Relaxin antagonizes hypertrophy and apoptosis in neonatal rat cardiomyocytes.
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 microM) 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 microM). 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.
Moore
Xiao-lei
XL
Baker Heart Research Institute, P.O. Box 6492, St. Kilda Road Central, Melbourne, Victoria 8008, Australia. shirley.moore@baker.edu.au
Tan
Su-ling
SL
Lo
Chen-yi
CY
Fang
Lu
L
Su
Yi-Dan
YD
Gao
Xiao-Ming
XM
Woodcock
Elizabeth A
EA
Summers
Roger J
RJ
Tregear
Geoffrey W
GW
Bathgate
Ross A D
RA
Du
Xiao-Jun
XJ
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D006332:Cardiomegaly / Q000517:prevention & control*; D049108:Cell Enlargement / Q000187:drug effects*; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000494:pharmacology; D032383:Myocytes, Cardiac / Q000187:drug effects*; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012065:Relaxin / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects
D051017:Apoptosis Regulatory Proteins; D017077:Culture Media, Conditioned; D012065:Relaxin