High Molecular Weight Fibroblast Growth Factor-2 in the Human Heart Is a Potential Target for Prevention of Cardiac Remodeling | Zendy

JonJon Santiago | Zendy; Leslie J. McNaughton | Zendy; Navid Koleini | Zendy; Xin Ma | Zendy; Brian P. Bestvater | Zendy; Barbara E. Nickel | Zendy; Robert R. Fandrich | Zendy; Jeffrey T. Wigle | Zendy; Darren H. Freed | Zendy; Rakesh C. Arora | Zendy; Elissavet Kardami | Zendy

Open Access

High Molecular Weight Fibroblast Growth Factor-2 in the Human Heart Is a Potential Target for Prevention of Cardiac Remodeling

Author(s) -

JonJon Santiago,

Leslie J. McNaughton,

Navid Koleini,

Xin Ma,

Brian P. Bestvater,

Barbara E. Nickel,

Robert R. Fandrich,

Jeffrey T. Wigle,

Darren H. Freed,

Rakesh C. Arora,

Elissavet Kardami

Publication year - 2014

Publication title -

plos one

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 0.99

H-Index - 332

ISSN - 1932-6203

DOI - 10.1371/journal.pone.0097281

Subject(s) - fibroblast growth factor , endocrinology , medicine , fibroblast , fibrosis , cardiac fibrosis , myofibroblast , fibronectin , chemistry , microbiology and biotechnology , biology , receptor , extracellular matrix , biochemistry , in vitro

Fibroblast growth factor 2 (FGF-2) is a multifunctional protein synthesized as high (Hi-) and low (Lo-) molecular weight isoforms. Studies using rodent models showed that Hi- and Lo-FGF-2 exert distinct biological activities: after myocardial infarction, rat Lo-FGF-2, but not Hi-FGF-2, promoted sustained cardioprotection and angiogenesis, while Hi-FGF-2, but not Lo-FGF-2, promoted myocardial hypertrophy and reduced contractile function. Because there is no information regarding Hi-FGF-2 in human myocardium, we undertook to investigate expression, regulation, secretion and potential tissue remodeling-associated activities of human cardiac (atrial) Hi-FGF-2. Human patient-derived atrial tissue extracts, as well as pericardial fluid, contained Hi-FGF-2 isoforms, comprising, respectively, 53%(±20 SD) and 68% (±25 SD) of total FGF-2, assessed by western blotting. Human atrial tissue-derived primary myofibroblasts (hMFs) expressed and secreted predominantly Hi-FGF-2, at about 80% of total. Angiotensin II (Ang II) up-regulated Hi-FGF-2 in hMFs, via activation of both type 1 and type 2 Ang II receptors; the ERK pathway; and matrix metalloprotease-2. Treatment of hMFs with neutralizing antibodies selective for human Hi-FGF-2 (neu-Ab Hi-FGF-2 ) reduced accumulation of proteins associated with fibroblast-to-myofibroblast conversion and fibrosis, including α-smooth muscle actin, extra-domain A fibronectin, and procollagen. Stimulation of hMFs with recombinant human Hi-FGF-2 was significantly more potent than Lo-FGF-2 in upregulating inflammation-associated proteins such as pro-interleukin-1β and plasminogen-activator-inhibitor-1. Culture media conditioned by hMFs promoted cardiomyocyte hypertrophy, an effect that was prevented by neu-Ab Hi-FGF-2 in vitro . In conclusion, we have documented that Hi-FGF-2 represents a substantial fraction of FGF-2 in human cardiac (atrial) tissue and in pericardial fluid, and have shown that human Hi-FGF-2, unlike Lo-FGF-2, promotes deleterious (pro-fibrotic, pro-inflammatory, and pro-hypertrophic) responses in vitro. Selective targeting of Hi-FGF-2 production may, therefore, reduce pathological remodelling in the human heart.

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