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- Title
Preferential accumulation and export of high molecular weight FGF-2 by rat cardiac non-myocytes.
- Authors
Santiago, Jon-Jon; Ma, Xin; McNaughton, Leslie J.; Nickel, Barbara E.; Bestvater, Brian P.; Yu, Liping; Fandrich, Robert R.; Netticadan, Thomas; Kardami, Elissavet
- Abstract
Aims Fibroblast growth factor-2 (FGF-2), implicated in paracrine induction of cardiac hypertrophy, is translated as high molecular weight (Hi-FGF-2) and low molecular weight (Lo-FGF-2) isoforms. Paracrine activities are assigned to Lo-FGF-2, whereas Hi-FGF-2 is presumed to have nuclear functions. In this work, we re-examined the latter presumption by asking whether: cardiac non-myocytes (CNMs) accumulate and export Hi-FGF-2 in response to pro-hypertrophic [angiotensin II (Ang II)] stimuli; an unconventional secretory pathway requiring activated caspase-1 affects Hi-FGF2 export; and secreted Hi-FGF-2 is pro-hypertrophic. Methods and results Using neonatal rat heart-derived cultures and immunoblotting, we show that CNMs accumulated over 90% Hi-FGF-2, at levels at least five-fold higher than cardiomyocytes (CMs). Pro-hypertrophic agents (Ang II, endothelin-1, and isoproterenol) up-regulated CNM-associated Hi-FGF-2. The Ang II effect was mediated by Ang II receptor-1 but not Ang II receptor-2 as it was blocked by losartan but not PD123319. CNM-derived Hi-FGF-2 was detected in two extracellular pools: in conditioned medium from Ang II-stimulated CNMs and in association with the cell surface/matrix, eluted with a gentle 2 M NaCl wash of the cell monolayer. Conditioned medium from Ang II-treated CNMs increased neonatal CM size, an effect prevented by anti-FGF-2-neutralizing antibodies. The caspase-1 inhibitor YVAD prevented the Ang II-induced release of Hi-FGF-2 to both extracellular pools. Conclusion CNMs are major producers of Hi-FGF-2, up-regulated by hypertrophic stimuli and exported to the extracellular environment by a mechanism requiring caspase-1 activity, suggesting a link to the innate immune response. Hi-FGF-2 is likely to promote paracrine induction of myocyte hypertrophy in vivo.
- Subjects
FIBROBLAST growth factors; MOLECULAR weights; MUSCLE cells; LABORATORY rats; CARDIAC hypertrophy; PARACRINE mechanisms; ANGIOTENSIN II
- Publication
Cardiovascular Research, 2011, Vol 89, Issue 1, p139
- ISSN
0008-6363
- Publication type
Article
- DOI
10.1093/cvr/cvq261