Factors and signals regulating expression of the pro-hypertrophic, high molecular weight FGF-2, by human cardiac myofibroblasts

Abstract

Bacl{gl'Ound. Chronic activation of the renin-aogiotensin-aldosterone axis causes maladaptive cardiac remodeling leading to heart failure. This is partially due to the conversion of cardiac fibroblasts to an 'activated' hyper-secretory myofibroblast phenotype. Fibroblast growth factor 2 (FGF-2) is a protein implicated in myofibroblast-mediated remodeling. FGF-2 exists as high (Hi-) and low molecular weight (Lo-) isoforms. Hi-FGF-2 stimulates cardiomyocyte hypertrophy and secretion of cytokines associated with heart failure. The main hypothesis under investigation is that human heart-derived myofibroblasts express Hi-FGF-2, which is upregulated by angiotensin II (Ang II), by a mechanism engaging the ATl (aod/or AT2) receptor(s), ERr< kinase, and/or matrix metalloprotease, MMP-2, activities. Also under investigation is the effect of an anti-hypertrophic polyphenol, resveratrol, on Hi-FGF-2 expression. Methods. Primary cultures of human patient heart-derived myofibroblasts were stimulated with Aug II, in the presence or absence of: inhibitors of the AT 1 or A T2 receptors, ERK, aod MMP-2; or resveratrol. Cell-associated FGF-2, and exported, cell surface-bound FGF- 2 levels were examined by western blot analyses, using aoti-FGF-2 antibodies. Results. Humao heart myofibroblasts express Hi-FGF-2, which was upregulated by Aug II. This upregulation was reduced by A Tl aod AT2 inhibitors, and eliminated by simultaneous ATl aod AT2 blockade. Inhibiting ERK, or MMP-2, or supplementing with resveratrol, eliminated the Aug II-induced Hi-FGF-2 upregulation. Conclusions. Chronic Aug II elevation in patients may exert some of its deleterious effects via cardiac myofibroblast Hi-FGF-2 upregulation. Both the ATl and AT2 receptors, as well as the ERK aod MMP-2 pathways, are potential targets to reduce Hi-FGF-2 levels. Furthermore, resveratrol, or clinically usable analogs, could be used to decrease myofibroblast Hi-FGF-2.