Experimental and Clinical Studies on the Role of Inflammatory Mechanisms in the Pathogenesis of Ischemic Heart Disease

(实验研究)1.长期外膜注射IL-1β可导致猪在体冠状动脉血管重塑和新生内膜形成，而血管内皮扩张剂功能得到较好保护。在该猪模型中，诱导型一氧化氮合酶(INOS)在VSMC中瞬时表达，并在体内发挥抑制血管病变形成的作用。关于猪冠状动脉痉挛的分子机制，研究表明，Rho-Kinase上调并抑制肌球蛋白磷酸酶，导致肌球蛋白磷酸化增加和VSMC.4的过度收缩。我们已经建立了利用浸润性球囊血管成形术导管(IABC)将基因体内转移到冠状动脉内的方法。利用这种新的方法，我们能够通过在活体内过表达CNP来抑制猪冠状动脉球囊损伤后的新生内膜形成。长期应用Rho-K的特异性抑制剂--羟基法舒地尔抑制Rho-K，或体内基因转移显性阴性Rho-K，可逆转炎症细胞因子引起的血管重塑。临床研究表明，冠心病患者血浆巨噬细胞集落刺激因子(M-CSF)水平升高，转化因子-b(TGF-b)水平降低，从而刺激动脉粥样硬化的进程。

(Experimental studies)1. The long-term adventitial treatment with IL-1βresulted in the development of vascular remodeling and neointimal formation of the porcine coronary artery in vivo, whereas endothelial vasodilator functions were fairly preserved.2. In this porcine model, inducible NO synthase (iNOS) was transiently expressed in VSMC and exerted an inhibitory effect against vascular lesion formation in vivo.3. Regarding the molecular mechanism of the coronary artery spasm in this porcine model, it was shown that Rho-kinase is upregulated and inhibits myosin phosphatase, resulting in the increased myosin phosphorylations and hypercontractions of VSMC.4. We have established the method of in vivo gene transfer into the coronary artery in vivo using the infiltrator balloon angioplasty catheter (IABC). Using this novel method, we were able to inhibit the neointimal formation after balloon injury in porcine coronary arteries by overexpressing CNP in vivo.5. The long-term inhibitation of Rho-kinase by either hydroxyfasudil (a specific inhibitor of Rho-kinase) or in vivo gene transfer of dominant negative Rho-kinase resulted in the regression of vascular remodeling caused by inflammatory cytokines.(Clinical studies)In patients with coronary artery disease, the plasma levels of macrophage-colony stimulating factor (M-CSF) were increased while those of transforming factor-b (TGF-b) were decreased, thus stimulating the process of atherosclerosis.