Introduction: Heart failure is the leading cause of mortality worldwide. Despite progresses made in the treatment of most cardiovascular diseases, the prevalence and mortality of heart failure are still rising. Thus, new targets for heart failure treatment are in desperate need. Based on an integrated transcriptional analysis, we identified a previously unknown target—Homeodomain-interacting protein kinase 2 (HIPK2), potentially involved in cardiac remodeling process. HIPK2 is a nuclear serine-threonine kinase and functions as a transcriptional corepressor. However, the role of HIPK2 in cardiac biology is unknown.
Methods and Results: To determine the role of HIPK2 in the heart, we generated αMHC-Cre driven cardiomyocyte-specific HIPK2 knockout (KO) mice and αMHC-MerCreMer driven conditional HIPK2 KO mice. The heart function was examined by echocardiography. We found that the heterozygous HIPK2 KO mice (Het, HIPK2flox/ αMHC-Cre/ ) developed cardiac dysfunction at the age of 6 months, as reflected by significantly reduced fractional shortening (FS, WT=46.73±2.52% vs Het=27.80±2.16%, n=8/group, p<0.001) and ejection fraction (EF, p<0.001), while heart function was comparable between the WT and Het mice at 3 months of age. Consistent with the decreased contractile function, the left ventricle internal dimension at end-diastole and systole was also enlarged in the Het mice. Furthermore, Tamoxifen-induced deletion of HIPK2 in the adult mouse heart (KO, HIPK2flox/flox αMHC-MerCreMer/ ) resulted in dramatic decrease of heart function with significantly decreased FS and EF (FS: WT=42.98±0.75% vs KO=34.43±1.22%, p<0.0001, n=38-41). In the in vitro study using neonatal rat ventricular cardiomyocytes, overexpression of HIPK2 suppressed the expression of Nppa and Nppb at basal condition (Nppa: -44±5%, p<0.05; Nppb: -46±4%, p<0.01, n=3). With phenylephrine treatment to induce hypertrophy, the suppression of Nppa and Nppb was maintained in the HIPK2 overexpression group (p<0.05).
Conclusions: These findings suggest that cardiomyocyte HIPK2 is required to maintain normal cardiac homeostasis and its deletion leads to marked cardiac dysfunction. Overexpression of HIPK2 is protective for the cardiomyocyte from pathological hypertrophy.