Endogenously generated reactive oxygen species reduce PMCA activity in platelets from patients with non-insulin-dependent diabetes mellitus

Abstract

Intracellular Ca²⁺ homeostasis in platelets of patients with non-insulin-dependent diabetes mellitus (NIDDM) has been reported to be altered, leading to an increased adhesiveness and spontaneous aggregation. Among the disturbed Ca²⁺ mechanism in platelets from NIDDM subjects, a reduced Ca²⁺ extrusion by the plasma membrane Ca²⁺-ATPase (PMCA) is especially relevant, maintaining an elevated cytosolic free Ca²⁺ concentration that results in platelet hypersensitivity. Here we show that treatment of platelets from NIDDM patients with 300 U/mL catalase or 5 mM D-mannitol, which prevent H₂O₂- and hydroxyl radicals-mediated oxidative stress, respectively, increases Ca²⁺ extrusion after treatment with thapsigargin (TG) plus ionomycin (Iono). In contrast, 1 mM trolox, a scavenger of ONOO^–, did not alter TG + Iono-induced response. Catalase and D-mannitol reversed the enhanced tyrosine phosphorylation of PMCA induced by TG + Iono in NIDDM patients. These findings open up new horizon for the development of therapeutic strategies to palliate cardiovascular disorders in NIDDM.

• Antioxidant
• non-insulin-dependent diabetes mellitus
• PMCA