Endogenously generated reactive oxygen species reduce PMCA activity in platelets from patients with non-insulin-dependent diabetes mellitus.
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.
Jardín
Isaac
I
Department of Physiology, University of Extremadura, 10071 Cáceres, Spain.
Redondo
Pedro C
PC
Salido
Ginés M
GM
Pariente
José A
JA
Rosado
Juan A
JA
D000975:Antioxidants / Q000494:pharmacology; D001792:Blood Platelets / Q000187:drug effects / Q000201:enzymology*; D002118:Calcium / Q000378:metabolism*; D000252:Calcium-Transporting ATPases / Q000097:blood / Q000187:drug effects*; D002374:Catalase / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D015759:Ionomycin / Q000494:pharmacology; D007476:Ionophores / Q000494:pharmacology; D019000:Phosphotyrosine / Q000032:analysis; D015539:Platelet Activation / Q000187:drug effects / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D019284:Thapsigargin / Q000494:pharmacology
D000975:Antioxidants; D004791:Enzyme Inhibitors; D007476:Ionophores; D017382:Reactive Oxygen Species; D019000:Phosphotyrosine; D015759:Ionomycin; D019284:Thapsigargin; D002374:Catalase; D000252:Calcium-Transporting ATPases; D002118:Calcium