Aims/hypothesis: In a mouse model of diabetic cardiomyopathy (DCM) the expression of the circular RNA circHIPK3 was found to be significantly increased. This study aimed to discover the molecular mechanisms linking circHIPK3 to the pathogenesis of DCM.
Methods: The diabetic mouse model was established by i.p. injection of streptozotocin, which led to the development of DCM. Echocardiographic measurements were used to evaluate cardiac structure and function, and histological staining was applied to detect myocardial fibrosis in mice. 5-Ethynyl-2'-deoxyuridine incorporation was performed to determine cell proliferation and RNA fluorescent in situ hybridisation was employed to examine circHIPK3 expression in cardiac fibroblasts. RNA immunoprecipitation and luciferase reporter assay were conducted to explore the pathological mechanism of circHIPK3 in myocardial fibrosis.
Results: Knockdown of circHIPK3 was found to attenuate myocardial fibrosis and enhance cardiac function in DCM mice. In addition, silencing of circHIPK3 could suppress proliferation of cardiac fibroblasts treated with angiotensin II. Furthermore, RNA immunoprecipitation and luciferase reporter assay revealed a circHIPK3-miR-29b-3p-Col1a1-Col3a1 regulatory network in the pathogenesis of myocardial fibrosis.
Conclusions/interpretation: circHIPK3 contributes to increased myocardial fibrosis during DCM by functioning as a competing endogenous RNA that upregulates Col1a1 and Col3a1 expression through suppressing miR-29b-3p.
Keywords: Diabetic cardiomyopathy; Myocardial fibrosis; circHIPK3.