Cardiomyocytes HIPK2 regulates myocardial inflammation and heart function through purinergic signaling

Purinergic signaling is critical to myocardial inflammation and function. However, the underlying mechanisms are not well defined. Herein, we identified a protein kinase, homeodomain-interacting protein kinase 2 (HIPK2), as a novel regulator of purinergic signaling. Cardiomyocyte-specific HIPK2 knockout (CM-HIPK2-KO) hearts exhibited reduced expression of multiple key players of canonical purinergic signaling, including ectonucleases CD39 and CD73, and led to excessive inflammation and cardiac dysfunction. Multiple in vitro experiments with gain-of-function (adenovirus expressing HIPK2, Ad-HIPK2), and loss-of-function (Ad-sh-RNA-HIPK2) approaches were performed to establish that HIPK2-mediated regulation of purinergic signaling is a conserved mechanism in many cell types of diverse backgrounds. Mechanistically, we identified that the signaling circuit of HIPK2-ERK-CREB exerts its effects on purinergic signaling through transcriptional control on CD39 and CD73. Aberrant activation of purinergic signaling and inflammation was critical to cardiac pathologies because interventions with purinergic signaling inhibitor apyrase or NLRP3 inflammasome inhibitor CY09 largely rescued the detrimental cardiac phenotype of CM-HIPK2 KOs. Thus, herein, we identified HIPK2 as a novel regulator of purinergic signaling. Its deletion leads to excessive inflammation and cardiac dysfunction. Therefore, strategies to maintain HIPK2 are critical to sustaining cardiac health.