Dual effect of heparin on cultured adult rat cardiomyocytes

Heparin has been widely reported to inhibit the growth of several cell types including neonatal rat cardiac myocyte (NRCM) but its effect on adult rat ventricular myocyte (ARVM) is unknown. To determine whether heparin is able to modulate ARVM protein synthesis capacity and if so which pathway is involved in this response, ARVM were cultured in presence or absence of 5% human serum and exposed to heparin (2–2,000 μg/ml) or its analogue xylan (0.5 and 50 μg/ml), and either the Ca 2+ chelator BAPTA/AM (10 μg/ml), or the calcineurin inhibitor FK506 (10 μg/ml), and heparinase I (0.1–10 U/ml) for 2 days. The protein synthesis (PS) was measured after 24 h incorporation of [14C]‐Phenylalanine in ARVM. Independently of the serum presence, heparin and xylan altered PS in a bimodal dose‐dependent manner. At high doses, heparin and xylan (2,000 and 50 μg/ml, respectively) either had no effect (without serum) or inhibited PS (with serum). In absence of serum, low doses of heparin or xylan (20 and 0.5 μg/ml, respectively) amplified the PS process in ARVM (2‐fold, P  < 0.05). FK506 inhibited the trophic response to 20 μg/ml heparin alone (−39%, P  < 0.05). In presence of serum, the heparin induced‐trophic effect, that was not significantly altered by FK506, was inhibited by BAPTA/AM (−32%, P  < 0.05). Finally, heparinase I that increased PS in NRCM had no effect on ARVM growth. This study strongly suggests that heparin dose‐dependently modulated PS in ARVM, this result being not observed in neonatal cells. Different mechanisms involving intracellular Ca 2+ play a role in the PS response of ARVM to low concentrations of heparin, the intracellular pathways depending on the presence of serum. © 2004 Wiley‐Liss, Inc.