Endoplasmic Reticulum Stress Sensor IRE1 alpha Preserves Function of the Stressed Myocardium

Many diseases and insults to the heart disrupt homeostasis in the endoplasmic reticulum (ER) and cause ER Stress, leading to activation of the ER stress response, or Unfolded Protein Response (UPR) signaling pathway. The UPR from the endoplasmic reticulum is emerging to play a vital role in health and disease. The most ancient member of this signaling pathway, IRE1 alpha, has been reported to induce both protective UPR and apoptotic downstream signaling events in various tissues, but the role for IRE1 alpha in heart is unknown. We aimed to characterize the specific contribution of IRE1 alpha in heart in health and in response to stress. We generated a mouse model with inducible, heart-specific IRE1 alpha overexpression in order to investigate a role for IRE1 alpha in heart under baseline and stressed conditions. We observed that IRE1 alpha did not induce a detrimental phenotype in the absence of stress. Moreover, IRE1 alpha overexpression preserved heart function in response to pressure overload. Adaptive UPR signaling was enhanced while inflammatory and fetal gene program members were blunted. Also, IRE1 alpha activation and downstream signaling was transient in cardiac myocytes in vitro. Inflammatory cytokine expression was reduced following IRE1 alpha expression, recapitulating observations made in vivo. IRE1 alpha induces adaptive, transient signaling in heart. We conclude that the UPR signaling repertoire includes unknown, heart-specific endogenous regulatory mechanisms. To our knowledge, this is the first report of a specific and protective role for IRE1 alpha in heart and provides new evidence for the integration of ER stress and inflammatory signaling

The serine/threonine-protein kinase/endoribonuclease IRE1α protects the heart against pressure overload–induced heart failure

Heart failure is associated with induction of endoplasmic reticulum (ER) stress and the unfolded protein response (UPR). The serine/threonine protein kinase/endoribonuclease IRE1α is a key protein in ER stress signal transduction. IRE1α activity can induce both protective UPR and apoptotic downstream signaling events, but the specific role for IRE1α activity in the heart is unknown. A major aim of this study was to characterize the specific contribution of IRE1α in cardiac physiology and pathogenesis. We used both cultured myocytes and a transgenic mouse line with inducible and cardiomyocyte-specific IRE1α overexpression as experimental models to achieve targeted IRE1α activation. IRE1α 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 IRE1α-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 IRE1α 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 IRE1α in the heart and reveals an interaction between ER stress signaling and inflammatory regulation in the pathologically stressed heart