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.
- © 2011 by American Heart Association, Inc.