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The Effects of Relaxin and Estrogen Deficiency on Collagen Deposition and Hypertrophy of Nonreproductive Organs

Howard Florey Institute (E.D.L., C.Z., G.W.T., R.A.D.B., C.S.S.), University of Melbourne, Parkville, Victoria 3010, Australia; Baker Heart Research Institute (E.D.L., X.L.M., X.-J.D.), Melbourne, Victoria 8008, Australia; Department of Immunology (S.G.R., M.L.K.T.), Murdoch Children’s Research Institute, Royal Children’s Hospital, Parkville, Victoria 3052, Australia; and Department of Nephrology (T.D.H), Royal Melbourne Hospital, Parkville, Victoria 3050, Australia

Address all correspondence and requests for reprints to: Chrishan Samuel, Ph.D., Howard Florey Institute, Gate 11, University of Melbourne, Parkville, Victoria 3010, Australia. E-mail: c.samuel{at}hfi.unimelb.edu.au.

In this study, we determined the effects of relaxin and estrogen deficiency and estrogen replacement therapy (ERT) on the cardiac, renal, and pulmonary phenotypes of female relaxin gene knockout (Rln1–/–) and age-matched wild-type (Rln1+/+) mice. One-month-old Rln1+/+ and Rln1–/– mice were bilaterally ovariectomized or sham-operated and aged until 9 or 12 months. A subgroup of ovariectomized mice received ERT from 9 to 12 months of age. At the appropriate time points, heart, kidney, and lung tissues from these mice were collected and analyzed for changes in organ fibrosis, hypertrophy, and airway thickening. Neither ovariectomy nor ERT had any effect on cardiac or renal collagen concentration in all groups studied. In contrast, total lung collagen concentration and airway subepithelial collagen deposition were significantly increased in ovariectomized Rln1+/+ mice (P < 0.05 vs. sham) and to a greater extent in ovariectomized Rln1–/– mice (P < 0.01 vs. sham). Ovariectomy of Rln1+/+ mice also led to a significant increase in airway smooth muscle (SM) (lung) thickening, which was further exaggerated in Rln1–/– mice. Cardiac hypertrophy, evidenced by increased heart weight and expression of hypertrophy-related genes (all P < 0.05 vs. sham) was only observed in Rln1–/– mice. These findings demonstrated an increased pathology in mice that were deficient of both relaxin and estrogen. ERT significantly decreased airway fibrosis, airway SM thickening, and cardiac hypertrophy when administered to ovariectomized Rln1–/– mice (all P < 0.05 vs. ovariectomy alone). These findings suggest that relaxin and estrogen appear to play protective roles against airway fibrosis, airway SM thickening, and cardiac hypertrophy in female mice.

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