vasostatin-2对糖尿病和非糖尿病动脉粥样硬化的干预及其机制研究

The studies have been scarce regarding inhibiting atherosclerosis with physiological elements. We found that chromogranin A (CgA)-derived vasostatin-2 inhibited TNF-alpha, Ang II and oxLDL-induced expression of adhesive molecules (ICAM-1, VCAM-1 and E-selectin) in human aortic endothelial cells and abrogated TNF-alpha-induced adhesion of monocyte U937 to endothelial cells. Serum levels of vasostatin-2 were significantly decreased in diabetic patients and patients with coronary artery disease, and further declined in patients with both diabetes and coronary artery disease. Moreover, the protein levels of vasostatin-2 were obviously lower in endarterectomy and atherosclerotic aortic samples from patients severe coronary artery disease undergoing CABG than in non-atherosclerotic arteries. In animal study of apoE-KO, intra-peritoneal injection of recombinant vasostatin-2 every other day for 24 weeks remarkably attenuated aortic atherosclerosis. Collectively, these results indicate that vaostatin-2 has anti-atherosclerotic effects, and these protective effects are mitigated due to decreased level in patients...Thus, we will validate in next studies the inhibition of vasostatin-2 on atheroclerosis in apoE-KO mice with and without diabetes, and dissect the mechanisms. We will test whether vasostatin-2 display synergistic effects with combination of other CgA-derived peptides, such as catestatin.

运用自身生理性成分来干预动脉粥样硬化发生进展的研究很少。我们发现Chromogranin A(CgA)降解产物vasostatin-2能够拮抗TNF-a、Ang II和oxLDL促内皮细胞黏附分子表达和抑制单核细胞体外黏附。冠心病和糖尿病患者血清vasostatin-2水平较正常对照显著降低，糖尿病合并冠心病患者更低。冠心病患者冠脉剥脱内膜和粥样硬化主动脉中vasostatin-2水平较正常动脉显著降低。ApoE-KO小鼠腹腔隔日注射重组vasostatin-2蛋白24周显著抑制动脉粥样硬化发生。结合文献提示vasostatin-2具抗动脉粥样硬化作用，其保护作用因在冠心病糖尿病中显著降低而削弱。后续研究将验证和明确vasostatin-2对糖尿病和非糖尿病动脉粥样硬化的干预作用，及vasostatin-2与CgA其他降解产物的协同效应。挖掘vasostatin-2的作用位点，阐明机制。

运用自身生理性成分来干预动脉粥样硬化发生进展的研究很少，本小组开展动脉动脉粥样硬化保护因素的研究。脂肪因子Chromogranin A（CgA）蛋白广泛存在于内分泌、神经系统和心血管系统组织的分泌细胞中。生理情况下，CgA能被蛋白酶或纤溶酶降解形成约10个肽段，包括：vasostatin-1 (人CgA1-76)、vasostatin-2 (人CgA1-113)、chromacin (人CgA173-194)、pancreastatin (人CgA 250-301)和catestatin (人CgA 352-372)等。我们发现vasostatin-2能够拮抗TNF-a、Ang II和oxLDL促内皮细胞黏附分子表达和抑制单核细胞体外黏附。冠心病和糖尿病患者血清vasostatin-2水平较正常对照显著降低，糖尿病合并冠心病患者更低。冠心病患者冠脉剥脱内膜和粥样硬化主动脉中vasostatin-2水平较正常动脉显著降低。ApoE-KO小鼠腹腔隔日注射重组vasostatin-2蛋白24周显著抑制动脉粥样硬化发生。表明vasostatin-2具抗动脉粥样硬化作用，其保护作用因在冠心病糖尿病中显著降低而削弱。我们体内和体外研究发现vasostatin-2能够通过抑制单核巨噬细胞的迁移，来干预炎性细胞对血管壁的滞留和向泡沫细胞的转变，并阐明vasostatin-2抑制Rac1通路而产生上述效应的机制。