Circulation：MicroRNA-145或可靶向治疗动脉粥样硬化

 国际期刊Circulation昨日发表了圣迈克尔医院（St. Michael's Hospital）研究人员的新发现，microRNA-145基因治疗可以显著缓解小鼠动脉粥样硬化症状和进程。

动脉粥样硬化，又称为动脉硬化，是由于脂肪，胆固醇等物质堆积在动脉壁上，逐渐形成动脉硬化斑块。动脉粥样硬化在加拿大的死亡率位居第一。

心脏外科医生Dr. Subodh Verma说，大多数的心脏病发作都是因为动脉粥样硬化斑块的破裂，就好像蛋壳破碎之后将它的内容物释放到动脉中一样。

斑块的外层由平滑肌细胞构成，问题的关键是什么原因导致了斑块外表层的破裂。这些平滑肌细胞在各种压力环境和心血管风险因素之下表型发生转换，使得斑块外层容易发生破裂而引起心脏病。microRNA-145是预防血管平滑肌细胞向易碎细胞转化的一个至关重要的因子。

在动物中，基于microRNA-145的基因治疗使动脉粥样硬化斑块减小近一半，而且提高了斑块和纤维帽的胶原含量，这表明，基因治疗可以减少斑块积聚并可以使其不易碎，从而不会因为心脏病。

研究人员也发现，人动脉硬化斑块中microRNA-145的总量比正常的有所减少。

doi：10.1161/CIRCULATIONAHA.111.084186

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MicroRNA-145 Targeted Therapy Reduces Atherosclerosis Fina Lovren，PhD； Yi Pan，MD； Adrian Quan，MPhil； Krishna K. Singh，PhD； Praphulla C. Shukla，PhD； Nandini Gupta，BSc； Brent M. Steer，BSc (Hons)； Alistair J. Ingram，MD，FRCPC； Milan Gupta，MD，FRCPC； Mohammed Al-Omran，MD，MSc，FRCSC； Hwee Teoh，PhD； Philip A. Marsden，MD， FRCPC； Subodh Verma，MD，PhD，FRCSC，FAHA Abstract Background—MicroRNA are essential posttranscriptional modulators of gene expression implicated in various chronic diseases. Because microRNA-145 is highly expressed in vascular smooth muscle cells (VSMC) and regulates VSMC fate and plasticity， we hypothesized that it may be a novel regulator of atherosclerosis and plaque stability. Methods and Results—Apolipoprotein E knockout mice (ApoE) mice were treated with either a microRNA-145 lentivirus under the control of the smooth muscle cell (SMC)-specific promoter SM22α or a SM22α control lentivirus before commencing the Western diet for 12 weeks. The SMC-targeted microRNA-145 treatment markedly reduced plaque size in aortic sinuses， ascending aortas， and brachiocephalic arteries. It also significantly increased fibrous cap area， reduced necrotic core area， and increased plaque collagen content. Cellular plaque composition analyses revealed significantly less macrophages in ApoE？/？ mice treated with the SMC-specific microRNA-145. These mice also demonstrated marked increases in calponin levels and α-smooth muscle actin–positive SMC areas in their atherosclerotic lesions. Furthermore， lentiviral delivery of microRNA-145 resulted in reduced KLF4 and elevated myocardin expression in aortas from ApoE mice， consistent with an effect of microRNA-145 to promote a contractile phenotype in VSMC. Conclusions—VSMC-specific overexpression of microRNA-145 is a novel in vivo therapeutic target to limit atherosclerotic plaque morphology and cellular composition， shifting the balance toward plaque stability vs plaque rupture.