thapsigargin and Aortic-Valve-Stenosis

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.. 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.. 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.

Topics: Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Animals; Aortic Valve Stenosis; Apoptosis; Cardiomegaly; Cells, Cultured; Disease Models, Animal; Disease Progression; Endoplasmic Reticulum; Gene Expression Regulation; Heart Failure; Humans; Imidazoles; Ligation; Male; Mice; Mice, Inbred C57BL; Molecular Chaperones; Myocytes, Cardiac; Natriuretic Peptide, Brain; Olmesartan Medoxomil; Rats; Rats, Inbred WKY; RNA, Messenger; Signal Transduction; Stress, Physiological; Tetrazoles; Thapsigargin; Tunicamycin