title: TNNI3K, a cardiac-specific kinase, promotes physiological cardiac hypertrophy in transgenic mice.
abstract: OBJECTIVE
  Protein kinase plays an essential role in controlling cardiac growth and hypertrophic remodeling. The cardiac troponin I-interacting kinase (TNNI3K), a novel cardiac specific kinase, is associated with cardiomyocyte hypertrophy. However, the precise function of TNNI3K in regulating cardiac remodeling has remained controversial.
  
  
  RESULTS
  In a rat model of cardiac hypertrophy generated by transverse aortic constriction, myocardial TNNI3K expression was significantly increased by 1.62 folds (P<0.05) after constriction for 15 days. To investigate the role of TNNI3K in cardiac hypertrophy, we generated transgenic mouse lines with overexpression of human TNNI3K specifically in the heart. At the age of 3 months, the high-copy-number TNNI3K transgenic mice demonstrated a phenotype of concentric hypertrophy with increased heart weight normalized to body weight (1.31 fold, P<0.01). Echocardiography and non-invasive hemodynamic assessments showed enhanced cardiac function. No necrosis or myocyte disarray was observed in the heart of TNNI3K transgenic mice. This concentric hypertrophy maintained up to 12 months of age without cardiac dysfunction. The phospho amino acid analysis revealed that TNNI3K is a protein-tyrosine kinase. The yeast two-hybrid screen and co-immunoprecipitation assay identified cTnI as a target for TNNI3K. Moreover, TNNI3K overexpression induced cTnI phosphorylation at Ser22/Ser23 in vivo and in vitro, suggesting that TNNI3K is a novel upstream regulator for cTnI phosphorylation.
  
  
  CONCLUSIONS
  TNNI3K promotes a concentric hypertrophy with enhancement of cardiac function via regulating the phosphorylation of cTnI. TNNI3K could be a potential therapeutic target for preventing from heart failure.
authors.affiliation: Sino-German Laboratory for Molecular Medicine, State Key Laboratory of Cardiovascular Disease, FuWai Hospital & Cardiovascular Institute, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, People's Republic of China.
authors.forename: Xiaojian
authors.initials: X
authors.lastname: Wang
authors.forename: Jizheng
authors.initials: J
authors.lastname: Wang
authors.forename: Ming
authors.initials: M
authors.lastname: Su
authors.forename: Changxin
authors.initials: C
authors.lastname: Wang
authors.forename: Jingzhou
authors.initials: J
authors.lastname: Chen
authors.forename: Hu
authors.initials: H
authors.lastname: Wang
authors.forename: Lei
authors.initials: L
authors.lastname: Song
authors.forename: Yubao
authors.initials: Y
authors.lastname: Zou
authors.forename: Lianfeng
authors.initials: L
authors.lastname: Zhang
authors.forename: Youyi
authors.initials: Y
authors.lastname: Zhang
authors.forename: Rutai
authors.initials: R
authors.lastname: Hui
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000378:metabolism*; D018076:DNA, Complementary / Q000378:metabolism; D004452:Echocardiography; D006333:Heart Failure / Q000517:prevention & control*; D006439:Hemodynamics; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism*; D019606:Phosphoamino Acids / Q000378:metabolism; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020798:Two-Hybrid System Techniques
chemical_list: D018076:DNA, Complementary; D019606:Phosphoamino Acids; D011505:Protein-Tyrosine Kinases; C584646:TNNI3K protein, rat; D017346:Protein Serine-Threonine Kinases; C481078:TNNI3K protein, human; D020930:MAP Kinase Kinase Kinases