（-）-表没食子儿茶素-3-没食子酸酯，绿茶中主要的儿茶素，通过 GRK2 调节实验性心力衰竭中β1 肾上腺素能受体的脱敏。
(-)-Epigallocatechin-3-gallate, the major green tea catechin, regulates the desensitization of β1 adrenoceptor via GRK2 in experimental heart failure.
机构信息
Geriatric Department of the Affiliated Provincial Hospital of Anhui Medical University, Anhui Institute of Cardiovascular Disease, Hefei, 230001, China.
出版信息
Inflammopharmacology. 2018 Aug;26(4):1081-1091. doi: 10.1007/s10787-017-0429-x. Epub 2017 Dec 16.
OBJECTIVE
We investigated the effect of (-)-epigallocatechin-3-gallate (EGCG) on cardiac function and its mechanism, which focused on the desensitization of β1-AR and GRK2 in heart failure (HF) rats.
METHODS
HF was induced by abdominal aortic coarctation. Four weeks after HF induction, the rats were given EGCG (25, 50, 100 mg/kg/day). Cardiac function was assessed by measuring haemodynamic parameters. Histological changes were analyzed by HE and Masson's trichrome staining. The expression of β1-AR was detected by immunohistochemistry and immunofluorescence. The membrane expression of β1-AR and GRK2 was detected by western blot. The expression levels of β1-AR mRNA and GRK2 mRNA were evaluated by Q-PCR.
RESULT
Compared to the control group, the left ventricular end diastolic pressure, mean blood pressure, heart weight/body weight, and posterior wall thickness in the HF group were significantly increased, whereas the left ventricular systolic pressure, maximum rate of left ventricular pressure rise (+ dP/dt ) and maximum rate of left ventricular pressure fall (- dP/dt ) were clearly decreased. EGCG could improve cardiac function by regulating these parameters. Inflammatory cell infiltration, irregularly arranged cardiomyocytes, swelling of cardiomyocytes and myocardial fibrosis were observed in HF rats' myocardial morphology, and EGCG obviously improved the morphological signs. The expression of β1-AR was significantly decreased in the left ventricle tissue of HF rats by immunohistochemistry and immunofluorescence. The membrane expression of β1-AR decreased, whereas GRK2 increased in vivo and in vitro by western blot. EGCG could down-regulate the membrane expression of GRK2 and up-regulate the expression of β1-AR. There were no significant differences in the total expression of β1-AR mRNA and GRK2 mRNA.
CONCLUSIONS
EGCG has therapeutic effects on the heart function of HF rats. The mechanism might be related to the inhibition of the transfer membrane of GRK2 and to the reduction of the desensitization of β1-AR.
目的
本研究旨在探讨表没食子儿茶素没食子酸酯（EGCG）对心力衰竭（HF）大鼠心脏功能的影响及其作用机制，重点关注β1-AR 和 GRK2 的脱敏作用。
方法
采用腹主动脉缩窄法诱导 HF。HF 诱导 4 周后，给予 EGCG（25、50、100 mg/kg/d）。通过测量血流动力学参数评估心功能。通过 HE 和 Masson 三色染色分析组织学变化。通过免疫组化和免疫荧光检测β1-AR 的表达。通过 Western blot 检测β1-AR 和 GRK2 的膜表达。通过 Q-PCR 评估β1-AR mRNA 和 GRK2 mRNA 的表达水平。
结果
与对照组相比，HF 组的左心室舒张末期压、平均血压、心脏重量/体重和后壁厚度明显增加，而左心室收缩压、左心室压力上升最大速率（+dP/dt）和左心室压力下降最大速率（-dP/dt）明显降低。EGCG 可通过调节这些参数改善心功能。HF 大鼠心肌形态学观察到炎性细胞浸润、排列不规则的心肌细胞、心肌细胞肿胀和心肌纤维化，EGCG 明显改善了形态学征象。免疫组化和免疫荧光显示，HF 大鼠左心室组织中β1-AR 的表达明显减少。Western blot 显示，体内和体外β1-AR 的膜表达减少，而 GRK2 增加。EGCG 可下调 GRK2 的膜表达并上调β1-AR 的表达。β1-AR mRNA 和 GRK2 mRNA 的总表达无明显差异。
结论
EGCG 对 HF 大鼠的心脏功能具有治疗作用。其机制可能与抑制 GRK2 的跨膜转移和减少β1-AR 的脱敏有关。
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