Abstract P210: Human Atrial Nonmyocytes Secrete Prohypertrophic, High-Molecular-Weight FGF-2, Which Is Upregulated by Angiotensin II via AT-1 and AT-2 Receptors, as Well as ERK and MMP Activation
Background: Very little is known about the expression and role of fibroblast growth factor-2 (FGF-2) isoforms in the human heart. Using the rat model we have documented that high molecular weight Hi-FGF-2 rather than the commonly studied 18 kDa low molecular weight isoform Lo-FGF-2 is a potent inducer of cardiac hypertrophy in vitro and in vivo ; and that Hi-FGF-2 is expressed and secreted predominantly by cardiac non-myocytes (fibroblasts). We have now examined (i) the expression of Hi-FGF-2 in adult human heart (atria) and heart-derived non-myocytes (HDNM), and; (ii) signals regulating Hi-FGF-2 expression in HDNM. Methods/Results: Atrial tissue, obtained from patients undergoing cardiac surgery, (blinded study), was used to obtain extracts, and to isolate migratory cells (fibroblastic, HDNM). All tissue extracts (n=30) contained Hi- as well as Lo-FGF-2, assessed by Western blotting. Amounts of total FGF-2 varied from 1.5 - 25.5 pg per µg of extracted protein. Immunohistochemistry of paraffin-embedded atrial tissue sections and immunofluorescence of HDNM illustrated that human Hi-FGF-2 is localized mainly in the nucleus but is also present in cytoplasm. As was the case with rat- (ventricle and/or atria) derived fibroblasts, HDNM expressed predominantly Hi-FGF-2 (90% of total). The expression/secretion of Hi-FGF-2 by HDNM, as well as by human embryonic heart-derived fibroblasts, was significantly up-regulated by angiotensin II (Ang II). Simultaneous inhibition of both AT-1 as well as AT-2 receptors (by losartan and PD123319, respectively) was required to fully prevent Ang II-induced Hi-FGF-2 up-regulation. In addition, both inhibition of ERK activation (by U0126), or MMP activity (by MMP-2 Inhibitor I) fully prevented Ang II-induced up-regulation of human Hi-FGF-2. Conclusions: We have shown for the first time that human heart-derived fibroblastic cells express and secrete pro-hypertrophic Hi-FGF-2 in culture; and thus are likely to do so in vivo . Our data also suggest that the beneficial effects of drugs targeting Ang II signal transduction may be due, in part to their effects on Hi-FGF-2 accumulation.