Study Of The Mechanisam Of Coronary Artery Ectasia

[Background] Along with the development of imaging technology of coronary artery, coronary artery ectasia (CAE) was known by more and more people, its prevalence was low but the absolute number of patients was huge. Its main manifestations were untypical chest pain, activity intolerance and even acute corornary events, it seriously threaten people’s health and life, but at present it was lack of specific treatment measures because the exact etiology and pathogenesis of CAE were still elusive. Thus study on the pathogenesis of CAE would move forward our understanding of CAE and contribute to the development of new treatment strategies, so as to relieve the clinical symptoms of the patients and improve their long-term prognosis.[Objective] Because of characteristic pathological manifestations of the CAE was the severe damage of extracellular matrix (ECM) components in coronary walls, we put forward a hypothesis that the proteases might play vital roles in the pathological process of CAE because the proteases usually served as the final executors of ECM degradation in lots of diseases. This study intended to answer the following questions:1) what were the characteristic changes of ECM metabolism in CAE? 2) did the proteases participate in the abnormal ECM metabolism process in CAE? 3) what was the sources of the proteases relaing to CAE? 4) were there endogenous substances which could regulate these enzymes? This study aimed to illustrate the relationship between proteases and CAE, the results would provide a theoretical basis for further indepth researches.[Method] Because the main ECM components of coronary artery wall were elastic fiber, I and III collagen fiber, this study firstly evaluated the overall changes of ECM metabolism in CAE patients by detecting five serum markers of the synthesis and degradation of those ECM components, at the same time the clinical diagnostic value of some indexes were also performanced. Then the detections of blood total activity of elastase activity and total matrix metalloproteinases (MMP) were implemented, and after analyzing the correlations between those proteases and coronary artery CAE metabolism, the further experiments were carried out as following:1) the systemic studies of neutrophil derived proteases and their endogenous inhibitors; 2) the comprehensive screening of the transcriptional profiles of proteases and their regulaters in peripheral blood mononuclear cells (PBMC); 3) the observation of the effects of pooled sera of CAE patients on various proteases and ECM components in cultured human umbilical vein smooth muscle cells (HUVSMC), and also the investigation of the protective effects of GDF-15.[Result] The turnover of ECM in CAE patients were:the degradation elastic fiber was increased, the total amount of collagens was reduced and the collagen polar was transfered form type Ⅲ collagen to type Ⅰ. These changes might be the underlying mechanism for coronary dilation and vascular sclerosis. And it was found the degradation marker of elastic fibers-soluble elastin (sElastin) was an usfull auxiliary diagnosis biomarker for CAE. Further studies showed that, the total elastase activiy and total MMP activity were closely related to elastin fibre degradation. The further experiments showed: 1) the neutrophil was activited in an unknown manner in CAE group, and the neutrophil serine proteinases (NSP) including neutrophil elastase (HNE) and cathepsin G (CG) were relased, at the same time the endogenous NSP inhibitor were also increased to restrict the effects of NSP. But at the same time these protease inhibitors also could inhibit plasmin and possibly increased the probability of thrombotic events in ectatic coronary.2) systemically screening proteases and their regulating system in PBMC:MMP1 and MMP9 were the main proteases particapating in CAE while interleukin 1 alpha (ILIA), platelet derived growth factor B (PDGF-B), interferon gamma (IFNγ) and growth differentiation factor 15 (GDF15) were the principal cytokines regulating the ECM metabolism in the progression of coronary artery dilatation.3) the expression of MMP 1 was increased by pooled CAE sera in cultured HUVSMC, and GDF 15 could inhibit this type of change suggesting that it might be an endogenous candidate of protective factor for CAE.[Conclusion] In this study, protease activity and ECM metablism were evaluated, our results confirmed that CAE was mainly due to the damage of collagen and elastic fibers by a series of proteases, and we also found soluble elastin (sElastin) was a new auxiliary diagnosis marker for CAE. The main source of proteases were:smooth muscle cells derived MMP1, PBMC produced MMP1 and MMP9, and neutrophil derived HNE and CG. Some kinds of endogenous substances relaing to ECM turnover, including protease inhibitors and cytokines, were also found out in CAE populations. Among them GDF 15 was a potential treatment drug for CAE. This study confirmed the close relationship between proteases and coronary artery dilatation, and provided a solid theoretical basis for further indepth study of pathogenesis of CAE.