p21-activated kinase 1 participates in vascular remodeling in vitro and in vivo.
p21-activated kinase 1 participates in vascular remodeling in vitro and in vivo.
复制标题
P21激活的激酶1参与体外和体内的血管重塑。
DOI：
10.1161/hypertensionaha.109.143057
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发表时间：
2010-01
期刊：
影响因子：
--
通讯作者：
Eguchi S
中科院分区：
文献类型：
--
作者：
Hinoki A;Kimura K;Higuchi S;Eguchi K;Takaguri A;Ishimaru K;Frank GD;Gerthoffer WT;Sommerville LJ;Autieri MV;Eguchi S
高血压、动脉粥样硬化和血管成形术后再狭窄时血管平滑肌细胞肥大、增殖或迁移，导致病理生理性血管重构。血管紧张素II和血小板衍生生长因子是众所周知的血管重构的参与者，并激活无数的下游蛋白激酶，包括PAK1。PAK1是一种小gtpase的效应激酶，磷酸化几种底物来调节细胞骨架重组。然而，PAK1激活在血管重构中的确切作用仍有待阐明。在这里，我们假设PAK1是预防血管重构干预的关键靶点。腺病毒表达显性阴性PAK1抑制血管紧张素II和血小板衍生生长因子刺激的血管平滑肌细胞迁移。对血小板源性生长因子诱导的血管平滑肌细胞增殖也有抑制作用。PAK1在大鼠颈动脉球囊损伤后的新生内膜中被激活。PAK1腺病毒阳性阴性处理的颈动脉球囊损伤后，新生内膜增生明显受到抑制。综上所述，这些结果表明PAK1参与血管紧张素II和血小板源性生长因子介导的VSMC重塑，体内PAK1的失活可能有效预防病理性血管重塑。
Vascular smooth muscle cell hypertrophy, proliferation or migration occurs in hypertension, atherosclerosis and restenosis after angioplasty leading to pathophysiological vascular remodeling. Angiotensin II and platelet-derived growth factor are well known participants of vascular remodeling, and activate a myriad of downstream protein kinases including PAK1. PAK1, an effector kinase of small GTPases, phosphorylates several substrates to regulate cytoskeletal reorganization. However, the exact role of PAK1 activation in vascular remodeling remains to be elucidated. Here, we have hypothesized that PAK1 is a critical target of intervention for prevention of vascular remodeling. Adenoviral expression of dominant-negative PAK1 inhibited both angiotensin II- and platelet-derived growth factor-stimulated vascular smooth muscle cell migration. It also inhibited vascular smooth muscle cell proliferation induced by platelet-derived growth factor. PAK1 was activated in neointima of the carotid artery after balloon injury in rat. Moreover, marked inhibition of the neointima hyperplasia was observed in dominant-negative PAK1 adenovirus treated carotid artery after the balloon injury. Taken together, these results suggest that PAK1 is involved in both angiotensin II and platelet-derived growth factor mediated VSMC remodeling, and inactivation of PAK1 in vivo could be effective in preventing pathophysiological vascular remodeling.