CB1 cannabinoid receptor deficiency promotes cardiac remodeling induced by pressure overload in mice.
CB1 cannabinoid receptor deficiency promotes cardiac remodeling induced by pressure overload in mice.
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DOI：
10.1016/j.ijcard.2012.05.033
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发表时间：
2013-09
影响因子：
3.5
通讯作者：
Y. Liao;J. Bin;T. Luo;Hui Zhao;C. Ledent;M. Asakura;Dingli Xu;S. Takashima;M. Kitakaze
中科院分区：
文献类型：
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作者：
Y. Liao;J. Bin;T. Luo;Hui Zhao;C. Ledent;M. Asakura;Dingli Xu;S. Takashima;M. Kitakaze
背景已知内源性大麻素系统在调节心肌收缩力中发挥作用，但大麻素受体1（CB 1）缺乏对慢性心力衰竭（CHF）的影响尚不清楚。在这项研究中，我们试图探讨CB 1缺陷对压力超负荷引起的CHF和可能的mechanisms involved.Methods和resultsA CHF模型建立了横向主动脉缩窄（TAC）在CB 1基因敲除小鼠和野生型小鼠。从TAC后4至8周，CB 1基因敲除小鼠显示CHF导致的死亡率显著增加（p= 0.021）。TAC后5周，与野生型小鼠相比，CB 1基因敲除小鼠具有较高的左心室（LV）舒张末期压、较低的LV压力变化率（± dp/dtmax）、较低的LV收缩指数以及较大的心脏重量与体重比和肺重量与体重比（allp< 0.05-0.001）。CB 1基因敲除小鼠表皮生长因子受体（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，CB 1激动剂减少了异丙肾上腺素或毛喉素刺激的cAMP产生，并抑制了EGFR、P38和ERK的磷酸化，结论大麻素受体1失活通过增强表皮生长因子受体的活性促进心脏重塑，丝裂原活化蛋白激酶。
BackgroundThe 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 resultsA 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/dtmax), 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 (allp< 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.ConclusionThese 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.