The ral exchange factor rgl2 promotes cardiomyocyte survival and inhibits cardiac fibrosis.
The ral exchange factor rgl2 promotes cardiomyocyte survival and inhibits cardiac fibrosis.
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DOI：
10.1371/journal.pone.0073599
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Post SR
中科院分区：
文献类型：
--
作者：
Scotland RL;Allen L;Hennings LJ;Post GR;Post SR
心肌细胞通过增加体积和收缩功能来补偿急性心脏应激。然而，长时间的应激导致以心肌细胞死亡、组织纤维化和心脏功能丧失为特征的失代偿反应。确定抑制这种向失代偿反应转变的方法可能揭示治疗心力衰竭的重要靶点。Ral鸟嘌呤核苷酸解离（RalGDS）蛋白是Ras相互作用蛋白，其被肥大刺激上调。Ral鸟嘌呤核苷酸解离刺激因子样2（Rgl 2）是调节心肌细胞中肥大基因表达的RalGDS家族的成员。然而，心肌细胞中Rgl 2表达增加的病理生理后果仍不清楚。为了评估增加心脏中Rgl 2活性的作用，产生了具有心脏靶向的Rgl 2过表达的转基因小鼠。虽然Ral激活增加，但Rgl 2转基因小鼠和非转基因小鼠的心脏之间没有明显的形态学或组织学差异，表明Rgl 2表达增加对基础心脏表型没有影响。为了确定Rg 12是否调节心脏对应激的反应，向小鼠输注β-肾上腺素能受体激动剂异丙肾上腺素。异丙肾上腺素输注增加Rgl 2转基因和非转基因小鼠的心脏质量。然而，与非转基因小鼠不同，Rgl 2转基因小鼠在输注异丙肾上腺素后没有表现出心肌细胞损伤或心脏纤维化增加的形态学证据。在培养的心肌细胞中增加Rg 12表达刺激Ral活化，并通过增加PI 3-激酶的活化抑制星形孢菌素诱导的细胞凋亡。在从Rgl 2转基因小鼠分离的心脏中证实了PI 3-激酶信号传导途径的激活。心肌细胞中Rgl 2表达和功能的增加促进PI 3-激酶信号级联的激活，并保护免于心肌细胞死亡和病理性心脏纤维化。进一步，这些结果表明，Rgl 2在肥大心脏中的上调可能是一种保护机制，并且Rgl 2可能是治疗心脏疾病的新的治疗靶点。
Cardiomyocytes compensate to acute cardiac stress by increasing in size and contractile function. However, prolonged stress leads to a decompensated response characterized by cardiomyocyte death, tissue fibrosis and loss of cardiac function. Identifying approaches to inhibit this transition to a decompensated response may reveal important targets for treating heart failure. The Ral guanine nucleotide disassociation (RalGDS) proteins are Ras-interacting proteins that are upregulated by hypertrophic stimuli. The Ral guanine nucleotide dissociation stimulator-like 2 (Rgl2) is a member of the RalGDS family that modulates expression of hypertrophic genes in cardiomyocytes. However, the pathophysiologic consequence of increased Rgl2 expression in cardiomyoctyes remains unclear. To evaluate the effect of increasing Rgl2 activity in the heart, transgenic mice with cardiac-targeted over-expression of Rgl2 were generated. Although Ral activation was increased, there were no apparent morphologic or histological differences between the hearts of Rgl2 transgenic and nontransgenic mice indicating that increased Rgl2 expression had no effect on basal cardiac phenotype. To determine if Rgl2 modulates the cardiac response to stress, mice were infused with the ß-adrenergic receptor agonist, isoproterenol. Isoproterenol infusion increased heart mass in both Rgl2 transgenic and nontransgenic mice. However, unlike nontransgenic mice, Rgl2 transgenic mice showed no morphologic evidence of cardiomyocyte damage or increased cardiac fibrosis following isoproterenol infusion. Increased Rgl2 expression in cultured cardiomyocytes stimulated Ral activation and inhibited staurosporine-induced apoptosis via increased activation of PI3-kinase. Activation of the PI3-kinase signaling pathway was confirmed in hearts isolated from Rgl2 transgenic mice. Increased expression and function of Rgl2 in cardiomyocytes promotes activation of the PI3-kinase signaling cascade and protects from carciomyocyte death and pathologic cardiac fibrosis. Taken further, these results suggest that Rgl2 upregulation in hypertrophic hearts may be a protetive mechanism, and that Rgl2 may be a novel therapeutic target in treating heart disease.
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