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Relaxin Ameliorates Fibrosis in Experimental Diabetic Cardiomyopathy

Howard Florey Institute (C.S.S.) and Department of Biochemistry and Molecular Biology (C.S.S.), University of Melbourne, Victoria 3010, Australia; Department of Nephrology (T.D.H.), Royal Melbourne Hospital and Department of Medicine (T.D.H), Royal Melbourne Hospital, University of Melbourne, Victoria 3050, Australia; and Department of Medicine (Y.Z., D.J.K.), University of Melbourne, St. Vincent’s Hospital, Victoria 3065, Australia

Address all correspondence and requests for reprints to: Dr. Chrishan Samuel, Howard Florey Institute and Department of Biochemistry and Molecular Biology, University of Melbourne, Victoria 3010, Australia. E-mail: chrishan.samuel{at}florey.edu.au; or Associate Professor Darren Kelly, Department of Medicine, University of Melbourne, St. Vincent’s Hospital, Victoria 3065, Australia. E-mail: dkelly{at}medstv.unimelb.edu.au.

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.