Over the past decade， endoplasmic reticulum (ER) stress has emerged as an important mechanism involved in the pathogenesis of cardiovascular diseases including heart failure. Cardiac therapy based on ER stress modulation is viewed as a promising avenue toward effective therapies for the diseased heart. Here， we tested whether sirtuin-1 (SIRT1)， a NAD-dependent deacetylase， participates in modulating ER stress response in the heart. Using cardiomyocytes and adult-inducible SIRT1 knockout mice， we demonstrate that SIRT1 inhibition or deficiency increases ER stress-induced cardiac injury， whereas activation of SIRT1 by the SIRT1-activating compound STAC-3 is protective. Analysis of the expression of ma... More
Over the past decade， endoplasmic reticulum (ER) stress has emerged as an important mechanism involved in the pathogenesis of cardiovascular diseases including heart failure. Cardiac therapy based on ER stress modulation is viewed as a promising avenue toward effective therapies for the diseased heart. Here， we tested whether sirtuin-1 (SIRT1)， a NAD-dependent deacetylase， participates in modulating ER stress response in the heart. Using cardiomyocytes and adult-inducible SIRT1 knockout mice， we demonstrate that SIRT1 inhibition or deficiency increases ER stress-induced cardiac injury， whereas activation of SIRT1 by the SIRT1-activating compound STAC-3 is protective. Analysis of the expression of markers of the three main branches of the unfolded protein response (i.e.， PERK/eIF2α， ATF6 and IRE1) showed that SIRT1 protects cardiomyocytes from ER stress-induced apoptosis by attenuating PERK/eIF2α pathway activation. We also present evidence that SIRT1 physically interacts with and deacetylates eIF2α. Mass spectrometry analysis identified lysines K141 and K143 as the acetylation sites on eIF2α targeted by SIRT1. Furthermore， mutation of K143 to arginine to mimic eIF2α deacetylation confers protection against ER stress-induced apoptosis. Collectively， our findings indicate that eIF2α deacetylation on lysine K143 by SIRT1 is a novel regulatory mechanism for protecting cardiac cells from ER stress and suggest that activation of SIRT1 has potential as a therapeutic approach to protect the heart against ER stress-induced injury.
