Division of Molecular Medical Biochemistry, Department of Biochemistry and Molecular Biology, Shiga University of Medical Science, Seta Tsukinowa-cho, Otsu, Shiga 520-2192, Japan.
Department of Molecular Biology, Osaka Medical Center for Cancer and Cardiovascular Disease, 1-3-3 Nakamichi, Higashinari-ku, Osaka 537-8511, Japan.
Sci Rep. 2017 Jan 3;7:39335. doi: 10.1038/srep39335.
Adhesive intercellular connections at cardiomyocyte intercalated disks (IDs) support contractile force and maintain structural integrity of the heart muscle. Disturbances of the proteins at IDs deteriorate cardiac function and morphology. An adaptor protein afadin, one of the components of adherens junctions, is expressed ubiquitously including IDs. At present, the precise role of afadin in cardiac physiology or disease is unknown. To explore this, we generated conditional knockout (cKO) mice with cardiomyocyte-targeted deletion of afadin. Afadin cKO mice were born according to the expected Mendelian ratio and have no detectable changes in cardiac phenotype. On the other hand, chronic pressure overload induced by transverse aortic constriction (TAC) caused systolic dysfunction, enhanced fibrogenesis and apoptosis in afadin cKO mice. Afadin deletion increased macrophage infiltration and monocyte chemoattractant protein-1 expression, and suppressed transforming growth factor (TGF) β receptor signaling early after TAC procedure. Afadin also associated with TGFβ receptor I at IDs. Pharmacological antagonist of TGFβ receptor I (SB431542) augmented mononuclear infiltration and fibrosis in the hearts of TAC-operated control mice. In conclusion, afadin is a critical molecule for cardiac protection against chronic pressure overload. The beneficial effects are likely to be a result from modulation of TGFβ receptor signaling pathways by afadin.
细胞间黏附连接位于心肌细胞闰盘（IDs），支持收缩力并维持心肌的结构完整性。IDs 中蛋白质的紊乱会恶化心脏功能和形态。黏着连接的组成部分之一连接黏附蛋白 afadin 是一种普遍表达的衔接蛋白，包括 IDs。目前，afadin 在心脏生理学或疾病中的精确作用尚不清楚。为了探索这一点，我们生成了具有心肌细胞靶向 afadin 缺失的条件性敲除（cKO）小鼠。afadin cKO 小鼠按照预期的孟德尔比例出生，心脏表型没有可检测到的变化。另一方面，横主动脉缩窄（TAC）引起的慢性压力超负荷导致 afadin cKO 小鼠的收缩功能障碍、纤维化和细胞凋亡增强。afadin 缺失增加了巨噬细胞浸润和单核细胞趋化蛋白-1 的表达，并在 TAC 手术后早期抑制转化生长因子（TGF）β受体信号。afadin 还与 IDs 处的 TGFβ 受体 I 相关。TGFβ 受体 I 的药理学拮抗剂（SB431542）增强了 TAC 手术对照小鼠心脏中的单核细胞浸润和纤维化。总之，afadin 是心脏抵抗慢性压力超负荷的关键分子。afadin 通过调节 TGFβ 受体信号通路产生有益作用。
