SCAD调控心肌纤维化的作用及其机制研究

Myocardial fibrosis is an important pathological process of hypertensive cardiac hypertrophy from compensatory stage to decompensation, which is the key link of heart failure development. Pathological cardiac hypertrophy will lead to myocardial fibrosis, on the contrary, exercise induced physiological hypertrophy has a protective effect on cardiovascular disease，which has not myocardial fibrosis. Our study found that short-chain acyl-CoA dehydrogenase (SCAD) was significantly down-regulated in the left ventricles of SHR (with pathological cardiac hypertrophy and myocardial fibrosis), however, SCAD was significantly increased in swimming-induced physiological cardiac hypertrophy (without myocardial fibrosis). In addition, AngII induced cardiac fibroblasts proliferation and collagen synthesis, the expression of SCAD was also significantly decreased in cardiac fibroblasts treated with AngII. Silencing SCAD by RNA interference also induced cardiac fibroblasts proliferation and collagen synthesis, which suggested that SCAD had a negative regulatory role on myocardial fibrosis. Based on our original findings, we plan to identify the role of SCAD on myocardial fibrosis and investigate the molecular mechanisms through myocardial fibrosis models, SCAD gene knockout mice, myocardial mitochondrial proteomics, and provide more adequate scientific evidences to identify SCAD as a new potential target of myocardial fibrosis.

心肌纤维化是高血压心肌肥厚由代偿期向失代偿期转变的重要病理过程，是引发心力衰竭的核心环节。病理性心肌肥厚将导致心肌纤维化，相反，运动引起的生理性心肌肥厚不存在心肌纤维化，对心血管疾病具有保护效应。我们研究发现，短链酰基辅酶A脱氢酶(SCAD)在病理性心肌肥厚大鼠(伴有心肌纤维化)左心室中的表达明显下调，然而，在生理性心肌肥厚大鼠(不伴有心肌纤维化)左心室中的表达明显上调。进一步研究显示，AngII诱导心肌成纤维细胞增殖和胶原合成的细胞模型中，SCAD的表达也显著下调。采用siRNA沉默SCAD基因后，心肌成纤维细胞增殖和胶原合成明显增多，提示SCAD对心肌纤维化具有负性调控作用。基于我们这些原创性的发现，本项目拟采用心肌纤维化模型、SCAD基因敲除小鼠、心肌线粒体蛋白质组学等技术，明确SCAD对心肌纤维化的调控作用，并探讨其分子机制，为确立SCAD作为心肌纤维化治疗的新靶点提供科学依据。

SCAD 是酰基辅酶A 脱氢酶家族中的一员，特异性地分解短链酰基辅酶A 底物，是脂肪酸β氧化第一步反应的限速酶。然而它在心肌纤维化中的作用尚不清楚。因此，我们研究了SCAD对心肌纤维化的调控作用及其分子机制。不论在自发性高血压诱导的体内病理性心肌肥厚及心肌纤维化模型还是在血管紧张素II（AngII）诱导的原代心肌成纤维细胞纤维化模型中，SCAD的表达均明显下调。相反，运动引起的生理性心肌肥厚不存在心肌纤维化，其心肌的SCAD表达显著上调。采用siRNA沉默SCAD基因后，心肌成纤维细胞增殖和胶原合成明显增多，提示SCAD对心肌纤维化具有负性调控作用。随之，我们采用了SCAD基因敲除小鼠，并进行4周TAC诱导心肌纤维化实验。结果显示，SCAD基因敲除小鼠发生了心肌纤维化，在TAC造模后，与野生型TAC组相比，SCAD基因敲除明显加重了小鼠心肌纤维化。此外，腺病毒过表达SCAD可以减轻AngII诱导的体外心肌成纤维细胞增殖和胶原合成。同时，SCAD重组腺病毒明显减轻SHR的心肌纤维化，心功能得到明显改善。体内、外心肌纤维化模型中，PI3K p110α、PPARα及SCAD表达显著下调，PI3K p110γ、p-ERK1/2、p-IκBα及p-p65蛋白表达显著上调。分别采用信号分子的特异性激动剂/抑制剂，进一步证实了PI3K-ERK1/2-NF-κB-PPARα-SCAD 信号途径对心肌纤维化的调控作用。本项目首次证实了SCAD对心肌纤维化的负性调控作用，上调SCAD表达可减轻心肌纤维化，并探讨其分子机制，为确立SCAD作为心肌纤维化药物治疗的新靶点提供了科学依据。

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