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Relaxin Antagonizes Hypertrophy and Apoptosis in Neonatal Rat Cardiomyocytes

Baker Heart Research Institute (X.L.M., S.L.T., C.Y.L., L.F., Y.D.S., X.M.G., E.A.W., X.J.D.), Melbourne, Victoria 8008, Australia; Howard Florey Institute of Experimental Physiology and Medicine (G.W.T., R.A.D.B.), University of Melbourne, Melbourne, Victoria 3010, Australia; and Department of Pharmacology (R.J.S.), Monash University, Clayton, Victoria 3800, Australia

Address all correspondence and requests for reprints to: X. L. Moore, Baker Heart Research Institute, P.O. Box 6492, St. Kilda Road Central, Melbourne, Victoria 8008, Australia. E-mail: shirley.moore{at}baker.edu.au.

The pregnancy hormone relaxin has recently been shown to be cardio-protective. Despite its well-established antifibrotic actions in the heart, the effects of relaxin on cardiomyocytes (CM) remain to be determined. We investigated effects of isoform 2 of the human relaxin (H2-relaxin) on CM hypertrophy and apoptosis. In cultured neonatal rat CM, phenylephrine (50 µM) and cardiac fibroblast-conditioned medium were used respectively to induce CM hypertrophy. The degree of hypertrophy was indicated by increased cell size, protein synthesis and gene expression of atrial natriuretic peptide. Although H2-relaxin (16.7 nM) alone failed to suppress hypertrophy induced by phenylephrine, it repressed the cardiac fibroblast-conditioned medium-induced increase in protein synthesis by 24% (P < 0.05) and reversed the increase in cell size (P < 0.001) and atrial natriuretic peptide expression (P<0.01). We further studied the effect of H2-relaxin on CM apoptosis induced by H₂O₂ (200 µM). Studies of DNA laddering and nuclear staining demonstrated that H2-relaxin treatment reduced H₂O₂-induced DNA fragmentation. Real-time PCR and Western blot analysis revealed a significant increase in the Bcl2/Bax ratio in H2-relaxin-treated CM. Further analysis showed that activation of Akt (1.8-fold, P< 0.001) and ERK (2.0-fold, P<0.01) were involved in the antiapoptotic action of H2-relaxin in CM, and that Gi/o coupling of relaxin receptors was associated with the H2-relaxin-induced Akt activation in CM. In conclusion, these results extend our current knowledge of the cardiac actions of relaxin by demonstrating that H2-relaxin indirectly inhibits CM hypertrophy and directly protects CM from apoptosis.

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