ROCK1 mediates leukocyte recruitment and neointima formation following vascular injury
ROCK1 mediates leukocyte recruitment and neointima formation following vascular injury
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DOI：
10.1172/jci29226
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发表时间：
2008-05-01
影响因子：
15.9
通讯作者：
Liao, James K.
中科院分区：
文献类型：
--
作者：
Noma, Kensuke;Rikitake, Yoshiyuki;Liao, James K.
尽管Rho相关激酶（ROCK）活性与心血管疾病有关，但ROCK在血管对损伤的反应中的组织特异性和亚型特异性作用尚不清楚。为了解决ROCK在这一过程中的作用，我们产生了单倍不足的Rock 1（Rock 1（+/-））和Rock 2（Rock 2（+/-））小鼠，并进行颈动脉结扎。在这种干预后，我们发现与WT或Rock 2（+/-）小鼠相比，Rock 1（+/-）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、促炎性粘附分子表达水平降低和白细胞浸润减少相关。此外，与WT和Rock 2（+/-）小鼠相比，Rock 1（+/-）小鼠中巯基乙酸盐诱导的腹膜白细胞募集和蓄积显著减少。为了确定白细胞衍生的ROCK 1在新生内膜形成中的作用，我们在WT和Rock 1（+/-）小鼠中进行了相互骨髓移植（BMT）。与WT-WT BMT相比，Rock 1（+/-）-WT 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至Rock 1（+/-）BMT导致新生内膜形成增加。这些发现表明，骨髓源性细胞中的ROCK 1介导血管损伤后的新生内膜形成，并表明ROCK 1可能代表血管炎性疾病中有前途的治疗靶点。
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.