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(Circulation. 1996;93:810-816.)
© 1996 American Heart Association, Inc.

Articles

Heparin and Heparan Sulfate Block Angiotensin IIInduced Hypertrophy in Cultured Neonatal Rat Cardiomyocytes

A Possible Role of Intrinsic Heparin-like Molecules in Regulation of Cardiomyocyte Hypertrophy

Hajime Akimoto, MD; Hiroshi Ito, MD; Masato Tanaka, MD; Susumu Adachi, MD; Mimi Hata, MD; Meihong Lin, MD; Hiroyuki Fujisaki, MD; Fumiaki Marumo, MD; Michiaki Hiroe, MD

From the Second Department of Internal Medicine, Tokyo (Japan) Medical and Dental University.

Correspondence to Hiroshi Ito, MD, Second Department of Internal Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113 Japan.

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 µg/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 -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 -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 -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.

Key Words: angiotensin • heparin • hypertrophy

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