Human paraoxonase gene cluster overexpression alleviates angiotensin II-induced cardiac hypertrophy in mice  

作　　者：Jian-Fei Pei Yun-Fei Yan Xiaoqiang Tang Yang Zhang Shen-Shen Cui Zhu-Qin Zhang Hou-Zao Chen De-Pei Liu 

机构地区：[1]State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences,Chinese Academy of Medical Sciences & Peking Union Medical College

出　　处：《Science China(Life Sciences)》2016年第11期1115-1122,共8页中国科学（生命科学英文版）

基　　金：supported by the National Natural Science Foundation of China(81422002,91339201,31271227,31571193);the National Science and Technology Support Project(2013YQ0309230502,2014BAI02B01);the Beijing Nova Program(XX2013064)

摘　　要：Cardiac hypertrophy is the strongest predictor of the development of heart failure, and anti-hypertrophic treatment holds the key to improving the clinical syndrome and increasing the survival rates for heart failure. The paraoxonase(PON) gene cluster(PC) protects against atherosclerosis and coronary artery diseases. However, the role of PC in the heart is largely unknown. To evaluate the roles of PC in cardiac hypertrophy, transgenic mice carrying the intact human PON1, PON2, and PON3 genes and their flanking sequences were studied. We demonstrated that the PC transgene(PC-Tg) protected mice from cardiac hypertrophy induced by Ang II; these mice had reduced heart weight/body weight ratios, decreased left ventricular wall thicknesses and increased fractional shortening compared with wild-type(WT) control. The same protective tendency was also observed with an Apoe^(-/-)background. Mechanically, PC-Tg normalized the disequilibrium of matrix metalloproteinases(MMPs)/tissue inhibitors of MMPs(TIMPs) in hypertrophic hearts, which might contribute to the protective role of PC-Tg in cardiac fibrosis and, thus, protect against cardiac remodeling. Taken together, our results identify a novel anti-hypertrophic role for the PON gene cluster, suggesting a possible strategy for the treatment of cardiac hypertrophy through elevating the levels of the PON gene family.Cardiac hypertrophy is the strongest predictor of the development of heart failure, and anti-hypertrophic treatment holds the key to improving the clinical syndrome and increasing the survival rates for heart failure. The paraoxonase （PON） gene cluster （PC） protects against atherosclerosis and coronary artery diseases. However, the role of PC in the heart is largely unknown. To evaluate the roles of PC in cardiac hypertrophy, transgenic mice carrying the intact human PON1, PON2, and PON3 genes and their flanking sequences were studied. We demonstrated that the PC transgene （PC-Tg） protected mice from cardiac hypertro- phy induced by Ang II; these mice had reduced heart weight/body weight ratios, decreased left ventricular wall thicknesses and increased fractional shortening compared with wild-type （WT） control. The same protective tendency was also observed with an Apoe -/- background. Mechanically, PC-Tg normalized the disequilibrium of matrix metalloproteinases （MMPs）/tissue inhibitors of MMPs （TIMPs） in hypertrophic hearts, which might contribute to the protective role of PC-Tg in cardiac fibrosis and, thus, protect against cardiac remodeling. Taken together, our results identify a novel anti-hypertrophic role for the PON gene cluster, suggesting a possible strategy for the treatment of cardiac hypertrophy through elevating the levels of the PON gene family.

关 键 词：cardiac hypertrophy FIBROSIS paraoxonase gene cluster angiotensin II 

分 类 号：R541.6[医药卫生—心血管疾病]