title: Antifibrotic response of cardiac fibroblasts in hypertensive hearts through enhanced TIMP-1 expression by basic fibroblast growth factor.
abstract: BACKGROUND
  Cardiac fibroblasts (CFs) play a pivotal role in the development of myocardial fibrosis. We previously demonstrated that direct injection of basic fibroblast growth factor (bFGF) into the hypertensive Dahl salt-sensitive (DS) rat heart prevented systolic dysfunction and left ventricular dilation effectively. However, the precise role played by bFGF in fibrotic response of CFs remains unclear. We suggested potential effects of bFGF on the fibrotic response of CFs in vitro.
  
  
  RESULTS
  Histopathologic assessment of cardiac fibrosis demonstrated a marked decline in the extent of perivascular and interstitial fibrosis in bFGF-injected hypertensive DS rat hearts. CFs harvested from the hearts of noninjected DS rats demonstrated a significantly increased messenger RNA (mRNA) expression of matrix metalloproteinase (MMP)-2, MMP-9, and both collagen I and III. In contrast, bFGF treatment in the CFs induced a marked increase in tissue inhibitor of MMP (TIMP)-1 expression and a marked decline in MMP-9 activation. bFGF also induced a decline in α-smooth muscle actin and collagen I and III mRNA expression in the CFs accompanied by inhibited differentiation of CFs into myofibroblasts. Small interfering RNA targeting FGF receptor 1 confirmed a specific interference of the mRNA expression changes elicited by bFGF. In vivo examination confirmed many TIMP-1-positive CFs in perivascular spaces of bFGF-injected hearts.
  
  
  CONCLUSIONS
  Up-regulated TIMP-1 expression and down-regulated MMP-9 activation by bFGF in CFs could prevent excessive ECM degradation and collagen deposition in perivascular spaces effectively, leading to prevention of cardiac fibrosis during hypertensive heart failure.
  
  
  CONCLUSIONS
  Cardiac fibroblasts (CFs) play a pivotal role in myocardial fibrosis. The precise role of CFs in fibrotic response played by growth factors remains unclear. Our results indicates that basic fibroblast growth factor could up-regulate TIMP-1 expression and down-regulate MMP-9 activation in CFs in perivascular spaces, leading to inhibited progression of cardiac fibrosis during hypertensive heart failure.
authors: Department of Cardiovascular Medicine, Toho University Faculty of Medicine, 6-11-1 Omori-Nishi, Ohta-City, Tokyo 143-8541, Japan.
authors: Toshio
authors: T
authors: Kinoshita
authors: Department of Pathology, School of Medicine, Toho University, 5-21-16 Omori-Nishi, Ohta-City, Tokyo 143-8540, Japan.
authors: Yukio
authors: Y
authors: Ishikawa
authors: Department of Molecular Immunology, School of Medicine, Toho University, 5-21-16 Omori-Nishi, Ohta-City, Tokyo 143-8540, Japan.
authors: Michitsune
authors: M
authors: Arita
authors: Department of Pathology, School of Medicine, Toho University, 5-21-16 Omori-Nishi, Ohta-City, Tokyo 143-8540, Japan.
authors: Yuri
authors: Y
authors: Akishima-Fukasawa
authors: Department of Pathology, School of Medicine, Toho University, 5-21-16 Omori-Nishi, Ohta-City, Tokyo 143-8540, Japan.
authors: Kazuko
authors: K
authors: Fujita
authors: Department of Plastic and Reconstructive Surgery, School of Medicine, Toho University, 5-21-16 Omori-Nishi, Ohta-City, Tokyo 143-8540, Japan.
authors: Naomi
authors: N
authors: Inomata
authors: Department of Cardiovascular Medicine, Toho University Faculty of Medicine, 6-11-1 Omori-Nishi, Ohta-City, Tokyo 143-8541, Japan.
authors: Takeya
authors: T
authors: Suzuki
authors: Department of Cardiovascular Medicine, Toho University Faculty of Medicine, 6-11-1 Omori-Nishi, Ohta-City, Tokyo 143-8541, Japan.
authors: Atsushi
authors: A
authors: Namiki
authors: Department of Pathology, School of Medicine, Toho University, 5-21-16 Omori-Nishi, Ohta-City, Tokyo 143-8540, Japan.
authors: Tetuo
authors: T
authors: Mikami
authors: Department of Cardiovascular Medicine, Toho University Faculty of Medicine, 6-11-1 Omori-Nishi, Ohta-City, Tokyo 143-8541, Japan.
authors: Takanori
authors: T
authors: Ikeda
authors: Department of Cardiovascular Medicine, Toho University Faculty of Medicine, 6-11-1 Omori-Nishi, Ohta-City, Tokyo 143-8541, Japan.
authors: Junichi
authors: J
authors: Yamazaki
authors: Department of Pathology, School of Medicine, Toho University, 5-21-16 Omori-Nishi, Ohta-City, Tokyo 143-8540, Japan.
authors: Toshiharu
authors: T
authors: Ishii
authors: Division of Chronic Inflammatory Diseases, Advanced Medical Research Center, Toho University Graduate School of Medicine, 5-21-16 Omori-Nishi, Ohta-City, Tokyo 143-8540, Japan. Electronic address: akasakay@med.toho-u.ac.jp.
authors: Yoshikiyo
authors: Y
authors: Akasaka
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D024061:Collagen Type III / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004789:Enzyme Activation; D016222:Fibroblast Growth Factor 2 / Q000008:administration & dosage*; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis; D006973:Hypertension / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D007267:Injections; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D020303:Rats, Inbred Dahl; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D017673:Sodium Chloride, Dietary; D013997:Time Factors; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism*
chemical_list: D000199:Actins; D024042:Collagen Type I; D024061:Collagen Type III; D016222:Fibroblast Growth Factor 2; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D012333:RNA, Messenger; D051496:Receptor, Fibroblast Growth Factor, Type 1; D017673:Sodium Chloride, Dietary; D019715:Tissue Inhibitor of Metalloproteinase-1; C576839:TIMP1 protein, rat; C498862:Acta2 protein, rat; C496350:Fgfr1 protein, rat; C522363:Mmp2 protein, rat; C572337:Mmp9 protein, rat
keywords: Basic fibroblast growth factor; Cardiac fibroblasts; Matrix metalloproteinase; Myocardial fibrosis; Tissue inhibitor of matrix metalloproteinase