| dc.description.abstract | Cardiac kinases play a critical role in the development of heart failure, and represent potential tractable therapeutic targets. However, only a very small fraction of the cardiac kinome has been investigated. To identify novel cardiac kinases involved in heart failure, we employed Expression2Kinase algorithm, an integrated transcriptomics and bioinformatics analysis, to screen kinase targets in heart failure and identified Homeodomain-Interacting Protein Kinase 2 (HIPK2) as a novel candidate kinase. HIPK2 is a nuclear serine/threonine kinase and is known as a transcription suppressor and cell death regulator. However, the role of HIPK2 in cardiac biology is unknown. To determine the role of HIPK2 in the heart, we examined HIPK2 global knockout (KO) mice, generated and characterized cardiomyocyte-specific HIPK2 knockout (CM-KO), heterozygous mice and cardiomyocyte-specific HIPK2 conditional KO. Using multiple HIPK2 loss-of-function mouse models, we demonstrated that deletion of HIPK2 is detrimental to adult heart function. Importantly, cardiac dysfunction in HIPK2 KOs developed with advancing age, and this may be partially attributable to the elevated expression of HIPK2 in the adult heart. Mechanistically, an array of mechanistic studies revealed impaired ERK1/2 signaling in HIPK2 deficient hearts. We then performed a rescue experiment with AAV9 carrying cardiac-specific constitutively active MEK1, which nearly abolished the detrimental phenotype of KOs suggesting that impaired ERK signaling mediated apoptosis as the key factor driving the detrimental phenotype in CM-KO hearts. In vitro studies with neonatal rat ventricular cardiomyocytes corroborated the in vivo findings. Specifically, adenovirus-mediated overexpression of HIPK2 suppressed the expression of heart failure markers at basal condition and abolished phenylephrine-induced pathological gene expression. Since HIPK2 expression in the heart was significantly reduced in human end-stage ischemic cardiomyopathy compared to non-failing myocardium, HIPK2 could be a potential target in heart failure treatment. Beyond cardiomyocytes, we also identified that HIPK2 deficiency in cardiac fibroblasts makes the heart more susceptible to myocardial infarction. Taken together, these findings suggest that HIPK2 is required to maintain normal cardiac homeostasis. | |
