TNNI3K, a Cardiac-Specific Kinase, Promotes Physiological Cardiac Hypertrophy in Transgenic Mice

Xiaojian Wang,Lianfeng Zhang,Jingzhou Chen,Ming Su,Changxin Wang,Jizheng Wang,Hu Wang,Yubao Zou,Rutai Hui,Lei Song,Youyi Zhang,Tohru Fukai

doi:10.1371/journal.pone.0058570

Abstract

PurposeProtein 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.Methods and ResultsIn 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.ConclusionTNNI3K 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.

Highlights

In response to increased workload, the heart undergoes hypertrophic enlargement, which is characterized by an increase in the size of individual cardiac myocyte.[1]
TNNI3K promotes a concentric hypertrophy with enhancement of cardiac function via regulating the phosphorylation of cardiac troponin I (cTnI)
As heart failure is almost invariably associated with cardiac hypertrophy, the elucidation of signaling cascades involved in these two forms of hypertrophy will be of critical importance for the design of specific therapy against heart failure.[4,5]

Summary

Introduction

In response to increased workload, the heart undergoes hypertrophic enlargement, which is characterized by an increase in the size of individual cardiac myocyte.[1]. Levels of contractile protein phosphorylation are associated with stretch of the myocardium, the myofilament response to Ca2+ and the progression of cardiac remodeling.[7,8,9] Despite considerable progress has been made in elucidating the roles of various kinases in regulating myofilament during the past decades, understanding the molecular mechanism underlying myofilament phosphorylation and cardiac hypertrophy remains limited. This is due to, at least in part, lack of knowledge for the function of novel protein kinases in the heart. It is crucial to identify novel genes potential involved in cardiac hypertrophy

Methods

Results

Conclusion