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.
