Relaxin modulates cardiac fibroblast proliferation, differentiation, and collagen production and reverses cardiac fibrosis in vivo.
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-beta or angiotensin II (Ang II), accelerated fibroblast differentiation into myofibroblasts, as demonstrated by significantly increased alpha-smooth muscle actin expression, collagen synthesis, and collagen deposition (by up to 95% with TGF-beta 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 microg/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-beta-mediated fibroblast differentiation, as detected by decreased expression of alpha-smooth muscle actin (by 65-88%) and collagen (by 60-80%). Relaxin also increased matrix metalloproteinase-2 expression in the presence of TGF-beta (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 beta2-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.
Samuel
Chrishan S
CS
Howard Florey Institute, Gate 11, University of Melbourne, Parkville, Victoria 3010, Australia. c.samuel@hfi.unimelb. edu.au.
Unemori
Elaine N
EN
Mookerjee
Ishanee
I
Bathgate
Ross A D
RA
Layfield
Sharon L
SL
Mak
John
J
Tregear
Geoffrey W
GW
Du
Xiao-Jun
XJ
D000595:Amino Acid Sequence; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D009202:Cardiomyopathies / Q000188:drug therapy* / Q000473:pathology*; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000166:cytology / Q000473:pathology*; D005355:Fibrosis; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000473:pathology*; D009419:Nerve Tissue Proteins / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics; D043562:Receptors, G-Protein-Coupled; D018000:Receptors, Peptide / Q000235:genetics; D012065:Relaxin / Q000235:genetics / Q000494:pharmacology*; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D009419:Nerve Tissue Proteins; C466742:RLN3 protein, rat; D012333:RNA, Messenger; D018343:Receptors, Adrenergic, beta-2; D043562:Receptors, G-Protein-Coupled; D018000:Receptors, Peptide; D016212:Transforming Growth Factor beta; D014662:Vasoconstrictor Agents; C033395:relaxin receptors; D000804:Angiotensin II; D012065:Relaxin; D003094:Collagen; D000242:Cyclic AMP; D020782:Matrix Metalloproteinases