Inhibition of HIPK2 protects stress-induced pathological cardiac remodeling

Background Homeodomain-Interacting Protein Kinase 2 (HIPK2) has been reported to maintain basal cardiac func-tion, however, its role in pathological cardiac remodeling remains unclear.Methods HIPK2 inhibitors (tBID and PKI1H) treated mice and two lines of HIPK2-/- mice were subjected to trans-verse aortic constriction (TAC). HIPK2 knockdown were performed in neonatal rat cardiomyocytes (NRCMs), neo-natal rat cardiac fibroblasts (NRCFs), and human embryonic stem cell-derived cardiomyocytes (hESC-CMs). Microarray analysis was used to screen HIPK2 targets. Overexpression of early growth response 3 (EGR3) and C-type lectin receptor 4D (CLEC4D) were performed in NRCMs, while an activator of Smad3 was used in NRCFs, to rescue the effects of HIPK2 knockdown. Finally, the effects of EGR3 and CLEC4D knockdown by AAV9 in TAC were determined.indings HIPK2 was elevated in TAC mice model, as well as cardiomyocyte hypertrophy and NRCFs fibrosis model. Pharmacological and genetic inhibition of HIPK2 improved cardiac function and suppressed cardiac hypertrophy and fibrosis induced by TAC. In vitro, HIPK2 inhibition prevented cardiomyocyte hypertrophic growth and NRCFs proliferation and differentiation. At the mechanistic level, we identified EGR3 and CLEC4D as new targets of HIPK2, which were regulated by ERK1/2-CREB and mediated the protective function of HIPK2 inhibition in cardio-myocytes. Meanwhile, inhibition of phosphorylation of Smad3 was responsible for the suppression of cardiac fibro-blasts proliferation and differentiation by HIPK2 inhibition. Finally, we found that inhibition of EGR3 or CLEC4D protected against TAC.Interpretation HIPK2 inhibition protects against pathological cardiac remodeling by reducing EGR3 and CLEC4D with ERK1/2-CREB inhibition in cardiomyocytes, and by suppressing the phosphorylation of Smad3 in cardiac fibroblasts.

Automated summary

In this study, HIPK2 inhibition was found to protect against pathological cardiac remodeling by reducing the expression of EGR3 and CLEC4D in cardiomyocytes, and by suppressing the phosphorylation of Smad3 in cardiac fibroblasts.