title: Relaxin ameliorates fibrosis in experimental diabetic cardiomyopathy.
abstract: Fibrosis (extracellular matrix accumulation) is the final end point in diabetic cardiomyopathy. The current study evaluated the therapeutic effects of the antifibrotic hormone relaxin (RLX) in streptozotocin-treated transgenic mRen-2 rats, which undergo pathological and functional features similar to human diabetes. Twelve-week-old hyperglycemic mRen-2 rats, normoglycemic control rats, and animals treated with recombinant human gene-2 (H2) RLX from wk 10-12 were assessed for various measures of left ventricular (LV) fibrosis, hemodynamics, and function, while the mechanism of RLX's actions was also determined. Hyperglycemic mRen-2 rats had increased LV collagen concentration (fibrosis) and gelatinase activity (all P < 0.05 vs. controls) but equivalent levels of interstitial collagenase and tissue inhibitor of metalloproteinase-1 to that measured in control rats. The increased LV fibrosis associated with diabetic animals led to significant alterations in the E/A wave ratio and E-wave deceleration time (both P < 0.05 vs. controls) in the absence of blood pressure changes, reflective of myocardial stiffness and LV diastolic dysfunction. H2-RLX treatment of diabetic rats led to significant decreases in interstitial and total LV collagen deposition (both P < 0.05 vs. diabetic group), resulting in decreased myocardial stiffness and improved LV diastolic function, without affecting nondiabetic animals. The protective effects of H2-RLX in diabetic rats were associated with a reduction in mesenchymal cell differentiation and tissue inhibitor of metalloproteinase-1 expression in addition to a promotion of extracellular matrix-degrading matrix metalloproteinase-13 (all P < 0.05 vs. diabetic group) but were independent of blood pressure regulation. These findings demonstrate that RLX is an antifibrotic with rapid-occurring efficacy and may represent a novel therapy for the treatment of diabetes.
authors.affiliation: Howard Florey Institute and Department of Biochemistry and Molecular Biology, University of Melbourne, Victoria 3010, Australia. chrishan.samuel@florey.edu.au
authors.forename: Chrishan S
authors.initials: CS
authors.lastname: Samuel
authors.forename: Tim D
authors.initials: TD
authors.lastname: Hewitson
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Darren J
authors.initials: DJ
authors.lastname: Kelly
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D030801:Animals, Genetically Modified; D001794:Blood Pressure / Q000187:drug effects; D015153:Blotting, Western; D009202:Cardiomyopathies / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D003094:Collagen / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D004452:Echocardiography; D004789:Enzyme Activation / Q000187:drug effects; D005355:Fibrosis; D018093:Gelatinases / Q000378:metabolism; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D008297:Male; D053509:Matrix Metalloproteinase 13 / Q000378:metabolism; D051379:Mice; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism / Q000494:pharmacology; D012065:Relaxin / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D012083:Renin / Q000235:genetics / Q000502:physiology; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism
chemical_list: D000199:Actins; D003094:Collagen; D018093:Gelatinases; D053509:Matrix Metalloproteinase 13; D011994:Recombinant Proteins; D012065:Relaxin; D012083:Renin; D019715:Tissue Inhibitor of Metalloproteinase-1; C473112:Ren2 protein, mouse; C498862:Acta2 protein, rat