Morishige K, Shimokawa H, Eto Y, Hoshijima M, Kaibuchi K, Takeshita A
Department of Cardiovascular Medicine, Kyushu University, Graduate School of Medical Sciences, Fukuoka, Japan.
Ann N Y Acad Sci. 2001 Dec;947:407-11. doi: 10.1111/j.1749-6632.2001.tb03974.x.
Small GTPase Rho and its target Rho-kinase play an important role in various cellular functions that may be involved in the pathogenesis of arteriosclerosis. Here we show that adenovirus-mediated transfer of dominant-negative Rho-kinase (AdDNRhoK) induces a regression of coronary constrictive remodeling and abolishes coronary vasospastic activity in vivo. Porcine coronary segments were chronically treated with interleukin-1,beta which resulted in the development of constrictive remodeling and vasospastic responses to serotonin in vivo. AdDNRhoK, but not that of beta-galactosidase, into the interleukin-1beta-treated coronary segment caused regression of constrictive remodeling and abolished vasospastic activity in 3 weeks. The unregulated phosphorylation of the target proteins of Rho-kinase at the coronary lesion was significantly suppressed by AdDNRhoK. These results indicate that Rho-kinase is substantially involved in the mechanism of coronary arteriosclerosis, which can be reversed by selective inhibition of the molecule in our porcine model in vivo.
小GTP酶Rho及其靶标Rho激酶在各种细胞功能中发挥重要作用，这些功能可能参与了动脉粥样硬化的发病机制。在此我们表明，腺病毒介导的显性负性Rho激酶（AdDNRhoK）转移可诱导冠状动脉缩窄性重塑的消退，并在体内消除冠状动脉痉挛活性。用白细胞介素-1β长期处理猪冠状动脉段，导致体内出现缩窄性重塑和对5-羟色胺的血管痉挛反应。将AdDNRhoK而非β-半乳糖苷酶导入经白细胞介素-1β处理的冠状动脉段，可在3周内使缩窄性重塑消退并消除血管痉挛活性。AdDNRhoK可显著抑制冠状动脉病变处Rho激酶靶蛋白的失控磷酸化。这些结果表明，Rho激酶在冠状动脉粥样硬化机制中起重要作用，在我们的猪体内模型中，通过对该分子的选择性抑制可使其逆转。
