Department of Cardiology, and Organ Failure Key Laboratory of Ministry of Education, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou 510515, China.
Int J Cardiol. 2013 Sep 1;167(5):1936-44. doi: 10.1016/j.ijcard.2012.05.033. Epub 2012 May 31.
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.
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.
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.
内源性大麻素系统被认为在调节心肌收缩力方面发挥作用，但大麻素受体 1 (CB1) 缺乏对慢性心力衰竭 (CHF) 的影响尚不清楚。在这项研究中，我们试图研究 CB1 缺乏对压力超负荷引起的 CHF 的影响及其可能涉及的机制。
通过横主动脉缩窄 (TAC) 在 CB1 敲除小鼠和野生型小鼠中建立 CHF 模型。CB1 敲除小鼠在 TAC 后 4 至 8 周因 CHF 导致死亡率明显增加（p=0.021）。与野生型小鼠相比，TAC 后 5 周，CB1 敲除小鼠的左心室 (LV) 舒张末期压更高，LV 压力变化率（±dp/dt max）更低，LV 收缩力指数更低，以及更大的心脏重量与体重比和肺重量与体重比（所有 p<0.05-0.001）。CB1 敲除小鼠中表皮生长因子受体 (EGFR) 和丝裂原活化蛋白激酶 (P38 和 ERK) 的磷酸化水平高于野生型小鼠。在培养的新生大鼠心肌细胞中，CB1 激动剂降低异丙肾上腺素或 forskolin刺激的 cAMP 产生，并抑制 EGFR、P38 和 ERK 的磷酸化，而 CB1 激动剂对 EGFR 磷酸化的抑制作用被 CB1 敲低所消除。
这些发现表明，大麻素受体 1 失活通过增强表皮生长因子受体和丝裂原活化蛋白激酶的活性促进心脏重塑。
