Prolonged Endoplasmic Reticulum Stress in Hypertrophic and Failing Heart After Aortic Constriction

Abstract

Background-The endoplasmic reticulum (ER) is recognized as an organelle that participates in folding secretory and membrane proteins. The ER responds to stress by upregulating ER chaperones, but prolonged and/or excess ER stress leads to apoptosis. However, the potential role of ER stress in pathophysiological hearts remains unclear. Methods and Results-Mice were subjected to transverse aortic constriction (TAC) or sham operation. Echocardiographic analysis demonstrated that mice 1 and 4 weeks after TAC had cardiac hypertrophy and failure, respectively. Cardiac expression of ER chaperones was significantly increased 1 and 4 weeks after TAC, indicating that pressure overload by TAC induced prolonged ER stress. In addition, the number of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL)-positive cells increased, and caspase-3 was cleaved in failing hearts. The antagonism of angiotensin II type 1 receptor prevented upregulation of ER chaperones and apoptosis in failing hearts. On the other hand, angiotensin II upregulated ER chaperones and induced apoptosis in cultured adult rat cardiac myocytes. We also investigated possible signaling pathways for ER-initiated apoptosis. The CHOP-(a transcription factor induced by ER stress), but not JNK-or caspase-12-, dependent pathway was activated in failing hearts by TAC. Pharmacological ER stress inducers upregulated ER chaperones and induced apoptosis in cultured cardiac myocytes. Finally, mRNA levels of ER chaperones were markedly increased in failing hearts of patients with elevated brain natriuretic peptide levels. Conclusions-These findings suggest that pressure overload by TAC induces prolonged ER stress, which may contribute to cardiac myocyte apoptosis during progression from cardiac hypertrophy to failure.

Participation of endoplasmic reticulum stress in the pathogenesis of spontaneous glomerulosclerosis–Role of intra-renal angiotensin system

“…Hypertension and proteinuria have been shown to induce ER stress. 22,[44][45][46] Activation of Representative western blots and group data depicting the abundance of proteins mediating ER stressinduced apoptotic response (IRE1, ASK1, p-ASK1, p-Bcl2, BAX, and NFkB) in the control group and in the untreated Imai and ARB-treated Imai groups. n 5 6 in each group.…”

Proteostasis in cardiac health and disease

“…Increasing proteo toxic stress in experimental animal models by inhibition or knock out of important enzymes involved in PQCoften in mice with transverse aortic binding -implicate the cardiac activation of various signalling pathways associated with progression or attenu ation of heart dis ease. Signalling includes detrimental pathways, such as the calcineurin-NFAT pathway 150 , phosphorylation of eukaryotic translation initiation factor (eIF) 2α 151 , and induction of apoptosis [151][152][153] , but also favourable path ways, such as protection against oxidative stress through upregu lation of catalase 154 , or transcriptional activation of the hexo samine biosynthetic pathway supplying the sub strate for protein glycosylation 150 . Nevertheless, despite disclosure of these pathways, the dominant pathways linking cardio myocyte proteotoxic stress to subsequent cell death and cardiac remodelling in various cardiac conditions are still not well defined.…”

Redox-Sensitive Endoplasmic Reticulum Stress and Autophagy at Rostral Ventrolateral Medulla Contribute to Hypertension in Spontaneously Hypertensive Rats

“…Sustained ER stress results in activation of apoptotic 7 and autophagic 30 signaling pathways. We therefore investigated whether the observed oxidative stress-associated ER stress activates these signaling pathways in RVLM.…”

“…In patients with heart failure, the expression of GRP78 is significantly increased, and UPR is activated. 7 In advanced atherosclerotic plaques, the presence of oxidized lipids, inflammation, and metabolic stress induces ER stress and activates UPR. 8 ER stress is also related to cardiac damage and vascular endothelial dysfunction in angiotensin II (Ang II)-induced hypertension.…”