Abstract
Cardiac fibrosis is a major pathological manifestation of diabetic cardiomyopathy, which is a leading cause of mortality in patients with diabetes. MicroRNA (miR)‑155 is upregulated in cardiomyocytes in cardiac fibrosis, and the aim of the present study was to investigate if the inhibition of miR‑155 was able to ameliorate cardiac fibrosis by targeting the nuclear factor erythroid‑2‑related factor 2 (Nrf2)/heme oxygenase‑1 (HO‑1) signaling pathway. H9C2 rat cardiomyocytes were cultured with high glucose (HG; 30 mM) to establish an in vitro cardiac fibrosis model that mimicked diabetic conditions; a miR‑155 inhibitor and a miR‑155 mimic were transfected into H9C2 cells. Following HG treatment, H9C2 cells exhibited increased expression levels of miR‑155 and the fibrosis markers collagen I and α‑smooth muscle actin (α‑SMA). In addition, the expression levels of endonuclear Nrf2 and HO‑1 were decreased, but the expression level of cytoplasmic Nrf2 was increased. Moreover, oxidative stress, mitochondrial damage and cell apoptosis were significantly increased, as indicated by elevated reactive oxygen species, malonaldehyde and monomeric JC‑1 expression levels. In addition, superoxide dismutase expression was attenuated and there was an increased expression level of released cytochrome‑c following HG treatment. Furthermore, it was demonstrated that expression levels of Bcl‑2 and uncleaved Poly (ADP‑ribose) polymerase were downregulated, whereas Bax, cleaved caspase‑3 and caspase‑9 were upregulated after HG treatment. However, the miR‑155 inhibitor significantly restored Nrf2 and HO‑1 expression levels, and reduced oxidative stress levels, the extent of mitochondrial damage and the number of cells undergoing apoptosis. Additionally, the miR‑155 inhibitor significantly reversed the expression levels of collagen I and α‑SMA, thus ameliorating fibrosis. Furthermore, the knockdown of Nrf2 reversed the above effects induced by the miR‑155 inhibitor. In conclusion, the miR‑155 inhibitor may ameliorate diabetic cardiac fibrosis by reducing the accumulation of oxidative stress‑related molecules, and preventing mitochondrial damage and cardiomyocyte apoptosis by enhancing the Nrf2/HO‑1 signaling pathway. This mechanism may facilitate the development of novel targets to prevent cardiac fibrosis in patients with diabetes.