title: H-Ras Isoform Mediates Protection Against Pressure Overload-Induced Cardiac Dysfunction in Part Through Activation of AKT.
abstract: BACKGROUND
  In general, Ras proteins are thought to promote cardiac hypertrophy, an important risk factor for cardiovascular disease and heart failure. However, the contribution of different Ras isoforms has not been investigated. The objective of this study was to define the role of H- and K-Ras in modulating stress-induced myocardial hypertrophy and failure.
  
  
  RESULTS
  We used H- and K-Ras gene knockout mice and subjected them to pressure overload to induce cardiac hypertrophy and dysfunction. We observed a worsened cardiac phenotype inHras-/-mice, while outcomes were improved inKras+/-mice. We also used a neonatal rat cardiomyocyte culture system to elucidate the mechanisms underlying these observations. Our findings demonstrate that H-Ras, but not K-Ras, promotes cardiomyocyte hypertrophy both in vivo and in vitro. This response was mediated in part through the phosphoinositide 3-kinase-AKT signaling pathway. Adeno-associated virus-mediated increase in AKT activation improved the cardiac function in pressure overloadedHrasnull hearts in vivo. These findings further support engagement of the phosphoinositide 3-kinase-AKT signaling axis by H-Ras.
  
  
  CONCLUSIONS
  Taken together, these findings indicate that H- and K-Ras have divergent effects on cardiac hypertrophy and heart failure in response to pressure overload stress.
authors.affiliation: From the Cardiovascular Research Institute and the Department of Cell Biology and Molecular Medicine, Rutgers, New Jersey Medical School, Newark, NJ.
authors.forename: Takahisa
authors.initials: T
authors.lastname: Matsuda
authors.affiliation: From the Cardiovascular Research Institute and the Department of Cell Biology and Molecular Medicine, Rutgers, New Jersey Medical School, Newark, NJ.
authors.forename: Jae Im
authors.initials: JI
authors.lastname: Jeong
authors.affiliation: From the Cardiovascular Research Institute and the Department of Cell Biology and Molecular Medicine, Rutgers, New Jersey Medical School, Newark, NJ.
authors.forename: Shohei
authors.initials: S
authors.lastname: Ikeda
authors.affiliation: From the Cardiovascular Research Institute and the Department of Cell Biology and Molecular Medicine, Rutgers, New Jersey Medical School, Newark, NJ.
authors.forename: Takanobu
authors.initials: T
authors.lastname: Yamamoto
authors.affiliation: From the Cardiovascular Research Institute and the Department of Cell Biology and Molecular Medicine, Rutgers, New Jersey Medical School, Newark, NJ.
authors.forename: Shumin
authors.initials: S
authors.lastname: Gao
authors.affiliation: From the Cardiovascular Research Institute and the Department of Cell Biology and Molecular Medicine, Rutgers, New Jersey Medical School, Newark, NJ.
authors.forename: Gopal J
authors.initials: GJ
authors.lastname: Babu
authors.affiliation: From the Cardiovascular Research Institute and the Department of Cell Biology and Molecular Medicine, Rutgers, New Jersey Medical School, Newark, NJ.
authors.forename: Peiyong
authors.initials: P
authors.lastname: Zhai
authors.affiliation: From the Cardiovascular Research Institute and the Department of Cell Biology and Molecular Medicine, Rutgers, New Jersey Medical School, Newark, NJ. delredo@njms.rutgers.edu.
authors.forename: Dominic P
authors.initials: DP
authors.lastname: Del Re
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001013:Aorta, Thoracic / Q000503:physiopathology / Q000601:surgery; D062186:Arterial Pressure; D006332:Cardiomegaly / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004789:Enzyme Activation; D005838:Genotype; D006333:Heart Failure / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control*; D008026:Ligation; D008297:Male; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000201:enzymology* / Q000473:pathology; D015513:Oncogene Proteins / Q000378:metabolism*; D010641:Phenotype; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras) / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D017208:Rats, Wistar; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D018631:ras Proteins / Q000378:metabolism*
chemical_list: C528429:Hras protein, rat; D015513:Oncogene Proteins; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins
keywords: Ras proteins; cardiomyocytes; heart failure; hypertension; hypertrophy