High molecular weight fibroblast growth factor-2 in the human heart is a potential target for prevention of cardiac remodeling.
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-AbHi-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-AbHi-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.
Institute of Cardiovascular Sciences, St. Boniface Hospital Research Centre, University of Manitoba, Winnipeg, Manitoba, Canada; Department of Physiology, University of Manitoba, Winnipeg, Manitoba, Canada.
Jon-Jon
JJ
Santiago
Institute of Cardiovascular Sciences, St. Boniface Hospital Research Centre, University of Manitoba, Winnipeg, Manitoba, Canada.
Leslie J
LJ
McNaughton
Institute of Cardiovascular Sciences, St. Boniface Hospital Research Centre, University of Manitoba, Winnipeg, Manitoba, Canada; Department of Physiology, University of Manitoba, Winnipeg, Manitoba, Canada.
Navid
N
Koleini
Institute of Cardiovascular Sciences, St. Boniface Hospital Research Centre, University of Manitoba, Winnipeg, Manitoba, Canada; Department of Human Anatomy & Cell Sciences, University of Manitoba, Winnipeg, Manitoba, Canada.
Xin
X
Ma
Institute of Cardiovascular Sciences, St. Boniface Hospital Research Centre, University of Manitoba, Winnipeg, Manitoba, Canada.
Brian
B
Bestvater
Institute of Cardiovascular Sciences, St. Boniface Hospital Research Centre, University of Manitoba, Winnipeg, Manitoba, Canada.
Barbara E
BE
Nickel
Institute of Cardiovascular Sciences, St. Boniface Hospital Research Centre, University of Manitoba, Winnipeg, Manitoba, Canada; Department of Human Anatomy & Cell Sciences, University of Manitoba, Winnipeg, Manitoba, Canada.
Robert R
RR
Fandrich
Institute of Cardiovascular Sciences, St. Boniface Hospital Research Centre, University of Manitoba, Winnipeg, Manitoba, Canada; Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Manitoba, Canada.
Jeffrey T
JT
Wigle
Institute of Cardiovascular Sciences, St. Boniface Hospital Research Centre, University of Manitoba, Winnipeg, Manitoba, Canada; Department of Surgery, University of Manitoba, Winnipeg, Manitoba, Canada.
Darren H
DH
Freed
Institute of Cardiovascular Sciences, St. Boniface Hospital Research Centre, University of Manitoba, Winnipeg, Manitoba, Canada; Department of Surgery, University of Manitoba, Winnipeg, Manitoba, Canada.
Rakesh C
RC
Arora
Institute of Cardiovascular Sciences, St. Boniface Hospital Research Centre, University of Manitoba, Winnipeg, Manitoba, Canada; Department of Human Anatomy & Cell Sciences, University of Manitoba, Winnipeg, Manitoba, Canada; Department of Physiology, University of Manitoba, Winnipeg, Manitoba, Canada.
Elissavet
E
Kardami
D000199:Actins / Q000378:metabolism; D000804:Angiotensin II / Q000378:metabolism; D001158:Arteries / Q000378:metabolism; D002478:Cells, Cultured; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism; D005355:Fibrosis / Q000378:metabolism; D006321:Heart / Q000502:physiology*; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D008970:Molecular Weight; D009206:Myocardium / Q000378:metabolism*; D058628:Myofibroblasts / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D011347:Procollagen / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D044139:Receptor, Angiotensin, Type 2 / Q000378:metabolism; D015854:Up-Regulation / Q000502:physiology
C541116:ACTA2 protein, human; D000199:Actins; D005353:Fibronectins; D053583:Interleukin-1beta; D017395:Plasminogen Activator Inhibitor 1; D011347:Procollagen; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D016222:Fibroblast Growth Factor 2; D000804:Angiotensin II; D020778:Matrix Metalloproteinase 2