大麻素受体
内分泌学
内科学
医学
压力过载
基因剔除小鼠
大麻素
收缩性
MAPK/ERK通路
兴奋剂
蛋白激酶A
激酶
受体
心力衰竭
生物
细胞生物学
心肌肥大
作者
Yulin Liao,Jianping Bin,Tao Luo,Hui Zhao,Catherine Ledent,Masanori Asakura,Dingli Xu,Seiji Takashima,Masafumi Kitakaze
标识
DOI:10.1016/j.ijcard.2012.05.033
摘要
Background The endocannabinoid system is known to play a role in regulating myocardial contractility, but the influence of cannabinoid receptor 1 (CB1) deficiency on chronic heart failure (CHF) remains unclear. In this study we attempted to investigate the effect of CB1 deficiency on CHF induced by pressure overload and the possible mechanisms involved. Methods and results A CHF model was created by transverse aortic constriction (TAC) in both CB1 knockout mice and wild-type mice. CB1 knockout mice showed a marked increase of mortality due to CHF from 4 to 8 weeks after TAC (p=0.021). Five weeks after TAC, in contrast to wild-type mice, CB1 knockout mice had a higher left ventricular (LV) end-diastolic pressure, lower rate of LV pressure change (±dp/dt max), lower LV contractility index, and a larger heart weight to body weight ratio and lung weight to body weight ratio compared with wild-type mice (all p<0.05–0.001). Phosphorylation of the epidermal growth factor receptor (EGFR) and mitogen-activated protein kinases (P38 and ERK) was higher in CB1 knockout mice than that in wild-type mice. In cultured neonatal rat cardiomyocytes, a CB1 agonist reduced cAMP production stimulated by isoproterenol or forskolin, and suppressed phosphorylation of the EGFR, P38, and ERK, while the inhibitory effect of a CB1 agonist on EGFR phosphorylation was abrogated by CB1 knockdown. Conclusion These findings indicate that cannabinoid receptor 1 inactivation promotes cardiac remodeling by enhancing the activity of the epidermal growth factor receptor and mitogen-activated protein kinases.
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