# RIPK3 inhibitor GSK872 targets angiotensin II induced cardiomyocyte hypertrophy by regulating Ca2+/ calmodulin dependent protein kinase II

## TL;DR

This study shows that the RIPK3 inhibitor GSK872 reduces heart cell enlargement caused by AngII by controlling CaMKII activity and oxidative stress.

## Contribution

The study identifies a novel mechanism by which GSK872 alleviates AngII-induced cardiomyocyte hypertrophy through RIPK3 and CaMKII regulation.

## Key findings

- GSK872 reduces AngII-induced cardiomyocyte hypertrophy by inhibiting RIPK3 and CaMKII activation.
- Treatment with GSK872 corrects CaMKIIδ splicing and reduces oxidative stress and mitochondrial dysfunction.
- Inhibiting RIPK3 with GSK872 shows protective effects against myocardial dysfunction and regulated necrosis.

## Abstract

Receptor interacting protein kinase 3 (RIPK3) plays a crucial role in the signaling pathway of necrotic apoptosis, and calcium/calmodulin dependent protein kinase II (CaMKII) is a novel substrate for RIPK3 induced regulated necrosis. The aim of this study is to investigate the regulation and mechanism of RIPK3 on AngII induced cardiomyocyte hypertrophy. Using AngII to stimulate myocardial cells for 72 hours, inducing myocardial cell hypertrophy; Intervention of RIPK3 expression using RIPK3 inhibitor GSK872. Detect indicators related to myocardial hypertrophy, cell damage, regulatory necrosis, CaMKII activation and gene expression, oxidative stress, mitochondrial membrane potential, etc. After AngII stimulation of cardiomyocytes, the expression of hypertrophy markers ANP and BNP increased, LDH release increased, ATP levels decreased, splicing factors ASF and SC35 expression increased, CaMKII oxidation and phosphorylation levels increased, and CaMKIIδ alternative splicing was disrupted. However, treatment with GSK872 can alleviate myocardial dysfunction, inhibit CaMKII activation, correct CaMKIIδ variant splicing disorder and ultimately alleviating myocardial hypertrophy. In addition, pretreatment with RIPK3 can reduce the accumulation of reactive oxygen species (ROS) induced by AngII, decrease the activity of ASF and SC35, and restore mitochondrial membrane potential. RIPK3 inhibitor GSK872 can inhibit the activation of CaMKII, alleviate regulated necrosis and oxidative stress to alleviate myocardial hypertrophy. It has a protective effect on myocardial hypertrophy and is expected to become a new targeted drug for clinical treatment of dilated cardiomyopathy and heart failure.