Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China; Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, China; Department of Scientific Research, The Fourth Affiliated Hospital, Harbin Medical University, Harbin, China.
Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China; Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, China.
Eur J Pharmacol. 2024 May 15;971:176488. doi: 10.1016/j.ejphar.2024.176488. Epub 2024 Mar 7.
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.
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.
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.
These results suggested that GIPC1 plays a cardioprotective role and is a promising therapeutic target for the treatment of cardiac remodelling and heart failure.
病理性心脏重构，包括心肌肥厚和纤维化，是心力衰竭发展的关键病理过程。然而，有效的治疗方法有限。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 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 端结合。然而，其在心脏功能中的作用知之甚少。因此，我们研究了 GIPC1 在心脏重构中的作用及其潜在的分子机制。
通过腹腔注射异丙肾上腺素 14 天或横主动脉缩窄术 8 周建立小鼠病理性心脏重构模型。使用肌球蛋白重链 6（Myh6）驱动的心肌细胞特异性 GIPC1 条件性敲除（GIPC1 cKO）小鼠和腺相关病毒 9（AAV9）介导的 GIPC1 过表达小鼠。通过超声心动图、组织学和生化分析评估 GIPC1 对心脏重构的影响。
在心脏重构模型中，GIPC1 的表达持续降低。GIPC1 cKO 小鼠表现出自发异常，包括心肌肥厚、纤维化和收缩功能障碍。相反，AAV9 介导的心脏中 GIPC1 的过表达减轻了异丙肾上腺素诱导的小鼠病理性心脏重构。机制上，GIPC1 与β1-肾上腺素能受体相互作用，通过防止其泛素化和降解稳定其表达，维持β1-肾上腺素能受体/β2-肾上腺素能受体的平衡，并抑制丝裂原活化蛋白激酶信号通路的过度激活。
这些结果表明，GIPC1 发挥心脏保护作用，是治疗心脏重构和心力衰竭的有前途的治疗靶点。
