Fasudil alleviates pressure overload‐induced heart failure by activating Nrf2‐mediated antioxidant responses

• Published in: Journal of cellular biochemistry Vol. 119; no. 8; pp. 6452 - 6460
• Main Authors: Guan, Peng, Liang, Yingran, Wang, Na
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.08.2018
• Subjects: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine - analogs & derivatives; 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine - pharmacology; Animals; Antioxidants; Antioxidants - metabolism; Aorta; Banding; Cardiovascular system; Catalase; Deoxyribonucleic acid; Disease Models, Animal; DNA; Echocardiography; Enzyme inhibitors; fasudil; Glutathione; Glutathione peroxidase; Heart; Heart diseases; Heart failure; Heart Failure - drug therapy; Heart Failure - metabolism; Heart Failure - pathology; Heart Failure - physiopathology; Iron; Kinases; Male; Malondialdehyde; NF-E2-Related Factor 2 - metabolism; Nrf2; NRF2 protein; Nuclear transport; Oxidative stress; Oxidative Stress - drug effects; Peroxidase; Pressure; Rats; Rats, Sprague-Dawley; Receptors, Transferrin - biosynthesis; RhoA protein; Rodents; Superoxide dismutase; Transcriptional Activation - drug effects; Transferrin; Transferrins; Translocation; Transmission electron microscopy; heart failure; iron; Nrf2; fasudil; oxidative stress
• ISSN: 0730-2312; 1097-4644
• DOI: 10.1002/jcb.26662

The RhoA/Rho‐kinase cascade plays an important role in many aspects of cardiovascular function. This study aims to investigate the protective effects of fasudil, a Rho‐kinase inhibitor, on pressure overload induced heart failure in rats. Pressure overload induced heart failure was induced in SD rats by banding the abdominal aorta for 8 weeks. The rats were divided into four groups: Sham, TAC, TAC plus low dose of fasudil, and TAC plus high dose of fasudil group. Low dose and high dose fasudil were 5 and 10 mg/kg/day, respectively. Rats in the Sham and TAC groups were treated with vehicle. Fasudil effectively inhibited TAC‐induced heart failure, as evaluated by echocardiography and transmission electron microscopy. Fasudil could significantly promote superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) activity and significantly decrease malondialdehyde (MDA) content in a dose‐dependent maner in TAC rats. Consistently, fasudil evoked significant nuclear translocation of Nuclear factor (erythroid‐derived 2)‐like 2 (Nrf2) with increased DNA/promoter binding and transactivation of Nrf2 targets. In addition, fasudil increased the content of iron as well as transferrin receptor 1 (TfR1) in TAC rats. A mild oxidative stress induced by iron may activate the antioxidant enzymes by feedback response. Taken together, these results indicate that the protective effect of fasudil may be due to its strong antioxidative activities which related with the activated Nrf2 and its down‐regulated genes. These findings provide a new treatment concept and support the benefit of fasudil treatment in heart failure. Fasudil treatment prevents the ventricular dysfunction in pressure overload‐induced heart failure. The remarkable cardioprotection of fasudil was associated with activation of Nrf2. A mild oxidative stress induced by iron may activate the antioxidant enzymes by feedback response.