H11 kinase is a novel mediator of myocardial hypertrophy in vivo.
By subtractive hybridization, we found a significant increase in H11 kinase transcript in large mammalian models of both ischemia/reperfusion (stunning) and chronic pressure overload with hypertrophy. Because this gene has not been characterized in the heart, the goal of the present study was to determine the function of H11 kinase in cardiac tissue, both in vitro and in vivo. In isolated neonatal rat cardiac myocytes, adenoviral-mediated overexpression of H11 kinase resulted in a 37% increase in protein/DNA ratio, reflecting hypertrophy. A cardiac-specific transgene driven by the alphaMHC-promoter was generated, which resulted in an average 7-fold increase in H11 kinase protein expression. Transgenic hearts were characterized by a 30% increase of the heart weight/body weight ratio, by the reexpression of a fetal gene program, and by concentric hypertrophy with preserved contractile function at echocardiography. This phenotype was accompanied by a dose-dependent activation of Akt/PKB and p70(S6) kinase, whereas the MAP kinase pathway was unaffected. Thus, H11 kinase represents a novel mediator of cardiac cell growth and hypertrophy.
Depre
Christophe
C
Cardiovascular Research Institute, Department of Cell Biology and Molecular Medicine, University of Medicine and Dentistry New Jersey, New Jersey Medical School, Newark, NJ 07103, USA. deprech@umdnj.edu
Hase
Makoto
M
Gaussin
Vinciane
V
Zajac
Anna
A
Wang
Li
L
Hittinger
Luc
L
Ghaleh
Bijan
B
Yu
Xianzhong
X
Kudej
Raymond K
RK
Wagner
Thomas
T
Sadoshima
Junichi
J
Vatner
Stephen F
SF
D000818:Animals; D006332:Cardiomegaly / Q000209:etiology / Q000473:pathology / Q000503:physiopathology*; D002455:Cell Division / Q000502:physiology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004285:Dogs; D005260:Female; D017930:Genes, Reporter; D006360:Heat-Shock Proteins; D017379:Hypertrophy, Left Ventricular / Q000503:physiopathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D018832:Molecular Chaperones; D009206:Myocardium / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D009693:Nucleic Acid Hybridization / Q000379:methods; D009928:Organ Specificity; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D014161:Transduction, Genetic; D015854:Up-Regulation
C413214:HSPB8 protein, human; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; C494920:Akt1 protein, rat; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa