Division of Molecular Medical Biochemistry, Department of Biochemistry and Molecular Biology, Shiga University of Medical Science, Otsu, Japan.
Department of Emergency, The Fourth Affiliated Hospital of China Medical University, Shenyang, China.
Commun Biol. 2022 Oct 7;5(1):1071. doi: 10.1038/s42003-022-04042-z.
Whether a small GTPase RhoA plays a role in the pathology of abdominal aortic aneurysm (AAA) has not been determined. We show here that RhoA expression is reduced in human AAA lesions, compared with normal areas. Furthermore, incidence of AAA formation is increased in vascular smooth muscle cell (VSMC)-specific RhoA conditional knockout (cKO) mice. The contractility of the aortic rings and VSMCs from RhoA cKO mice is reduced, and expression of genes related to the VSMC contractility is attenuated by loss of RhoA. RhoA depletion activates the mitogen-activated protein (MAP) kinase signaling, including MAP4K4, in the aorta and VSMCs. Inhibition of MAP4K4 activity by DMX-5804 decreases AAA formation. Set, a binding protein to active RhoA, functions as an activator of MAP4K4 by sequestering PP2A, an inhibitor of MAP4K4, in the absence of RhoA. In conclusion, RhoA counteracts AAA formation through inhibition of MAP4K4 in cooperation with Set.
尚未确定小分子 GTPase RhoA 是否在腹主动脉瘤 (AAA) 的病理学中发挥作用。我们在这里显示，与正常区域相比，RhoA 在人 AAA 病变中的表达减少。此外，血管平滑肌细胞 (VSMC) 特异性 RhoA 条件性敲除 (cKO) 小鼠中 AAA 形成的发生率增加。RhoA cKO 小鼠的主动脉环和 VSMC 的收缩性降低，并且 RhoA 的缺失减弱了与 VSMC 收缩性相关的基因的表达。RhoA 耗竭激活了 MAP 激酶信号通路，包括 MAP4K4，在主动脉和 VSMCs 中。通过 DMX-5804 抑制 MAP4K4 活性可减少 AAA 的形成。Set 是一种与活性 RhoA 结合的结合蛋白，通过在没有 RhoA 的情况下将 PP2A（MAP4K4 的抑制剂）隔离在体内，充当 MAP4K4 的激活剂。总之，RhoA 通过与 Set 合作抑制 MAP4K4 来拮抗 AAA 的形成。
