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Howard Florey Institute of Experimental Physiology and Medicine (C.S.S., I.M., R.A.D.B., S.L.L., G.W.T.), University of Melbourne, Victoria 3010, Australia; Connetics Corporation (E.N.U., J.M.), Palo Alto, California 94303; and Baker Heart Research Institute (X.-J.D.), Melbourne, Victoria 8008, Australia
Address all correspondence and requests for reprints to: Chrishan S. Samuel, Ph.D., Howard Florey Institute, Gate 11, University of Melbourne, Parkville, Victoria 3010, Australia. E-mail: c.samuel{at}hfi.unimelb edu.au.
Cardiac fibrosis is a key component of heart disease and involves the proliferation and differentiation of matrix-producing fibroblasts. The effects of an antifibrotic peptide hormone, relaxin, in inhibiting this process were investigated. We used rat atrial and ventricular fibroblasts, which respond to profibrotic stimuli and express the relaxin receptor (LGR7), in addition to two in vivo models of cardiac fibrosis. Cardiac fibroblasts, when plated at low density or stimulated with TGF-ß or angiotensin II (Ang II), accelerated fibroblast differentiation into myofibroblasts, as demonstrated by significantly increased 
-smooth muscle actin expression, collagen synthesis, and collagen deposition (by up to 95% with TGF-ß and 40% with Ang II; all P < 0.05). Fibroblast proliferation was significantly increased by 10–8 M and 10–7 M Ang II (63–75%; P < 0.01) or 0.1–1 µg/ml IGF-I (27–40%; P < 0.05). Relaxin alone had no marked effect on these parameters, but it significantly inhibited Ang II- and IGF-I-mediated fibroblast proliferation (by 15–50%) and Ang II- and TGF-ß-mediated fibroblast differentiation, as detected by decreased expression of -smooth muscle actin (by 65–88%) and collagen (by 60–80%). Relaxin also increased matrix metalloproteinase-2 expression in the presence of TGF-ß (P < 0.01) and Ang II (P < 0.05). Furthermore, relaxin decreased collagen overexpression when administered to two models of established fibrotic cardiomyopathy, one due to relaxin deficiency (by 40%; P < 0.05) and the other to cardiac-restricted overexpression of ß2-adrenergic receptors (by 58%; P < 0.01). These coherent findings indicate that relaxin regulates fibroblast proliferation, differentiation, and collagen deposition and may have therapeutic potential in diseased states characterized by cardiac fibrosis.
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Q. Xu, E. D. Lekgabe, X.-M. Gao, Z. Ming, G. W. Tregear, A. M. Dart, R. A. D. Bathgate, C. S. Samuel, and X.-J. Du Endogenous Relaxin Does Not Affect Chronic Pressure Overload-Induced Cardiac Hypertrophy and Fibrosis Endocrinology, February 1, 2008; 149(2): 476 - 482. [Abstract] [Full Text] [PDF]
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E. D. Lekgabe, S. G. Royce, T. D. Hewitson, M. L. K. Tang, C. Zhao, X. L. Moore, G. W. Tregear, R. A. D. Bathgate, X.-J. Du, and C. S. Samuel The Effects of Relaxin and Estrogen Deficiency on Collagen Deposition and Hypertrophy of Nonreproductive Organs Endocrinology, December 1, 2006; 147(12): 5575 - 5583. [Abstract] [Full Text] [PDF]
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E. D. Lekgabe, H. Kiriazis, C. Zhao, Q. Xu, X. L. Moore, Y. Su, R. A.D. Bathgate, X.-J. Du, and C. S. Samuel Relaxin Reverses Cardiac and Renal Fibrosis in Spontaneously Hypertensive Rats Hypertension, August 1, 2005; 46(2): 412 - 418. [Abstract] [Full Text] [PDF]
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 L. Formigli, F. Francini, A. Tani, R. Squecco, D. Nosi, L. Polidori, S. Nistri, L. Chiappini, V. Cesati, A. Pacini, et al. Morphofunctional integration between skeletal myoblasts and adult cardiomyocytes in coculture is favored by direct cell-cell contacts and relaxin treatment Am J Physiol Cell Physiol, April 1, 2005; 288(4): C795 - C804. [Abstract] [Full Text] [PDF]
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