Pivotal Role of Regulator of G-protein Signaling 12 in Pathological Cardiac Hypertrophy
Pivotal Role of Regulator of G-protein Signaling 12 in Pathological Cardiac Hypertrophy
复制标题
G 蛋白信号传导 12 调节剂在病理性心脏肥大中的关键作用
DOI：
10.1161/hypertensionaha.115.06877
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发表时间：
2016-06-01
期刊：
影响因子：
8.3
通讯作者：
Ma, Genshan
中科院分区：
文献类型：
--
作者：
Huang, Jia;Chen, Lijuan;Ma, Genshan
心脏肥大是心力衰竭的主要预测因素，并受到多种信号通路的调节。 RGS12作为G蛋白信号传导调节因子(RGS)家族的典型多结构域成员，在多种信号通路中发挥调节作用。然而，RGS12 对心脏肥大的确切作用仍然很大程度上未知。在这项研究中，我们观察到 RGS12 在病理性心脏肥大和心力衰竭的发展过程中表达增加。然后，我们生成了基因工程小鼠和新生大鼠心肌细胞，以研究 RGS12 在此病理过程中的影响。主动脉结扎后 4 周，RGS12 缺陷心脏显示心肌细胞横截面积减少（对照组为 374.7±43.2 µm2，对照为 487.1±47.9 µm2；P<0.05），缩短分数保留（对照为 43.0±3.4%，对照为 28.4±2.2%；P<0.05），而 RGS12 过表达心脏表现出心肌细胞横截面积增加（对照组为 582.4±46.7 µm2，对照为 474.8±40.0 µm2；P<0.05），缩短分数减少（对照组为 20.8±4.1%，对照为 28.6±3.2%；P<0.05）。 RGS12 还导致血管紧张素 II 诱导的离体心肌细胞肥大。从机制上讲，我们的数据表明 MEK1/2–ERK1/2 信号传导的激活可能是 RGS12 的促肥大作用的原因。此外，在使用 MEK1/2 特异性抑制剂 U0126 的救援实验中证实了 RGS12 介导的心脏肥大需要 MEK1/2–ERK1/2 信号传导。总之，我们的研究结果为病理性心脏肥大和心力衰竭提供了新的诊断和治疗靶点。
Cardiac hypertrophy is a major predictor of heart failure and is regulated by diverse signaling pathways. As a typical multi-domain member of the regulator of G-protein signaling (RGS) family, RGS12 plays a regulatory role in various signaling pathways. However, the precise effect of RGS12 on cardiac hypertrophy remains largely unknown. In this study, we observed increased expression of RGS12 in the development of pathological cardiac hypertrophy and heart failure. We then generated genetically engineered mice and neonatal rat cardiomyocytes to investigate the effects of RGS12 during this pathological process. Four weeks after aortic banding, RGS12-deficient hearts showed decreased cardiomyocyte cross area (374.7±43.2 &mgr;m2 versus 487.1±47.9 &mgr;m2 in controls; P<0.05) with preserved fractional shortening (43.0±3.4% versus 28.4±2.2% in controls; P<0.05), whereas RGS12-overexpressing hearts exhibited increased cardiomyocyte cross area (582.4±46.7 &mgr;m2 versus 474.8±40.0 &mgr;m2 in controls; P<0.05) and reduced fractional shortening (20.8±4.1% versus 28.6±3.2% in controls; P<0.05). RGS12 also contributed to angiotensin II–induced hypertrophy in isolated cardiomyocytes. Mechanistically, our data indicated that the activation of MEK1/2–ERK1/2 signaling may be responsible for the prohypertrophic action of RGS12. In addition, the requirement of the MEK1/2–ERK1/2 signaling for RGS12-mediated cardiac hypertrophy was confirmed in rescue experiments using the MEK1/2-specific inhibitor U0126. In conclusion, our findings provide a novel diagnostic and therapeutic target for pathological cardiac hypertrophy and heart failure.