Department of Molecular and Biomedical Pharmacology, University of Kentucky, Lexington, Kentucky, United States of America.
PLoS One. 2013 Sep 17;8(9):e73599. doi: 10.1371/journal.pone.0073599. eCollection 2013.
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.
心肌细胞通过增大和增强收缩功能来补偿急性心脏应激。然而，长期的应激会导致代偿失调的反应，表现为心肌细胞死亡、组织纤维化和心脏功能丧失。确定抑制这种向代偿失调反应转变的方法可能会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，受肥大刺激而上调。Ral 鸟嘌呤核苷酸解离刺激因子样 2（Rgl2）是 RalGDS 家族的一员，可调节心肌细胞中肥大基因的表达。然而，心肌细胞中 Rgl2 表达增加的病理生理后果尚不清楚。为了评估增加 Rgl2 活性对心脏的影响，生成了心脏靶向过表达 Rgl2 的转基因小鼠。尽管 Ral 激活增加，但 Rgl2 转基因和非转基因小鼠的心脏在形态或组织学上没有明显差异，表明增加的 Rgl2 表达对基础心脏表型没有影响。为了确定 Rgl2 是否调节心脏对应激的反应，用 β-肾上腺素能受体激动剂异丙肾上腺素对小鼠进行了输注。异丙肾上腺素输注增加了 Rgl2 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的是，在异丙肾上腺素输注后，Rgl2 转基因小鼠没有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 Rgl2 的表达刺激了 Ral 的激活，并通过增加 PI3-激酶的激活抑制了 staurosporine 诱导的细胞凋亡。在从 Rgl2 转基因小鼠分离的心脏中证实了 PI3-激酶信号通路的激活。心肌细胞中 Rgl2 的表达和功能增加促进了 PI3-激酶信号级联的激活，并保护心肌细胞免受死亡和病理性心肌纤维化的影响。更进一步，这些结果表明，在肥大心脏中 Rgl2 的上调可能是一种保护机制，Rgl2 可能是治疗心脏病的一个新的治疗靶点。
