RIPK3-Mediated Necroptosis in Diabetic Cardiomyopathy Requires CaMKII Activation.

Abstract

Activation of Ca2+/calmodulin-dependent protein kinase (CaMKII) has been proved to play a vital role in cardiovascular diseases. Receptor-interaction protein kinase 3- (RIPK3-) mediated necroptosis has crucially participated in cardiac dysfunction. The study is aimed at investigating the effect as well as the mechanism of CaMKII activation and necroptosis on diabetic cardiomyopathy (DCM). Wild-type (WT) and the RIPK3 gene knockout (RIPK3-/-) mice were intraperitoneally injected with 60 mg/kg/d streptozotocin (STZ) for 5 consecutive days. After 12 w of feeding, 100 μL recombinant adenovirus solution carrying inhibitor 1 of protein phosphatase 1 (I1PP1) gene was injected into the caudal vein of mice. Echocardiography, myocardial injury, CaMKII activity, necroptosis, RIPK1 expression, mixed lineage kinase domain-like protein (MLKL) phosphorylation, and mitochondrial ultrastructure were measured. The results showed that cardiac dysfunction, CaMKII activation, and necroptosis were aggravated in streptozotocin- (STZ-) stimulated mice, as well as in (Lepr) KO/KO (db/db) mice. RIPK3 deficiency alleviated cardiac dysfunction, CaMKII activation, and necroptosis in DCM. Furthermore, I1PP1 overexpression reversed cardiac dysfunction, myocardial injury and necroptosis augment, and CaMKII activity enhancement in WT mice with DCM but not in RIPK3-/- mice with DCM. The present study demonstrated that CaMKII activation and necroptosis augment in DCM via a RIPK3-dependent manner, which may provide therapeutic strategies for DCM.

• Authors: Yun Chen, Xinshuai Li, Yuyun Hua, Yue Ding, Guoliang Meng, Wei Zhang
• Journal: Oxidative medicine and cellular longevity (Oxid Med Cell Longev) Vol. 2021 Pg. 6617816 ( 2021) ISSN: 1942-0994 [Electronic] United States
• PMID: 34194608 (Publication Type: Journal Article)
• Copyright: Copyright © 2021 Yun Chen et al.

Chemical References

• Receptor-Interacting Protein Serine-Threonine Kinases
• Ripk3 protein, mouse
• Calcium-Calmodulin-Dependent Protein Kinase Type 2

Topics

• Animals
• Calcium-Calmodulin-Dependent Protein Kinase Type 2 (metabolism)
• Diabetes Complications (complications)
• Diabetic Cardiomyopathies (genetics)
• Disease Models, Animal
• Humans
• Male
• Mice
• Mice, Knockout
• Necroptosis (genetics)
• Receptor-Interacting Protein Serine-Threonine Kinases (metabolism)