Dynamic Alterations in the Expression of P2Y12 Receptor but Not COX-1 in Platelets from Streptozocin-Induced Diabetic Rats.

In patients or animals with established diabetes mellitus, platelets have been shown to be hyperreactive to ADP. This alteration of the platelet function occurs independent of activation of the arachidonate pathway or release of dense granule contents. In the present study, we examined the expression of the platelet ADP-binding receptor, P2Y12, in early stage of streptozocin(STZ)-induced diabetes in rats. Platelet messenger RNA (mRNA) levels for P2Y12 and cyclooxygenase-1 (COX-1) were determined by comparative RT-PCR in 7 control rats on day 0, 6 diabetic rats each on days 2, 3, 4, and 4 diabetic rats on day 7 after intraperitoneal injection of streptozocin (50 mg/kg). The plasma glucose level was 406 ± 10 mg/dl in diabetic rats, significantly greater than 151 ± 12 mg/dl in control rats. After induction of diabetes, the expression of P2Y12 mRNA significantly decreased to 76 ± 9% of the level of control on day 2, 54 ± 6% of control on day 3, reached a nadir of 28 ± 6% of control on day 4, and rose to 43 ± 10% of control on day 7. These dynamic changes of P2Y12 mRNA in platelets reflected the expression of P2Y12 mRNA in megakaryocytes isolated to a high state of purity (>96 %) from rat bone marrow. Specifically, the megakaryocytic P2Y12 mRNA expression in the diabetic rats on days 1, 2 and 3 were 74 ± 8 %, 93 ± 1%, and 117 ± 6% of those in control rats, respectively. Treatment of diabetic rats with insulin reduced the trend of decline in the platelet P2Y12 expression. By contrast, the platelet COX-1 mRNA expression measured on days 2, 3, 4 and 7 after the induction of diabetes was similar to that in the control rats. These results in diabetic rats demonstrate dynamic alterations of the mRNA expression of megakaryocyte-platelet P2Y12, but not of COX-1. The decrease in the P2Y12 receptor expression in early stage of STZ-induced diabetes may serve to attenuate the hyperaggregability of platelets and reduce the risk of vascular thrombosis.