CaMKII activation and necroptosis augment in diabetic cardiomyopathy via
a RIPK3-dependent manner
Abstract
Background and Purpose 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 is crucially participated in cardiac dysfunction. The study
aimed to investigate the effect as well as mechanism of CaMKII
activation and necroptosis on diabetic cardiomyopathy (DCM).
Experimental Approach Primary cardiomyocytes were treated with AGEs (200
μg/mL) for 24 h. Cell injury, CaMKII activity and necroptosis were
detected. 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 feeding, 100 μL recombinant adenovirus
solution carrying I1PP1 gene were injected into the caudal vein of mice.
Echocardiography, myocardial injury, CaMKII activity, necroptosis, RIPK1
expression, MLKL phosphorylation, mitochondrial ultrastructure were
measured. Key Results 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. Cell
injury, CaMKII activation and necroptosis were augmented in advanced
glcation endproducts (AGEs)-stimulated cardiomyocytes, which was
attenuated after RIPK3 down-regulation. Furthermore, inhibitor 1 of
protein phosphatase 1 (I1PP1) over-expression reversed cardiac
dysfunction, myocardial injury and necroptosis augment, and CaMKII
activity enhancement in WT mice with DCM, but not in RIPK3 knockout mice
with DCM. Conclusion and Implications CaMKII activation and necroptosis
augment in DCM via a RIPK3-dependent manner, which may provide
therapeutic strategies for DCM.