Rnd3 haploinsufficient mice are predisposed to hemodynamic stress and develop apoptotic cardiomyopathy with heart failure.
Rnd3 haploinsufficient mice are predisposed to hemodynamic stress and develop apoptotic cardiomyopathy with heart failure.
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Rnd3 单倍体不足的小鼠容易受到血流动力学应激并发展为伴有心力衰竭的凋亡性心肌病
DOI：
10.1038/cddis.2014.235
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发表时间：
2014-06-05
影响因子：
9
通讯作者：
Chang J
中科院分区：
文献类型：
--
作者：
Yue X;Yang X;Lin X;Yang T;Yi X;Dai Y;Guo J;Li T;Shi J;Wei L;Fan GC;Chen C;Chang J
Rho 家族鸟苷三磷酸酶 (GTPase) 3 (Rnd3) 是小 Rho GTPase 家族的成员，已被认为通过 Rho 激酶依赖性信号通路调节细胞肌动蛋白细胞骨架动力学、细胞迁移和细胞凋亡。 Rnd3 在心脏中的生物学功能尚不清楚。在终末期心力衰竭患者中发现小 GTPase Rnd3 转录物的下调。 Rnd3 缺失在心力衰竭转变过程中的病理意义尚未被探索。为了研究 Rnd3 下调的功能后果和相关的分子机制，我们生成了 Rnd3+/- 单倍体不足的小鼠，以模拟在衰竭的人类心脏中观察到的 Rnd3 下调。 Rnd3+/- 小鼠可存活；然而，小鼠在横向主动脉缩窄（TAC）压力超负荷后出现心力衰竭。在 Rnd3+/- 单倍体不足的动物心脏中检测到显着的细胞凋亡、caspase-3 活性增加和 Rho 激酶活性升高。法舒地尔治疗对 Rho 激酶的药理抑制部分改善了 Rnd3+/- 小鼠心脏功能并减弱了心肌细胞凋亡。为了确定 Rho 相关卷曲螺旋激酶 1 (ROCK1) 是否与 Rnd3 缺陷介导的凋亡性心肌病有关，我们建立了双敲除小鼠系，即具有 ROCK1 缺失背景的 Rnd3 单倍体不足小鼠 (Rnd3+/-/ROCK1−/−)。同样，ROCK1 的基因删除部分但不能完全挽救 Rnd3 缺陷介导的心力衰竭表型。这些数据表明，Rnd3 的下调与心力衰竭患者的心脏功能丧失相关。 Rnd3 单倍体不足的动物容易出现血流动力学应激。 Rho 激酶活性的过度激活是细胞凋亡性心肌病发展的部分原因。进一步研究 Rnd3 介导的心脏重塑中 ROCK1 独立机制应该是未来研究的重点。
Rho family guanosine triphosphatase (GTPase) 3 (Rnd3), a member of the small Rho GTPase family, has been suggested to regulate cell actin cytoskeleton dynamics, cell migration, and apoptosis through the Rho kinase-dependent signaling pathway. The biological function of Rnd3 in the heart is unknown. The downregulation of small GTPase Rnd3 transcripts was found in patients with end-stage heart failure. The pathological significance of Rnd3 loss in the transition to heart failure remains unexplored. To investigate the functional consequence of Rnd3 downregulation and the associated molecular mechanism, we generated Rnd3+/− haploinsufficient mice to mimic the downregulation of Rnd3 observed in the failing human heart. Rnd3+/− mice were viable; however, the mice developed heart failure after pressure overload by transverse aortic constriction (TAC). Remarkable apoptosis, increased caspase-3 activity, and elevated Rho kinase activity were detected in the Rnd3+/− haploinsufficient animal hearts. Pharmacological inhibition of Rho kinase by fasudil treatment partially improved Rnd3+/− mouse cardiac functions and attenuated myocardial apoptosis. To determine if Rho-associated coiled-coil kinase 1 (ROCK1) was responsible for Rnd3 deficiency-mediated apoptotic cardiomyopathy, we established a double-knockout mouse line, the Rnd3 haploinsufficient mice with ROCK1-null background (Rnd3+/−/ROCK1−/−). Again, genetic deletion of ROCK1 partially but not completely rescued Rnd3 deficiency-mediated heart failure phenotype. These data suggest that downregulation of Rnd3 correlates with cardiac loss of function as in heart failure patients. Animals with Rnd3 haploinsufficiency are predisposed to hemodynamic stress. Hyperactivation of Rho kinase activity is responsible in part for the apoptotic cardiomyopathy development. Further investigation of ROCK1-independent mechanisms in Rnd3-mediated cardiac remodeling should be the focus for future study.