title: Aliskiren ameliorates pressure overload-induced heart hypertrophy and fibrosis in mice.
abstract: OBJECTIVE
  Aliskiren (ALK) is a renin inhibitor that has been used in the treatment of hypertension. The aim of this study was to determine whether ALK could ameliorate pressure overload-induced heart hypertrophy and fibrosis, and to elucidate the mechanisms of action.
  
  
  METHODS
  Transverse aortic constriction (TAC) was performed in mice to induce heart pressure overload. ALK (150 mg·kg(-1)·d(-1), po), the autophagy inhibitor 3-methyladenine (10 mg·kg(-1) per week, ip) or the PKCβI inhibitor LY333531 (1 mg·kg(-1)·d-(1), po) was administered to the mice for 4 weeks. Heart hypertrophy, fibrosis and function were evaluated based on echocardiography, histological and biochemical measurements. Mechanically stretched cardiomyocytes of rats were used for in vitro experiments. The levels of signaling proteins were measured using Western blotting, while the expression of the relevant genes was analyzed using real-time QRT-PCR.
  
  
  RESULTS
  TAC induced marked heart hypertrophy and fibrosis, accompanied by high levels of Ang II in plasma and heart, and by PKCβI/α and ERK1/2 phosphorylation in heart. Meanwhile, TAC induced autophagic responses in heart, i.e. increases in autophagic structures, expression of Atg5 and Atg16 L1 mRNAs and LC3-II and Beclin-1 proteins. These pathological alterations in TAC-mice were significantly ameliorated or blocked by ALK administration. In TAC-mice, 3-methyladenine administration also ameliorated heart hypertrophy, fibrosis and dysfunction, while LY333531 administration inhibited ERK phosphorylation and autophagy in heart. In mechanically stretched cardiomyocytes, CGP53353 (a PKCβI inhibitor) prevented ERK phosphorylation and autophagic responses, while U0126 (an ERK inhibitor) blocked autophagic responses.
  
  
  CONCLUSIONS
  ALK ameliorates heart hypertrophy, fibrosis and dysfunction in the mouse model in setting of chronic pressure overload, via suppressing Ang II-PKCβI-ERK1/2-regulated autophagy.
authors.affiliation: Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institute of Biomedical Science, Fudan University, Shanghai 200032, China.
authors.forename: Li-qing
authors.initials: LQ
authors.lastname: Weng
authors.affiliation: Sir Run Run SHAW Hospital, Zhejiang University, Hangzhou 310016, China.
authors.forename: Wen-bin
authors.initials: WB
authors.lastname: Zhang
authors.affiliation: Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institute of Biomedical Science, Fudan University, Shanghai 200032, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Ye
authors.affiliation: Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institute of Biomedical Science, Fudan University, Shanghai 200032, China.
authors.forename: Pei-pei
authors.initials: PP
authors.lastname: Yin
authors.affiliation: Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institute of Biomedical Science, Fudan University, Shanghai 200032, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Yuan
authors.affiliation: Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institute of Biomedical Science, Fudan University, Shanghai 200032, China.
authors.forename: Xing-xu
authors.initials: XX
authors.lastname: Wang
authors.affiliation: Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institute of Biomedical Science, Fudan University, Shanghai 200032, China.
authors.forename: Le
authors.initials: L
authors.lastname: Kang
authors.affiliation: Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institute of Biomedical Science, Fudan University, Shanghai 200032, China.
authors.forename: Sha-sha
authors.initials: SS
authors.lastname: Jiang
authors.affiliation: Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institute of Biomedical Science, Fudan University, Shanghai 200032, China.
authors.forename: Jie-yun
authors.initials: JY
authors.lastname: You
authors.affiliation: Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institute of Biomedical Science, Fudan University, Shanghai 200032, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Wu
authors.affiliation: Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institute of Biomedical Science, Fudan University, Shanghai 200032, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Gong
authors.affiliation: Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institute of Biomedical Science, Fudan University, Shanghai 200032, China.
authors.forename: Jun-bo
authors.initials: JB
authors.lastname: Ge
authors.affiliation: Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institute of Biomedical Science, Fudan University, Shanghai 200032, China.
authors.forename: Yun-zeng
authors.initials: YZ
authors.lastname: Zou
mesh_terms: D000577:Amides / Q000627:therapeutic use*; D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D001343:Autophagy / Q000187:drug effects; D006332:Cardiomegaly / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005355:Fibrosis / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D005650:Fumarates / Q000627:therapeutic use*; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013314:Stress, Mechanical
chemical_list: D000577:Amides; D000959:Antihypertensive Agents; D005650:Fumarates; C446481:aliskiren; D011493:Protein Kinase C; D048049:Extracellular Signal-Regulated MAP Kinases