【作者】 侯晓阳；

【导师】 卜培莉；

【作者基本信息】 山东大学 ， 内科学， 2006， 硕士

【摘要】 背景 左心室肥厚是影响原发性高血压患者病残率和病死率的一个重要独立危险因素。其细胞病理学基础不仅表现在心肌细胞的肥大，还有心脏成纤维细胞(cardic fibroblasts，CFs)的过度增殖和细胞外基质(extracellular matrix，ECM)大量沉积即心肌纤维化(myocardial fibrosis，MF)。ECM主要由纤维胶原网、基底膜、蛋白多糖和葡糖胺聚糖组成，还包括众多的生物活性因子，其中胶原占85％，主要是Ⅰ型和Ⅲ型胶原。CFs是心肌组织中含量最多的细胞，占心肌细胞总数的2／3；是心肌胶原合成最主要的细胞。 胶原的降解主要由基质金属蛋白酶(metalloproteases，MMPs)调节，而MMPs降解胶原的活性受内源性金属蛋白酶抑制因子(tissue inhibitor of metalloproteinase-1，TIMPs)的影响，MMPs-TIMPs的平衡对维持胶原的正常代谢有重要作用。因此，抑制CFs的增殖及胶原的合成并促进其降解是预防与逆转心肌纤维化，改善心功能的关键环节。过氧化物酶增殖物激活型受体(peroxisome proliferators-activated receptors，PPARs)是1990年发现的核激素受体超家族的新成员，包括PPARa、PPARβ和PPARγ三个成员。其中PPARγ在心脏中表达丰富，胰岛素增敏剂噻唑烷二酮类药物是PPARγ的合成配体。据报道活化的PPARγ可抑制AngⅡ与缺氧刺激所致CFs胶原的合成，并减少AP-1与NF-κB与靶基因的结合活性。但仍有许多问题尚未明了：1) PPARγ对心肌ECM重构是如何调控的；2) PPARγ调控心肌ECM重构的机制；3) AngⅡ系统与PPARγ的相互作用。 以上问题是构成本课题的设计思路和研究目的。对上述问题进行深入研究，不仅有助于阐明心肌ECM重构的细胞和分子机制，而且可为PPARγ激动剂扩大应用领域，为其应用于预防和逆转心肌纤维化提供理论基础。更多还原

【Abstract】 BackgroundThe extracellular matrix (ECM) in most tissues is composed of a complexarrangement of fibrillar collagen, elastin, microfibrillar proteins, proteoglycans and adhesive proteins such as laminin and fibronectin. Among the extracellular matrix (ECM) proteins, collagens constitute up to 85%. among which type I and type III constitute two-thirds. Fibroblasts are the major source of collagen in the myocardium. Collagen type I accumulation in the heart depends not only on its production, but also on its degradation, which is performed by proteinases, such as matrix metalloproteinase-1 (MMP-1). The activities of MMPs can be specifically inhibited by a family of protease inhibitors, termed tissue inhibitors of matrix metalloproteinases (TIMPs) , which are endogenous physiological inhibitors of MMPs, any aberrant deviation from the delicate balance between MMPs and TIMPs caused by alterations in their activity and regulators, mainly the cytokines may lead to pathological remodeling.So , inhibiting proliferation of cardiac fibroblasts and deposition of collagen are the key of the precaution and reversion of heart remolding and of improving heart function . Peroxisome proliferator-activated receptors (PPAR) are a family of at least 3 nuclear receptors (a, 8, andy). After activation by the ligand, PPARs heterodimerize with retinoic X receptor and recognize PPAR response element which exists in the promoter of target genes. The ligand-activated PPAR functions as a transcription factor and regulates target gene expression. PPARg has been implicated as a mediator of adipocyte differentiation and the mechanism by which更多还原