SIRT6 protects vascular endothelial cells from angiotensin II-induced apoptosis and oxidative stress by promoting the activation of Nrf2/ARE signaling.

Angiotensin II (Ang II) is a vasoactive peptide that elevates arterial blood pressure and leads to hypertension. Ang II has been reported to induce endothelial dysfunction by induction of apoptosis and oxidative stress in vascular endothelial cells. Sirtuin6 (SIRT6) has emerged as a critical regulator for modulating Ang II-induced injury of the cardiovascular system. However, little is known about the role of SIRT6 in regulating Ang II-induced injury in vascular endothelial cells. Here, our results showed that SIRT6 expression was decreased in vascular endothelial cells exposed to Ang II. This was accompanied by decreased cell viabilities as well as increased apoptosis and the production of reactive oxygen species. Functional experiments showed that the overexpression of SIRT6 significantly prohibited Ang II-induced apoptosis and reactive oxygen species generation, while silencing SIRT6 resulted in the opposite effect. Notably, our results showed that overexpression of SIRT6 resulted in a significant increase in the nuclear expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and upregulated the expression of the Nrf2 target gene in vascular endothelial cells exposed to Ang II. Moreover, knockdown of Nrf2 significantly blocked the SIRT6-mediated protection effect against Ang II-induced apoptosis and reactive oxygen species generation. Taken together, these results demonstrate that SIRT6 overexpression alleviates Ang II-induced apoptosis and oxidative stress in vascular endothelial cells by promoting Nrf2 antioxidant signaling. Our study suggests that SIRT6 may serve as a potential therapeutic target for treating hypertension associated with endothelial dysfunction.