Relaxin ameliorates fibrosis in experimental diabetic cardiomyopathy.
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.
Samuel
Chrishan S
CS
Howard Florey Institute and Department of Biochemistry and Molecular Biology, University of Melbourne, Victoria 3010, Australia. chrishan.samuel@florey.edu.au
Hewitson
Tim D
TD
Zhang
Yuan
Y
Kelly
Darren J
DJ
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
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