Cardiac fibrosis is associated with disruptions of the myocardial architecture through changes in volume, composition and organisation of the extracellular matrix. Ivabradine (IVA), a selective inhibitor of the pacemaker current, has shown to have beneficial effects on pathological remodelling. As fibroblasts are the predominant mediators of fibrosis we investigated whether IVA has direct effects on fibroblasts. Heart failure (HF) was induced by permanent coronary artery ligation in rats; sham-operated animals (S) were used as controls. After 12 weeks, HF animals were treated either with IVA or saline (HF-S) for a further 4 weeks. Discoidin domain-containing receptor-2 (DDR-2) and α-smooth muscle actin (α-SMA) were measured as markers of fibroblasts and activated fibroblasts respectively. IVA reduced the DDR-2 (in arbitrary units (a.u.), S: 0.33 ± 0.03, n = 4; HF-S: 0.77 ± 0.06, n = 5; HF-IVA: 0.57 ± 0.02, n = 5; p < 0.05) and α-SMA (S: 0.50 ± 0.13, n = 5; HF-S: 1.00 ± 0.13, n = 6; HF-IVA: 0.44 ± 0.08, n = 4; p < 0.05) expression observed in HF to sham levels. Chronic effects (4 weeks) of IVA (30 nM and 1 uM) were assessed on left ventricular fibroblasts isolated from a patient with dilated cardiomyopathy investigating α-SMA expression. IVA decreased α-SMA expression in fibroblasts (control: 535 ± 41; IVA 30 nM: 363 ± 20; IVA 1 uM: 181 ± 36; n = 4; p < 0.05). Expression of TGF-b1 (S: 0.26 ± 0.03, n = 4; HF-S: 0.49 ± 0.02, n = 5; HF-IVA: 0.34 ± 0.01, n = 4; p < 0.05) and SMAD-2 (S: 0.23 ± 0.01, n = 4; HF-S: 0.40 ± 0.04, n = 5; HF-IVA: 0.25 ± 0.03, n = 5; p < 0.05) was up-regulated during HF but IVA normalised this to sham levels. Our results on reduced TGF-b1 and α-SMA expression highlight a beneficial role of IVA in the reparative process of the failing heart.
Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.