Ca2+/Calmodulin-Dependent Protein Kinase II Regulation by Inhibitor of RIPK3 Protects against Cardiac Hypertrophy

Abstract

The activity of Ca2+/calmodulin-dependent protein kinase II δ (CaMKII δ) is central to the mechanisms of cardiovascular diseases. Receptor-interacting protein kinase 3- (RIPK3-) mediated necroptosis has been reported to contribute to cardiac dysfunction. However, the potential protective role of inhibition of RIPK3, a regulator of CaMKII, on cardiac hypertrophy remains unclear. The present study is aimed at investigating how the RIPK3 inhibitor GSK’872 regulates CaMKII activity and exploring its effect on hypertrophic cardiomyopathy (HCM). Wild-type (WT) and RIPK3 gene knockout (RIPK3-/-) mice were implanted subcutaneously with Alzet miniosmotic pumps (200 μL) and perfused with angiotensin II (AMP-AngII) to induce cardiac hypertrophy. After WT mice were induced by AngII for 72 hours, they were injected with GSK’872 with an intraperitoneal (IP) dose of 6 mg/kg once a day for two weeks. After this, they were physiologically examined for Echocardiography, myocardial injury, CaMKII activity, necroptosis, RIPK3 expression, mixed lineage kinase domain-like protein (MLKL) phosphorylation, and mitochondrial ultrastructure. The results indicated that deletion of the RIPK3 gene or administration of GSK’872 could reduce CaMKII activity, alleviate oxidative stress, reduce necroptosis, and reverse myocardial injury and cardiac dysfunction caused by AngII-induced cardiac hypertrophy in mice. The present study demonstrated that CaMKII activation and necroptosis augment cardiac hypertrophy in a RIPK3-dependent manner, which may provide therapeutic strategies for HCM. RIPK3 inhibitor GSK’872 has a protective effect on cardiac hypertrophy and could be an efficacious targeted medicine for HCM in clinical treatment.

Role of RIPK3‑CaMKII‑mPTP signaling pathway‑mediated necroptosis in cardiovascular diseases (Review)

“…The clinical manifestations of HCM include palpitations, exertional dyspnea, precordial pain, syncope, HF or even sudden death, and HCM is one of the main causes of sudden cardiac death in young adults ( 105 ). A growing body of evidence has suggested that necroptosis is also involved in the development of cardiac hypertrophy and HCM ( 22 , 23 ).…”

“…Previous studies have demonstrated that CaMKII expression was increased in cardiac hypertrophy and have also revealed that the regulation of CaMKIIδ alternative splicing may be related to cardiac function and was involved in cardiac hypertrophy in humans and mice ( 74 , 106 , 107 ). In a recent animal study, a murine model of HCM was constructed by subcutaneous infusion of angiotensin II using osmotic minipumps ( 22 ). The study revealed that, compared with those in the mice without myocardial hypertrophy (infusion of phosphate buffered solution), the levels of RIPK3 in HCM mice were markedly increased, and the levels of both the oxidation and phosphorylation of CaMKIIδ were also increased ( 22 ).…”

“…In a recent animal study, a murine model of HCM was constructed by subcutaneous infusion of angiotensin II using osmotic minipumps ( 22 ). The study revealed that, compared with those in the mice without myocardial hypertrophy (infusion of phosphate buffered solution), the levels of RIPK3 in HCM mice were markedly increased, and the levels of both the oxidation and phosphorylation of CaMKIIδ were also increased ( 22 ). The study also revealed that, compared with those in untreated mice, the levels of RIPK3, RIPK1, CaMKIIδ and p-MLKL were decreased in mice treated with the RIPK3 inhibitor (GSK'872) ( 22 ).…”

“…The study revealed that, compared with those in the mice without myocardial hypertrophy (infusion of phosphate buffered solution), the levels of RIPK3 in HCM mice were markedly increased, and the levels of both the oxidation and phosphorylation of CaMKIIδ were also increased ( 22 ). The study also revealed that, compared with those in untreated mice, the levels of RIPK3, RIPK1, CaMKIIδ and p-MLKL were decreased in mice treated with the RIPK3 inhibitor (GSK'872) ( 22 ). In another study by Wang et al ( 23 ), the oxidation and phosphorylation levels of CaMKIIδ were increased in myocardial cells in a phenylephrine (PE)-induced cardiac hypertrophy model, while downregulation of RIPK3 markedly inhibited CaMKII activation in PE-stimulated cardiomyocytes.…”

“…In addition, upregulation of RIPK3 in HCM mice resulted in CaMKIIδ alternative splicing impairment, a marked decrease in CaMKIIδA and CaMKIIδB expression, and a marked increase in CaMKIIδC expression compared with those of mice without myocardial hypertrophy, which in turn led to necroptosis of cardiomyocytes ( 22 , 23 ). However, compared with wild-type mice (infusion of angiotensin II), knockdown or deletion of RIPK3 inhibited CaMKII activation, corrected CaMKIIδ alternative splicing impairment, alleviated oxidative stress, reduced necroptosis and reversed myocardial injury in HCM mice ( 22 , 23 ). Therefore, targeting the RIPK3-CaMKII-mPTP signaling pathway may protect cardiomyocytes from necroptosis, which may be important for the prevention and treatment of HCM.…”