Abstract
Fibroblast-to-myofibroblast transition (FMT) is the primary inducer of cardiac fibrosis. ONO-1301, a synthetic prostacyclin agonist, reportedly promotes tissue fibrosis repair by enhancing anti-fibrotic cytokine production. We hypothesized that ONO-1301 attenuates pressure-overloaded cardiac fibrosis by modulating FMT and generated a pressure-overloaded murine model via transverse aortic constriction (TAC) to evaluate the in vivo effects of ONO-1301. Cardiac fibrosis, left ventricular dilatation, and systolic dysfunction were established 4 weeks after TAC; however, ONO-1301 treatment initiated 2 weeks after TAC significantly attenuated those effects. Furthermore, ONO-1301 treatment significantly upregulated expression levels of cardioprotective cytokines such as vascular endothelial growth factor and hepatocyte growth factor in TAC hearts, whereas FMT-related factors, including transforming growth factor (TGF)-β1 and connective tissue growth factor, were significantly downregulated. The number of α-smooth muscle actin (α-SMA)- and vimentin-positive cells, representing fibroblast-originated cells transitioned into myofibroblasts, was significantly reduced in ONO-1301-treated TAC hearts. We isolated cardiac fibroblasts (CFs) from the left ventricles of adult male mice and assessed the effects of ONO-1301 on CFs stimulated by TGF-β. Results showed that ONO-1301 co-incubation significantly suppressed TGF-β-induced α-SMA expression and collagen synthesis, and significantly inhibited TGF-β-induced CF proliferation and migration. Our findings suggest that ONO-1301 ameliorates pressure overloaded cardiac fibrosis by inhibiting TGF-β-induced FMT.
Highlights
Cardiac fibrosis is a feature of myocardial failure and is associated with increased ventricular stiffness, arrhythmia, diastolic dysfunction, and combined systolic and diastolic dysfunction.[1]
The severity of cardiac fibrosis has been reported to be a predictor of mortality in patients with heart failure caused by hypertension, valvular heart disease, and nonischemic dilated cardiomyopathy.[2,3]
The heart weight (HW) to body weight (BW) ratio significantly increased in the vehicle group compared to that in the sham group (10.4 ± 0.6 versus 4.5 ± 0.1, p < 0.01), but it was significantly reduced in the ONO group relative to that in the vehicle group (6.7 ± 0.2, p < 0.01)
Summary
Cardiac fibrosis is a feature of myocardial failure and is associated with increased ventricular stiffness, arrhythmia, diastolic dysfunction, and combined systolic and diastolic dysfunction.[1]. Effective anti-fibrotic therapies have not been established.[4]. Cardiac fibrosis is characterized by excessive deposition of extracellular matrix (ECM) proteins by cardiac fibroblasts (CFs), which reduces tissue compliance and leads to the progression of heart failure.[5] After a myocardial injury, CFs are activated and transformed to the myofibroblast phenotype and secrete elevated levels of collagen and other ECM proteins. Transforming growth factor b (TGF-b) signaling plays a pivotal role in the process of accumulation of CFs and fibroblast-to-myofibroblast transition (FMT).[6] Previous studies using animal models suggested that cardiac fibrosis could be prevented by the inhibition of TGF-b. TGF-b-based antifibrotic therapies have been limited due to their adverse effects on immune function.[7,8]
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