Department of Cardiology, Tongren Municipal People's Hospital, Tongren, China.
Department of Cardiology, Zhongnan Hospital, Wuhan University, Wuhan, China; and.
J Cardiovasc Pharmacol. 2020 Aug;76(2):237-245. doi: 10.1097/FJC.0000000000000857.
As a receptor for transforming growth factor-β, nodal and activin, activin receptor-like kinase 7 (ALK7) previously acts as a suppressor of tumorigenesis and metastasis, which has emerged to play a key role in cardiovascular diseases. However, the potential effect and molecular mechanism of ALK7 on vascular smooth muscle cells' (VSMCs) phenotypic modulation have not been investigated. Using cultured mouse VSMCs with platelet-derived growth factor-BB administration, we observed that ALK7 showed a significantly increased expression in VSMCs accompanied by decreased VSMCs differentiation marker genes. Loss-of-function study demonstrated that ALK7 knockdown inhibited platelet-derived growth factor-BB-induced VSMCs phenotypic modulation characterized by increased VSMCs differentiation markers, reduced proliferation, and migration of VSMCs. Such above effects were reversed by ALK7 overexpression. Notably, we noticed that ALK7 silencing dramatically enhanced PPARγ expression, which was required for the attenuated effect of ALK7 knockdown on VSMCs phenotypic modulation. Collected, we identified that ALK7 acted as a novel and positive regulator for VSMCs phenotypic modulation partially through inactivation of PPARγ, which suggested that neutralization of ALK7 might act as a promising therapeutic strategy of intimal hyperplasia.
作为转化生长因子-β、 nodal 和激活素的受体，激活素受体样激酶 7（ALK7）先前作为肿瘤发生和转移的抑制剂发挥作用，现已成为心血管疾病的关键因素。然而，ALK7 对血管平滑肌细胞（VSMCs）表型调节的潜在作用和分子机制尚未得到研究。使用血小板衍生生长因子-BB 处理的培养的小鼠 VSMCs，我们观察到 ALK7 在 VSMCs 中表达显著增加，同时 VSMCs 分化标记基因减少。功能丧失研究表明，ALK7 敲低抑制了血小板衍生生长因子-BB 诱导的 VSMCs 表型调节，其特征是 VSMCs 分化标记物增加、VSMCs 增殖和迁移减少。ALK7 的过表达逆转了上述作用。值得注意的是，我们注意到 ALK7 沉默显著增强了 PPARγ 的表达，这是 ALK7 敲低减弱对 VSMCs 表型调节作用所必需的。综上所述，我们确定 ALK7 通过失活 PPARγ 部分充当 VSMCs 表型调节的新型阳性调节剂，这表明中和 ALK7 可能是内膜增生的一种有前途的治疗策略。
