[C/EBP homologous protein-mediated endoplasmic reticulum stress-related apoptosis pathway is involved in abdominal aortic constriction-induced myocardium hypertrophy in rats.].
Endoplasmic reticulum stress (ERS) is an adaptive process in response to circumstantial changes, but excessive and/or prolonged ERS can induce cell apoptosis. C/EBP homologous protein (CHOP) is a very important marker participating in ERS-associated cell apoptosis, while the role of the myocyte apoptosis induced by CHOP remains unclear in the development of hypertrophy. The present study aimed to investigate the effect of CHOP-mediated ERS-associated apoptosis on myocardial hypertrophy induced by abdominal aortic constriction in rats. Healthy male Wistar rats were randomly divided into model group (n=45) and control group (n=40). The rats in model group received abdominal aortic constriction. Hemodynamic changes, whole heart weight/body weight (HW/BW) and left ventricular weight/body weight (LVW/BW) were measured on 1 d, 3 d, 7 d, 14 d and 28 d after surgery, respectively. The mRNA expression of glucose-regulated protein 78 (GRP78), calreticulin (CRT) and CHOP, which are important markers of ERS, were detected by RT-PCR, and Western blot was used to assess the protein level of GRP78, CRT, CHOP, and apoptosis-associated proteins, Bax and Bcl-2. The results obtained were as follows. Compared with control group, the blood pressure, LVW/BW, and HW/BW of rats in model group increased significantly and cardiac function enhanced compensatively on 7 d after surgery, and increased progressively during the experiment. As early as 1 d after surgery, the mRNA level of CRT in model group increased by 136% (P< 0.01) compared with control, while the protein expression increased by 69.2% on 7 d after surgery (P<0.01). Both mRNA and protein expression of GRP78 increased by 20% and 186% (P<0.01) respectively on 7 d after surgery, and the expression sustained high level during the experiment afterwards. Correlation analysis indicated a positive correlation between +dp/dt(max) and CRT protein expression (r=0.780, P<0.01) as well as GRP78 protein expression (r=0.694, P<0.01). Prolonged ERS triggered myocyte apoptosis, as both the mRNA and protein level of CHOP in model group increased by 22.2% (P<0.01) and 76.0% (P<0.01) respectively compared with control on 7 d after hypertrophy (14 d after surgery), and meanwhile, the protein expression of pro-apoptotic Bax increased by 41.1% (P<0.01) and anti-apoptotic Bcl-2 protein expression decreased by 25.5% (P<0.01). Correlation analysis indicated a positive correlation between CHOP and Bax expression (r=0.654, P<0.01), and a negative correlation between CHOP and Bcl-2 expression (r=-0.671, P<0.01). These results suggest that abdominal aortic constriction induces a significant up-regulation in ER molecular chaperones at early stage of post-surgery, indicating that ERS response is activated in the rat heart; while prolonged ERS could lead to myocyte apoptosis, and CHOP-mediated ERS-associated apoptosis may contribute to myocardial hypertrophy. We speculate that cell apoptosis may take part in the regulation of myocardial hypertrophy and heart failure, and determine the progression of decompensated hypertrophy.
Department of Pathophysiology, Chinese PLA General Hospital, Beijing, China.
Zhen-Ying
ZY
Zhang
Xiu-Hua
XH
Liu
Yong-Jun
YJ
Ye
Sheng
S
Sun
Fei
F
Rong
Xiao-Sun
XS
Guo
Wei-Cheng
WC
Hu
D000818:Animals; D001011:Aorta / Q000503:physiopathology; D017209:Apoptosis; D037282:Calreticulin / Q000378:metabolism; D003250:Constriction; D059865:Endoplasmic Reticulum Stress; D006360:Heat-Shock Proteins / Q000378:metabolism; D006984:Hypertrophy / Q000473:pathology; D008297:Male; D009206:Myocardium / Q000473:pathology*; D051381:Rats; D017208:Rats, Wistar; D051742:Transcription Factor CHOP / Q000378:metabolism*; D015854:Up-Regulation; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP
D037282:Calreticulin; D006360:Heat-Shock Proteins; D051742:Transcription Factor CHOP; D051028:bcl-2-Associated X Protein; C494828:Bax protein, rat; C051684:GRP78 protein, rat; D000091342:Endoplasmic Reticulum Chaperone BiP