Rnd3/RhoE Modulates Hypoxia-Inducible Factor 1α/Vascular Endothelial Growth Factor Signaling by Stabilizing Hypoxia-Inducible Factor 1α and Regulates Responsive Cardiac Angiogenesis.
Rnd3/RhoE Modulates Hypoxia-Inducible Factor 1α/Vascular Endothelial Growth Factor Signaling by Stabilizing Hypoxia-Inducible Factor 1α and Regulates Responsive Cardiac Angiogenesis.
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DOI：
10.1161/hypertensionaha.115.06412
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发表时间：
2016-03
期刊：
影响因子：
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通讯作者：
Chang J
中科院分区：
文献类型：
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作者：
Yue X;Lin X;Yang T;Yang X;Yi X;Jiang X;Li X;Li T;Guo J;Dai Y;Shi J;Wei L;Youker KA;Torre-Amione G;Yu Y;Andrade KC;Chang J
高血压患者心脏代偿性血管生成不足是导致心力衰竭转变的重要原因。HIF 1 α-VEGF信号级联控制响应性血管生成。重新编程血管生成不足的挑战之一是实现可持续的组织暴露于促血管生成因子，如HIF 1 α稳定化。在这项研究中，我们确定了Rnd 3，一个小的Rho GTd 3，作为一个促血管生成因子参与调节HIF 1 α-VEGF信号级联。Rnd 3与HIF 1 α相互作用并稳定HIF 1 α，从而促进VEGFA表达和内皮细胞管形成。为了证明Rnd 3在体内的促血管生成作用，我们产生了Rnd 3敲除小鼠。Rnd 3单倍不足（Rnd 3 +/−）小鼠存活，但在横向主动脉收缩应激后发生扩张型心肌病伴心力衰竭。应激后Rnd 3 +/−心脏显示血管生成显著受损，HIF 1 α和VEGFA表达降低。血管生成缺陷和心力衰竭表型被氯化钴治疗（一种HIF 1 α稳定剂）部分挽救，证实了Rnd 3在应激反应性血管生成中的关键作用。此外，我们产生了Rnd 3转基因小鼠，并证明Rnd 3在心脏中的过表达具有心脏保护作用，通过保留心脏功能和保留压力超负荷后的响应性血管生成。最后，我们评估了Rnd 3在人类心脏中的表达水平，并检测到终末期心力衰竭患者中Rnd 3的显著下调。我们的结论是，Rnd 3作为一种新的促血管生成因子，通过HIF 1 α-VEGFA信号促进心脏反应性血管生成。在心力衰竭患者中观察到的rnd 3下调可能解释了在心力衰竭转变中参与的代偿性血管生成不足。
The insufficiency of compensatory angiogenesis in the heart of hypertension patients contributes to heart failure transition. The HIF1α-VEGF signaling cascade controls responsive angiogenesis. One of the challenges in reprograming the insufficient angiogenesis is to achieve a sustainable tissue exposure to the pro-angiogenic factors, such as HIF1α stabilization. In this study, we identified Rnd3, a small Rho GTPase, as a pro-angiogenic factor participating in the regulation of the HIF1α-VEGF signaling cascade. Rnd3 physically interacted with and stabilized HIF1α, and consequently promoted VEGFA expression and endothelial cell tube formation. To demonstrate this pro-angiogenic role of Rnd3 in vivo, we generated Rnd3 knockout mice. Rnd3 haploinsufficient (Rnd3+/−) mice were viable, yet developed dilated cardiomyopathy with heart failure after transverse aortic constriction stress. The post-stress Rnd3+/− hearts showed significantly impaired angiogenesis and decreased HIF1α and VEGFA expression. The angiogenesis defect and heart failure phenotype were partially rescued by cobalt chloride treatment, a HIF1α stabilizer, confirming a critical role of Rnd3 in stress-responsive angiogenesis. Furthermore, we generated Rnd3 transgenic mice and demonstrated that Rnd3 overexpression in heart had a cardio-protective effect through reserved cardiac function and preserved responsive angiogenesis after pressure overload. Finally, we assessed the expression levels of Rnd3 in the human heart and detected significant downregulation of Rnd3 in patients with end-stage heart failure. We concluded that Rnd3 acted as a novel pro-angiogenic factor involved in cardiac responsive angiogenesis through HIF1α-VEGFA signaling promotion. Rnd3 downregulation observed in heart failure patients may explain the insufficient compensatory angiogenesis involved in the transition to heart failure.