Heparin and heparan sulfate block angiotensin II-induced hypertrophy in cultured neonatal rat cardiomyocytes. A possible role of intrinsic heparin-like molecules in regulation of cardiomyocyte hypertrophy.
BACKGROUND: Heparan sulfate, one of the primary components of extracellular matrix, is a potent antigrowth factor in certain types of cells. To elucidate a possible role of endogenous heparin-like molecules in regulating cardiomyocyte hypertrophy, we investigated the effects of heparin and heparan sulfate on angiotensin ( Ang) II-induced hypertrophy in cultured neonatal rat cardiomyocytes. METHODS AND RESULTS: Competitive [3H]heparin binding assay showed that cardiomyocytes had specific binding sites for heparin. In situ [3H]heparin binding assay demonstrated that heparin, which rapidly bound to the cardiomyocyte surface, was subsequently accumulated around the nuclei, suggesting that heparin might work in the nucleus. Cotreatment with heparin (20 micrograms/mL) completely inhibited increased cell surface area by Ang II (10(-6) mol/L). Increased [3H]leucine incorporation by Ang II was reduced by heparin dose-dependently. The inhibitory effect of heparin on Ang II-induced cardiomyocyte hypertrophy also was confirmed by Northern blot analysis: heparin dose-dependently inhibited skeletal alpha-actin and atrial natriuretic peptide gene expression, genetic markers for cardiomyocyte hypertrophy. Heparan sulfate showed similar inhibitory effects on cell surface area, [3H]leucine incorporation, and skeletal alpha-actin gene expression. Treatment with heparinase I or III, which specifically digests the disaccharide chains of endogenous heparin-like molecules, upregulated protein synthesis and skeletal alpha-actin and atrial natriuretic peptide gene expression in cardiomyocytes. CONCLUSIONS: Our findings in this study strongly suggest that heparin and heparan sulfate are potent inhibitors of cardiomyocyte hypertrophy and that endogenous heparin-like substances negatively regulate cardiomyocyte hypertrophy.[1]References
- Heparin and heparan sulfate block angiotensin II-induced hypertrophy in cultured neonatal rat cardiomyocytes. A possible role of intrinsic heparin-like molecules in regulation of cardiomyocyte hypertrophy. Akimoto, H., Ito, H., Tanaka, M., Adachi, S., Hata, M., Lin, M., Fujisaki, H., Marumo, F., Hiroe, M. Circulation (1996) [Pubmed]
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