on June 10, 2002
Circulation. 2002
Published online before print June 10, 2002, doi: 10.1161/01.CIR.0000020689.12472.E0
Published online before print June 10, 2002, doi: 10.1161/01.CIR.0000020689.12472.E0
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Submitted on February 22, 2002
From the Cardiovascular Research Institute and Internal Medicine III, Kurume University School of Medicine, Kurume (F.K., H.K., K.T., T.I.); the Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka (M.K.); and Cardiovascular Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka (A.T., K.E.), Japan. * To whom correspondence should be addressed. E-mail: naikai{at}med.kurume-u.ac.jp.
Background—Excessive myocardial fibrosis impairs cardiac function in hypertensive hearts. Roles of transforming growth factor (TGF)-ß in myocardial remodeling and cardiac dysfunction were examined in pressure-overloaded rats. Methods and Results—Pressure overload was induced by a suprarenal aortic constriction in Wistar rats. Fibroblast activation (proliferation and phenotype transition to myofibroblasts) was observed after day 3 and peaked at days 3 to 7. Thereafter, myocyte hypertrophy and myocardial fibrosis developed by day 28. At day 28, echocardiography showed normal left ventricular fractional shortening, but the decreased ratio of early to late filling velocity of the transmitral Doppler velocity and hemodynamic measurement revealed left ventricular end-diastolic pressure elevation, indicating normal systolic but abnormal diastolic function. Myocardial TGF-ß mRNA expression was induced after day 3, peaked at day 7, and remained modestly increased at day 28. An anti--TGF-ß neutralizing antibody, which was administered intraperitoneally daily from 1 day before operation, inhibited fibroblast activation and subsequently prevented collagen mRNA induction and myocardial fibrosis, but not myocyte hypertrophy. Neutralizing antibody reversed diastolic dysfunction without affecting blood pressure and systolic function. Conclusions—TGF-ß plays a causal role in myocardial fibrosis and diastolic dysfunction through fibroblast activation in pressure-overloaded hearts. Our findings may provide an insight into a new therapeutic strategy to prevent myocardial fibrosis and diastolic dysfunction in pressure-overloaded hearts.
Revised on April 19, 2002
Accepted on April 22, 2002
Transforming Growth Factor-ß Function Blocking Prevents Myocardial Fibrosis and Diastolic Dysfunction in Pressure-Overloaded Rats
Fumitaka Kuwahara MD,
Key words: growth substances • fibrosis • hypertension • diastole
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