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.
Highlights
Diabetes mellitus (DM) is an independent risk factor of diabetic cardiomyopathy (DCM), in the deficiency of coronary artery diseases, hypertension, and other cardiovascular risk factors
FPG, HbA1c, serum TG, and myocardial hypertrophic gene expression were increased significantly in mice with DCM, which suggested that STZ injection produced diabetes mellitus (Figure S1)
As apoptosis is a critical manifestation of necroptosis, TdT-Mediated dUTP Nick End Labeling (TUNEL) staining and cleaved-caspase 3
Summary
Diabetes mellitus (DM) is an independent risk factor of diabetic cardiomyopathy (DCM), in the deficiency of coronary artery diseases, hypertension, and other cardiovascular risk factors. DCM is characterized by a series of structural and functional abnormalities, including myocardial stiffness, contractility impairment, myocardial fibrosis, and hypertrophy [1, 2]. Special attention must be paid to DCM due to its concealed onset, rapid evolution but poor treatment efficacy. Possible pathophysiological factors of DCM involve hyperglycemia, hyperlipidemia, insulin resistance, oxidative stress, endoplasmic reticulum stress, cardiomyocyte death, and mitochondrial dysfunction [3, 4]. Investigation to find out potential preventative and therapeutic strategies is an urgent problem to be solved
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