Toshio Kinoshita1, Yukio Ishikawa2, Michitsune Arita3, Yuri Akishima-Fukasawa2, Kazuko Fujita2, Naomi Inomata4, Takeya Suzuki1, Atsushi Namiki1, Tetuo Mikami2, Takanori Ikeda1, Junichi Yamazaki1, Toshiharu Ishii2, Yoshikiyo Akasaka5. 1. Department of Cardiovascular Medicine, Toho University Faculty of Medicine, 6-11-1 Omori-Nishi, Ohta-City, Tokyo 143-8541, Japan. 2. Department of Pathology, School of Medicine, Toho University, 5-21-16 Omori-Nishi, Ohta-City, Tokyo 143-8540, Japan. 3. Department of Molecular Immunology, School of Medicine, Toho University, 5-21-16 Omori-Nishi, Ohta-City, Tokyo 143-8540, Japan. 4. Department of Plastic and Reconstructive Surgery, School of Medicine, Toho University, 5-21-16 Omori-Nishi, Ohta-City, Tokyo 143-8540, Japan. 5. 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.
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. METHODS AND 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. SUMMARY: 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.
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 hypertensiveDahl 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. METHODS AND RESULTS: Histopathologic assessment of cardiac fibrosis demonstrated a marked decline in the extent of perivascular and interstitial fibrosis in bFGF-injected hypertensiveDSrat hearts. CFs harvested from the hearts of noninjected DSrats 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. SUMMARY: 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: Viswanathan Rajagopalan; Youhua Zhang; Christine Pol; Clifford Costello; Samantha Seitter; Ann Lehto; Olga V Savinova; Yue-Feng Chen; A Martin Gerdes Journal: Front Physiol Date: 2017-04-12 Impact factor: 4.566
Authors: Daniyil A Svystonyuk; Holly E M Mewhort; Ali Fatehi Hassanabad; Bobak Heydari; Yoko Mikami; Jeannine D Turnbull; Guoqi Teng; Darrell D Belke; Karl T Wagner; Samar A Tarraf; Elena S DiMartino; James A White; Jacqueline A Flewitt; Matthew Cheung; David G Guzzardi; Sean Kang; Paul W M Fedak Journal: Sci Rep Date: 2020-06-11 Impact factor: 4.379