Fasudil Protects Against Adriamycin-induced Acute Heart Injury by Inhibiting Oxidative Stress, Apoptosis, and Cellular Senescence.

Abstract

The clinical utility of Adriamycin (ADR) is limited due to its toxicity, particularly cardiotoxicity. Therefore, effective cardioprotective adjuvants to minimize ADR-induced acute cardiotoxicity are urgently needed. Our previous studies have demonstrated the protective roles of fasudil on tissue injury. Here, we further explore whether inhibition of Rho-kinase could alleviate the acute heart injury induced by ADR. C57BL6 mice were randomly divided into the following four groups: ① ADR group; ② low-dose fasudil (ADR+L); ③ high-dose fasudil (ADR+H); and ④ control group (CON). Animals were injected i.p 20 mg/kg ADR once in group ①~③. Animals were injected i.p fasudil (2 or 10 mg/kg/day) daily for consecutive 6 days in groups ② and ③, respectively. Blood samples and heart tissues were collected for assays. H9C2 cells were treated with fasudil for 30 mins and then incubated with ADR for 24 hours. Cells were collected for immunohistochemistry and western blot study, respectively. In the mouse model, administration of fasudil significantly ameliorated ADR-induced cardiac damage, suppressed cell apoptosis and senescence, and ameliorated redox imbalance and DNA damage. In vitro, fasudil treatment ameliorated ADR-induced immunofluorescence reaction of 8-OHdG, decreased the expression of TUNEL cells and proteins of Bax, Caspase-3 and p53, and increased the expression of proteins of Bcl-2 and SIRT 1. Fasudil has a protective effect on ADR induced acute cardiotoxicity, which is partially attributed to its antioxidant, anti-senescence, and anti-apoptotic effects.