Cardioprotective effect of icariin against myocardial fibrosis and its molecular mechanism in diabetic cardiomyopathy based on network pharmacology: Role of ICA in DCM

Diabetic cardiomyopathy (DCM) is one of the most severe symptoms of diabetes. It continues to be a major clinical problem, but our knowledge of its molecular mechanisms and effective treatments are limited. Traditional Chinese medicine has been shown to be a pool of novel drugs for diabetes. Herein, we aim to define the molecular mechanism of icariin (ICA), an extract from a traditional Chinese medicine herb, in protecting cardiac structures and restoring cardiac functions of in a rat model of type 2 diabetes mellitus (T2DM). Candidate genes related to T2DM were identified through bioinformatics screening and their interactions were constructed by molecule docking technique, followed by pathway enrichment analyses of their cellular functions. A T2DM rat model was then established to evaluate the effects of ICA on cardiac structures, myocardial fibrosis, and cellular Ca2+ inflow, as reflected by HE and Masson staining, qRT-PCR and Western blot determination of related genes, and measurement of the L-type Ca2+ current. Four potential target genes (Jun, p65, NOS3, and PDE5A) were identified. ICA ameliorated the structural damage and myocardial fibrosis in T2DM rats. Intracellular Ca2+ hyperactivities and dysfunction in myocardium of T2DM rats were also repressed by ICA treatment. Furthermore, ICA-induced inhibition of Jun and p65 ameliorated the irregular collagen metabolism and myocardial fibrosis. NOS3, PDE5A and the related sGC-cGMP-PKG signaling pathway mediated the ICA-induced improvement of intracellular Ca2+ inflow. In conclusion, these results demonstrate the regulatory roles of potential target genes in DCM and suggest ICA as an effective treatment of DCM by targeting these genes specifically.