Irisin Treatment Prevents Isoproterenol-Induced Cardiac Fibrosis in Mice.

Abstract

Background: Cardiac fibrosis is a pathophysiological process that occurs as the end stage of cardiovascular diseases. Irisin is a myokine secreted mainly by skeletal muscle exerting pleiotropic effects. Previous studies found altered irisin levels in patients with cardiovascular diseases and irisin has been shown to preserve cardiac function after ischemia-reperfusion injury in mice. This study aimed to explore whether pretreatment with irisin prevents cardiac fibrosis induced in mice through a single injection of the beta-adrenergic agonist isoproterenol at a high dose.

Methods: The cardiac fibrosis model was obtained through a single intraperitoneal administration of 160 mg/kg isoproterenol [ISO] in young C57BL/6J mice. Before ISO injection, mice were pretreated with irisin 100 μg/kg/week [irisin-ISO] or saline [veh-ISO] for 4 weeks. A third group of mice received saline for 4 weeks without ISO injection [CTRL].

Results: The mice pretreated with irisin recovered faster than vehicle-treated mice after acute ISO stimulation, as measured by behavioral test. Twenty-four hours after ISO treatment, the serum levels of Troponin I were significantly lower in the group of mice pretreated with irisin compared with veh-ISO mice (p = 0.0117). Moreover, the expression of atrial natriuretic peptide (p = 0.0197) and alpha-smooth muscle actin (p = 0.0261) mRNAs in cardiac tissue of veh-ISO mice were 10- and 15-fold higher than CTRL mice, respectively, while pretreatment with irisin maintained their expression at control levels. Interestingly, 7 days after ISO, the expression of alpha-smooth muscle actin mRNA was still significantly lower in the irisin-ISO group than in the veh-ISO group (p = 0.0145). Moreover, we found increased cardiac hypertrophy, measured as heart-weight/tibia-length ratio, in veh-ISO mice versus CTRL mice (p = 0.0312) which was fully prevented in irisin-ISO mice (p = 0.0258). The cardiac fibrosis score assessed by Masson's trichrome staining was significantly lower in irisin-ISO mice versus veh-ISO mice (p = 0.0261). Notably, some mitochondrial genes, previously identified as controlled by irisin, were markedly increased in the early phase following ISO, whereas irisin maintained their expression similar to controls.

Conclusion: Our results demonstrate the beneficial effect of irisin in preventing isoproterenol-induced cardiac hypertrophy and fibrosis.