The serine/threonine-protein kinase/endoribonuclease IRE1 protects the heart against pressure overload–induced heart failure

Abstract

Heart failure is associated with induction of endoplasmic reticulum (ER) stress and the unfolded protein response (UPR). The serine/threonine protein kinase/endoribonuclease IRE1 is a key protein in ER stress signal transduction. IRE1 activity can induce both protective UPR and apoptotic downstream signaling events, but the specific role for IRE1 activity in the heart is unknown. A major aim of this study was to characterize the specific contribution of IRE1 in cardiac physiology and pathogenesis. We used both cultured myocytes and a transgenic mouse line with inducible and cardiomyocyte-specific IRE1 overexpression as experimental models to achieve targeted IRE1 activation. IRE1 expression induced a potent but transient ER stress response in cardiomyocytes and did not cause significant effects in the intact heart under normal physiological conditions. Furthermore, the IRE1-activated transgenic heart responding to pressure overload exhibited preserved function and reduced fibrotic area, associated with increased adaptive UPR signaling and with blunted inflammatory and pathological gene expression. Therefore, we conclude that IRE1 induces transient ER stress signaling and confers a protective effect against pressure overload–induced pathological remodeling in the heart. To our knowledge, this report provides first direct evidence of a specific and protective role for IRE1 in the heart and reveals an interaction between ER stress signaling and inflammatory regulation in the pathologically stressed heart.