Noma Kensuke, Rikitake Yoshiyuki, Oyama Naotsugu, Yan Guijun, Alcaide Pilar, Liu Ping-Yen, Wang Hongwei, Ahl Daniela, Sawada Naoki, Okamoto Ryuji, Hiroi Yukio, Shimizu Koichi, Luscinskas Francis W, Sun Jianxin, Liao James K
Vascular Medicine Research Unit, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
J Clin Invest. 2008 May;118(5):1632-44. doi: 10.1172/JCI29226.
Although Rho-associated kinase (ROCK) activity has been implicated in cardiovascular diseases, the tissue- and isoform-specific roles of ROCKs in the vascular response to injury are not known. To address the role of ROCKs in this process, we generated haploinsufficient Rock1 (Rock1(+/-)) and Rock2 (Rock2(+/-)) mice and performed carotid artery ligations. Following this intervention, we found reduced neointima formation in Rock1(+/-) mice compared with that of WT or Rock2(+/-) mice. This correlated with decreased vascular smooth muscle cell proliferation and survival, decreased levels proinflammatory adhesion molecule expression, and reduced leukocyte infiltration. In addition, thioglycollate-induced peritoneal leukocyte recruitment and accumulation were substantially reduced in Rock1(+/-) mice compared with those of WT and Rock2(+/-) mice. To determine the role of leukocyte-derived ROCK1 in neointima formation, we performed reciprocal bone marrow transplantation (BMT) in WT and Rock1(+/-) mice. Rock1(+/-) to WT BMT led to reduced neointima formation and leukocyte infiltration following carotid ligation compared with those of WT to WT BMT. In contrast, WT to Rock1(+/-) BMT resulted in increased neointima formation. These findings indicate that ROCK1 in BM-derived cells mediates neointima formation following vascular injury and suggest that ROCK1 may represent a promising therapeutic target in vascular inflammatory diseases.
尽管Rho相关激酶(ROCK)活性与心血管疾病有关,但ROCKs在血管损伤反应中的组织和亚型特异性作用尚不清楚。为了研究ROCKs在此过程中的作用,我们构建了Rock1(Rock1(+/-))和Rock2(Rock2(+/-))单倍体不足小鼠,并进行了颈动脉结扎。在该干预后,我们发现与野生型(WT)或Rock2(+/-)小鼠相比,Rock1(+/-)小鼠的新生内膜形成减少。这与血管平滑肌细胞增殖和存活减少、促炎粘附分子表达水平降低以及白细胞浸润减少相关。此外,与WT和Rock2(+/-)小鼠相比,Rock1(+/-)小鼠中巯基乙酸诱导的腹膜白细胞募集和积累显著减少。为了确定白细胞来源的ROCK1在新生内膜形成中的作用,我们在WT和Rock1(+/-)小鼠中进行了相互骨髓移植(BMT)。与WT到WT的BMT相比,Rock1(+/-)到WT的BMT导致颈动脉结扎后新生内膜形成和白细胞浸润减少。相反,WT到Rock1(+/-)的BMT导致新生内膜形成增加。这些发现表明骨髓来源细胞中的ROCK1介导血管损伤后的新生内膜形成,并提示ROCK1可能是血管炎性疾病中一个有前景的治疗靶点。