Catestatin蛋白肽段抑制动脉粥样硬化的作用及机制研究

Current understanding regarding the factors of vascular protection and anti-atherosclerosis remains largely limited. Catestatin, a peptide derived from adipokine Chromogranin A, can restrain catecholamine secretion, lower blood pressure and protect cardiac function. In our previous study, serum Catestatin levels were significantly lower in atherosclerotic vascular tissues and patients with coronary artery disease than in non-atherosclerotic vascular tissues and normal controls, respectively. In vitro experiments, Catestatin inhibited the inflammation and the expression of adhesion molecules in vascular endothelial cells, and decreased the adhesion of monocytoid cells to endothelial cells. Moreover, this protein reduced the inflammation, migration, and lipid intake in macrophages. These results jointly indicate that Catestatin has anti-atherosclerosis effects, and its function, is to some extent, attenuated in the atherogenesis. Catestatin can inhibit G-protein signaling activity. Since there is a close interaction between G-protein coupled receptors and Toll-like receptor downstream signaling, future in vivo and in vitro experiments will ascertain; (1) whether Catestatin can inhibit atherosclerosis in apoE-/- mice fed high-fat chow; (2) whether Catestatin can inhibit the atherosclerotic process aggravated by activated TLR-4 and TLR-2 pathways; (3)the impacts of Catestatin on G-protein coupled receptors, Toll-like receptor pathway and other important signaling pathways, as well as the downstream inflammatory factors and matrix metalloproteinases; (4) novel partners of Catestatin by coprecipitation - mass spectrum approach, which lay down the basis for the future translational research and clinical application.

脂肪因子Chromogranin A降解肽段Catestatin能抑制儿茶酚胺分泌，保护血管和心肌，但可否拮抗动脉粥样硬化不明。前期我们发现，动脉粥样硬化血管组织和冠心病患者血浆Catestatin水平低于非病变血管和健康人群；Catestatin抑制血管内皮细胞炎症、粘附分子表达和淋巴细胞粘附，降低单核巨噬细胞的炎症、迁移和吞脂反应。提示Catestatin能拮抗动脉粥样硬化，但在粥样硬化发病中其保护作用被削弱。后续体内体外研究将探讨（1）Catestatin能否抑制高脂饲养apoE-KO小鼠的动脉粥样硬化；（2）因Catestatin所抑制的GPCR通路与促动脉粥样硬化TLR通路有关，Catestatin能否拮抗因TLR-4和TLR-2通路活性增高而加重的动脉粥样硬化；（3）Catestatin对GPCR、TLR等通路途径及下游致病成分的影响；（4）挖掘Catestatin作用新位点。

研究背景：蛋白肽段Catestatin (以下简称CST)是嗜铬蛋白A (Chromogranin A, CgA)的降解肽段，为内源性烟碱型乙酰胆碱受体拮抗剂，并在多种心血管疾病中展现出广泛的心血管保护效应。本研究将探究CST与冠状动脉粥样硬化疾病之间的相关性并对潜在机制作进一步探究。.主要研究方法和结果：本研究比较了224名冠心病患者与204名健康人群的血清CST水平，并在921名冠心病患者中对血清CST水平与冠脉病变严重程度作进一步探究。结果发现，冠心病患者的血清CST水平显著低于健康人群，且血清CST水平的降低程度与冠脉病变的严重程度呈正相关（P<0.05）。在后续的细胞实验中我们发现，CST可通过增加内皮细胞内源性血管紧张素转化酶2的表达水平来抑制肿瘤坏死因子-α介导的炎症因子和粘附分子的表达。上述效应在在体的体内外实验中被进一步证实，CST不仅可削弱炎症环境下内皮细胞与白细胞的相互作用还可延缓斑块的生长，而该保护性效应可被血管紧张素转化酶2抑制剂所抵消。.研究意义：该研究首次发现血清CST水平可作为反应冠脉病变严重程度的重要生物学指标并对粥样硬化的血管具有保护作用，而该保护性效应主要通过血管紧张素转化酶2所介导。血管紧张素转化酶2和儿茶酚胺分别是是肾素-血管紧张素-醛固酮系统和交感神经系统中的两名关键成员，CST作为联结两大系统的关键效应蛋白，可能会成为未来冠心病治疗当中的重要靶点，为未来冠心病的治疗提供新的临床诊疗思路。