Division of Molecular Medical Biochemistry, Department of Biochemistry and Molecular Biology, Shiga University of Medical Science.
Circ J. 2017 Nov 24;81(12):1862-1870. doi: 10.1253/circj.CJ-17-0394. Epub 2017 Jun 28.
Pressure overload induces cardiac hypertrophy, which often ends in heart failure. Afadin is an adaptor protein that is ubiquitously expressed and, in the heart, it localizes at intercalated disks. The current study aimed to examine the afadin-mediated cardiac phenotype in mice exposed to different types of pressure overload: transverse aortic constriction (TAC) burden and angiotensin II (Ang II) stimulation.Methods and Results:Conditional knockout mice with selective deletion of afadin (afadin cKO) in cardiomyocytes were generated. TAC-operated and Ang II-infused mice at 4 weeks had a similar degree of pressure overload and cardiac hypertrophy in the heart. In afadin cKO mice, TAC operation caused progressive left ventricular dysfunction and heart failure, while Ang II infusion did not deteriorate cardiac function. Furthermore, TAC operation produced more fibrosis and apoptosis in the heart than Ang II infusion, and the expression of growth differentiation factor 15, which can promote apoptosis, in the afadin cKO heart was higher in TAC-operated mice than Ang II-infused ones.
In the 2 pressure overload models, myocardial afadin is involved in mechanical stress-induced, but not pharmacological Ang II-related, compensated cardiac hypertrophy.
压力超负荷可导致心肌肥厚，进而常引发心力衰竭。黏附蛋白 afadin 是一种广泛表达的衔接蛋白，在心脏中，它定位于闰盘。本研究旨在研究不同类型压力超负荷（主动脉缩窄[TAC]和血管紧张素 II[Ang II]刺激）下 afadin 介导的心脏表型。
生成了心肌细胞中 afadin 选择性缺失的条件性敲除小鼠（afadin cKO）。在 4 周时，TAC 手术和 Ang II 输注的小鼠具有相似程度的心脏压力超负荷和心肌肥厚。在 afadin cKO 小鼠中，TAC 手术导致进行性左心室功能障碍和心力衰竭，而 Ang II 输注并未使心脏功能恶化。此外，与 Ang II 输注相比，TAC 手术在心脏中产生了更多的纤维化和细胞凋亡，并且在 TAC 手术的 afadin cKO 心脏中，促凋亡的生长分化因子 15 的表达高于 Ang II 输注的心脏。
在这 2 种压力超负荷模型中，心肌 afadin 参与了机械应激诱导的、而非药理学 Ang II 相关的代偿性心肌肥厚。
