway to alleviate the early brain injury of subarachnoid hemorrhage in rats

“…Previous findings have indicated that hsp22 directly binds to AMPK and promotes its nuclear translocation and phosphorylation at Thr172, which results in a stimulation of survival mechanisms [ 27 ]. Additionally, activators and suppressants of AMPK have been employed to verify that AMPK exerts a protective role in mitochondrial dynamics imbalance and oxidative stress-mediated myocardium [ [50] , [51] , [52] ], brain [ 28 , 53 , 54 ] and liver injury [ 25 ]. But, it is still little known whether hsp22-induced upregulation of p-AMPK is answerable for its protective properties on mitochondrial dysfunction in SAH.…”

SIRT6‑specific inhibitor OSS‑128167 exacerbates diabetic cardiomyopathy by aggravating inflammation and oxidative stress

“…Additionally, previous studies have indicated that uncontrolled inflammation and oxidative stress may contribute to cardiac dysfunction in diabetic cardiac tissues (10,11). Extensive research has also revealed that mitochondrial injury may serve as a central mediator in the pathology of DCM (12,13). Therefore, identifying potential therapeutic strategies that target chronic inflammation and oxidative stress may aid in the management of DCM.…”

Melatonin Protects Cardiomyocytes from Oxygen Glucose Deprivation And Reperfusion-Induced Injury by Inhibiting Rac1/JNK/Foxo3a/Bim Signaling Pathway

“…The FOXO3a/Bim signaling pathway plays a crucial role in the modulation of I/R-induced cell apoptosis [21,28,29]. Previous studies demonstrated that melatonin inhibits I/R-induced cell apoptosis in many types of cells, including cardiomyocyte [5,6,9]. Importantly, FOXO3a has been shown to serve as an important downstream target of melatonin and mediate melatonin-induced transcriptional regulation of proapoptotic Bim [30,31].…”

“…Ischemia-reperfusion (I/R) injury is still one of the primary causes of death in ischemic heart disease [1,2]. Cardiomyocyte apoptosis plays an essential role in acute myocardial I/R injury [3][4][5]. It is well known that cardiomyocytes are vulnerable to energy and nutrition depletion, and they will experience cell death immediately after I/R injury [5,6].…”

“…Melatonin shows signi cant effects on numberous critical physiological and pathological processes due to its amphiphilic property [7,8]. Previous studies demonstrated that melatonin has bene cial effects in myocardial I/R injury [5,6,9]. However, the underlying mechanisms about how melatonin plays bene cial role in myocardial I/R injury remains to be further elucidated.…”