title: Human paraoxonase gene cluster overexpression alleviates angiotensin II-induced cardiac hypertrophy in mice.
abstract: 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.
authors: 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, Beijing, 100005, China.
authors: Jian-Fei
authors: JF
authors: Pei
authors: 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, Beijing, 100005, China.
authors: Yun-Fei
authors: YF
authors: Yan
authors: 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, Beijing, 100005, China.
authors: Xiaoqiang
authors: X
authors: Tang
authors: 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, Beijing, 100005, China.
authors: Yang
authors: Y
authors: Zhang
authors: 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, Beijing, 100005, China.
authors: Shen-Shen
authors: SS
authors: Cui
authors: 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, Beijing, 100005, China.
authors: Zhu-Qin
authors: ZQ
authors: Zhang
authors: 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, Beijing, 100005, China. chenhouzao@ibms.cams.cn.
authors: Hou-Zao
authors: HZ
authors: Chen
authors: 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, Beijing, 100005, China. liudp@pumc.edu.cn.
authors: De-Pei
authors: DP
authors: Liu
mesh_terms: D000804:Angiotensin II; D000818:Animals; D043303:Aryldialkylphosphatase / Q000235:genetics / Q000378:metabolism*; D001794:Blood Pressure / Q000235:genetics; D015153:Blotting, Western; D006332:Cardiomegaly / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics; D004452:Echocardiography; D005355:Fibrosis / Q000201:enzymology / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic; D006321:Heart / Q000503:physiopathology; D006801:Humans; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D005810:Multigene Family; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism; D020257:Ventricular Remodeling / Q000235:genetics
chemical_list: D019714:Tissue Inhibitor of Metalloproteinases; D000804:Angiotensin II; D043303:Aryldialkylphosphatase; C468406:PON1 protein, human; C468411:PON2 protein, human; C113656:PON3 protein, human; D020782:Matrix Metalloproteinases
keywords: angiotensin II; cardiac hypertrophy; fibrosis; paraoxonase gene cluster