SIRT6 protects cardiomyocytes against ischemia/reperfusion injury by augmenting FoxO3α-dependent antioxidant defense mechanisms

Abstract

SIRT6, a member of the NAD(+)-dependent class III deacetylase sirtuin family, has been revealed to play important roles in promoting cellular resistance against oxidative stress. The formation of reactive oxygen species (ROS) and oxidative stress are the crucial mechanisms underlying cellular damage and dysfunction in cardiac ischemia/reperfusion (I/R) injury, but the role of SIRT6 in I/R-induced ROS and oxidative stress is poorly understood. In this study, by using heterozygous SIRT6 knockout (SIRT6(+/-)) mice and cultured neonatal cardiomyocyte models, we investigated how SIRT6 mediates oxidative stress and myocardial injury during I/R. Partial knockout (KO) of SIRT6 aggravated myocardial damage, ventricular remodeling, and oxidative stress in mice subjected to myocardial I/R, whereas restoration of SIRT6 expression by direct cardiac injection of adenoviral constructs encoding SIRT6 reversed these deleterious effects of SIRT6 KO in the ischemic heart. In addition, partial deletion of the SIRT6 gene decreased myocardial functional recovery following I/R in a Langendorff perfusion model. Similarly, the protective effects of SIRT6 were also observed in cultured cardiomyocytes following hypoxia/reoxygenation. Intriguingly, SIRT6 was noticed to up-regulate AMP/ATP and then activate the adenosine 5'-monophosphate-activated protein kinase (AMPK)-forkhead box O3α (FoxO3α) axis and further initiated the downstream antioxidant-encoding gene expression (manganese superoxide dismutase and catalase), thereby decreasing cellular levels of oxidative stress and mediating cardioprotection in the ischemic heart. These results suggest that SIRT6 protects the heart from I/R injury through FoxO3α activation in the ischemic heart in an AMP/ATP-induced AMPK-dependent way, thus upregulating antioxidants and suppressing oxidative stress.

Over-expression of growth differentiation factor 15 (GDF15) preventing cold ischemia reperfusion (I/R) injury in heart transplantation through Foxo3a signaling

“…It has been reported that Foxo3a influences hypertrophy of heart cells, in the absence of active Akt [39] and promotes cardiomyocyte survival under oxidative stress through reduction of reactive oxygen species and cell death [40]. More recent studies have shown that Foxo3a signaling is involved in kidney and liver I/R injury in vivo [24, 25] and I/R injured cardiomyocytes and cardio endothelial cells in vitro [26, 41]. Foxo3a is also associated with inflammation and oxidative stress [42].…”

Irisin ameliorates angiotensin II‐induced cardiomyocyte apoptosis through autophagy

“…After 4‐week‐TAC treatment, the mice were euthanized by intraperitoneal injection of a lethal dosage of pentobarbital (at least 200 mg/kg). The hearts were arrested in diastole by intravenous injection of 0.2 mol/L KCl and perfused with 3.7% neutralized formaldehyde solution (Li et al, ; X. X. Wang et al, ). The excised hearts were further postfixed in the same fixative for another 12 hr.…”

SIRT1 and SIRT6 Signaling Pathways in Cardiovascular Disease Protection

“…Like SIRT1, SIRT6-FOXO3 complex enhances the transcription of FOXO-dependent antioxidant genes (MnSOD and CAT) to counteract the damage provoked by I/R (Fig. 6) (192). Furthermore, SIRT6 overexpression protects cardiomyocytes against hypoxic stress by activating AMPK, upregulating Bcl2, suppressing the activity of NFjB, and decreasing cellular ROS levels (Fig.…”