巨细胞病毒及相关miRNAs在高血压发病中作用和机制研究

源于人群关联研究显示人巨细胞病毒(HCMV)及HCMV编码一种微小RNA(miRNA) hcmv-miR-UL112与高血压相关,机制不明。巨细胞病毒(CMV)至少编码21种成熟miRNAs,并导致宿主体内miRNAs表达发生改变。预实验发现HCMV相关6个miRNAs在高血压患者表达发生改变，且与HCMV抗体滴度和高血压相关。我们推测：CMV通过CMV编码miRNAs与宿主体内发生改变的miRNAs及靶基因交互作用,导致炎症反应、血管重塑及内皮结构功能障碍,促进了高血压发生。为此本项目以鼠CMV感染WKY及主动脉内皮细胞和平滑肌细胞为疾病模型,采用miRNAs表达谱芯片、差异表达miRNAs及靶基因筛选验证、miRNAs慢病毒载体等方法,从不同层面探讨差异表达miRNAs及靶基因变化对WKY血压、炎症反应及血管增殖重构和心肌肥厚等影响,从miRNAs角度阐明CMV在高血压发病中作用和机制

Human cytomegalovirus (HCMV) is a double stranded DNA virus belonging to a member of the beta-herpesvirus group. The results from the population association study have been demonstrated that HCMV and a hcmv-miR-UL112, one of the HCMV-encoded microRNAs(miRNAs) were associated with essential hypertension (EH). However, the underlying pathologic mechanisms are poorly understood. And cytomegalovirus (CMV) encodes at least 21 mature miRNAs. In addition to expressing their own miRNAs, CMV infections can result in changes in the expression of the host cellular miRNAs that benefit virus replication. Our preliminary experiments have shown that six HCMV related miRNAs expressions were changed in hypertensive patients, and associated with HCMV IgG antibody titers and hypertension. Therefore, we hypothesized that in Wistar-Kyoto rat(WKY) of CMV infections, because of CMV-encoded miRNAs and target genes interaction with the host cellular changed miRNAs and target genes, resulting in inflammation response,vascular proliferation and remodeling as well as vascular endothelial dysfunction , then CMV promotes the development of hypertension. To prove this hypothesis, WKY and aortic endothelial cells and smooth muscle cells are infected with mouse cytomegalovirus (MCMV) as the disease model, miRNAs expression microarray, signature miRNAs and corresponding target genes screening and validation as well as miRNAs gene knock-down and overexpression lentiviral vectors are employed. We intend to study the effects of the differentially expressed miRNAs and target genes expression changes on WKY blood pressure ,inflammation response,vascular smooth muscle proliferation and remodeling,left ventricular hypertrophy as well as vascular endothelial structure and function based on vivo, tissue, cell and molecular levels. Eventually, we clarify the effects of CMV on hypertension and its mechanisms underlying miRNAs and to provide a new clinical target for the prevention and treatment of hypertension.