目的:病理性心脏重构,包括心脏肥大和纤维化,是心力衰竭发展的关键病理过程。然而,有效的治疗方法是有限的。β-肾上腺素能受体是调节心脏功能的关键信号分子。G-α相互作用蛋白(GAIP)-相互作用蛋白,C末端1(GIPC1)是一种多功能支架蛋白,可直接与β1-肾上腺素能受体(β1-肾上腺素能受体)的C末端结合。然而,人们对它在心脏功能中的作用知之甚少。因此,我们研究了GIPC1在心脏重塑中的作用及其潜在的分子机制.
方法:通过腹膜内注射异丙肾上腺素14d或横向主动脉缩窄手术8周建立小鼠病理性心脏重塑。使用Myh6驱动的心肌细胞特异性GIPC1条件敲除(GIPC1cKO)小鼠和腺相关病毒9(AAV9)介导的GIPC1过表达小鼠。使用超声心动图评估GIPC1对心脏重塑的影响,组织学,和生化分析。
结果:GIPC1表达在心脏重塑模型中持续降低。GIPC1cKO小鼠表现出自发性异常,包括心脏肥大,纤维化,和收缩功能障碍.相比之下,AAV9介导的GIPC1在心脏中的过表达减弱了异丙肾上腺素诱导的小鼠病理性心脏重塑。机械上,GIPC1与β1-肾上腺素能受体相互作用,并通过阻止其泛素化和降解来稳定其表达,维持β1-肾上腺素受体/β2-肾上腺素受体的平衡,并抑制丝裂原活化蛋白激酶信号通路的过度活化。
结论:这些结果表明GIPC1具有心脏保护作用,是治疗心脏重塑和心力衰竭的一个有希望的治疗靶点。
OBJECTIVE: Pathological cardiac remodelling, including cardiac hypertrophy and fibrosis, is a key pathological process in the development of heart failure. However, effective therapeutic approaches are limited. The β-adrenergic receptors are pivotal signalling molecules in regulating cardiac function. G-alpha interacting protein (GAIP)-interacting protein, C-terminus 1 (GIPC1) is a multifunctional scaffold protein that directly binds to the C-terminus of β1-adrenergic receptor (β1-adrenergic receptor). However, little is known about its roles in heart function. Therefore, we investigated the role of GIPC1 in cardiac remodelling and its underlying molecular mechanisms.
METHODS: Pathological cardiac remodelling in mice was established via intraperitoneal injection of isoprenaline for 14 d or transverse aortic constriction surgery for 8 weeks. Myh6-driving cardiomyocyte-specific GIPC1 conditional knockout (GIPC1 cKO) mice and adeno-associated virus 9 (AAV9)-mediated GIPC1 overexpression mice were used. The effect of GIPC1 on cardiac remodelling was assessed using echocardiographic, histological, and biochemical analyses.
RESULTS: GIPC1 expression was consistently reduced in the cardiac remodelling model. GIPC1 cKO mice exhibited spontaneous abnormalities, including cardiac hypertrophy, fibrosis, and systolic dysfunction. In contrast, AAV9-mediated GIPC1 overexpression in the heart attenuated isoproterenol-induced pathological cardiac remodelling in mice. Mechanistically, GIPC1 interacted with the β1-adrenergic receptor and stabilised its expression by preventing its ubiquitination and degradation, maintaining the balance of β1-adrenergic receptor/β2-adrenergic receptor, and inhibiting hyperactivation of the mitogen-activated protein kinase signalling pathway.
CONCLUSIONS: These results suggested that GIPC1 plays a cardioprotective role and is a promising therapeutic target for the treatment of cardiac remodelling and heart failure.