TY - JOUR
T1 - Iron-dependent human platelet activation and hydroxyl radical formation
T2 - Involvement of protein kinase C
AU - Praticò, Domenico
AU - Pasin, Mehtap
AU - Barry, Orla P.
AU - Ghiselli, Andrea
AU - Sabatino, Giuseppe
AU - Iuliano, Luigi
AU - Fitzgerald, Garret A.
AU - Violi, Francesco
PY - 1999/6/22
Y1 - 1999/6/22
N2 - Background - Iron is an important modulator of lipid peroxidation, and its levels have been associated with the progression of atherosclerosis. Little is known about the possibility that this metal, when released from tissue stores, may modulate the reactivity of blood cell components, in particular platelets. Therefore, we investigated a possible link between iron, oxygen free radical formation, and platelet function. Methods and Results - Human whole blood was stimulated with collagen 2 μg/mL, and an irreversible aggregation with thromboxane (Tx)B2 formation was observed (15±4 versus 130±10 ng/mL). Deferoxamine (DSF), a specific iron chelator, and catalase, an H2O2 scavenger, inhibited collagen-induced whole-blood aggregation. The aggregation was accompanied by an increase in hydroxyl radical (OH.) levels (30±8 versus 205±20 nmol/L dihydroxybenzoates), which were reduced by DSF and by 2 specific OH· scavengers, mannitol and deoxyribose. Iron (Fe2+) dose-dependently induced platelet aggregation, TxB2 formation (6±2 versus 135±8 ng/mL), and protein kinase C (PKC) translocation from the cytosol to the cell membrane when added to platelets that have been primed with a low concentration of collagen (0.2 μg/mL). In the same system, an increase in OH· levels was observed (37±12 versus 230±20 nmol/L dihydroxybenzoates). Mannitol and deoxyribose, but not urea, were able to reduce OH· formation, PKC activation, and platelet aggregation. Selective inhibition of PKC activity by GF 109203X prevented iron-dependent platelet aggregation without influencing OH. production. Conclusions - The present study shows that iron can directly interact with human platelets, resulting in their activation. Its action is mediated by OH· formation and involves PKC activity. Our findings provide an additional contribution to the understanding of the mechanism(s) by which iron overload might promote atherosclerosis and coronary artery disease.
AB - Background - Iron is an important modulator of lipid peroxidation, and its levels have been associated with the progression of atherosclerosis. Little is known about the possibility that this metal, when released from tissue stores, may modulate the reactivity of blood cell components, in particular platelets. Therefore, we investigated a possible link between iron, oxygen free radical formation, and platelet function. Methods and Results - Human whole blood was stimulated with collagen 2 μg/mL, and an irreversible aggregation with thromboxane (Tx)B2 formation was observed (15±4 versus 130±10 ng/mL). Deferoxamine (DSF), a specific iron chelator, and catalase, an H2O2 scavenger, inhibited collagen-induced whole-blood aggregation. The aggregation was accompanied by an increase in hydroxyl radical (OH.) levels (30±8 versus 205±20 nmol/L dihydroxybenzoates), which were reduced by DSF and by 2 specific OH· scavengers, mannitol and deoxyribose. Iron (Fe2+) dose-dependently induced platelet aggregation, TxB2 formation (6±2 versus 135±8 ng/mL), and protein kinase C (PKC) translocation from the cytosol to the cell membrane when added to platelets that have been primed with a low concentration of collagen (0.2 μg/mL). In the same system, an increase in OH· levels was observed (37±12 versus 230±20 nmol/L dihydroxybenzoates). Mannitol and deoxyribose, but not urea, were able to reduce OH· formation, PKC activation, and platelet aggregation. Selective inhibition of PKC activity by GF 109203X prevented iron-dependent platelet aggregation without influencing OH. production. Conclusions - The present study shows that iron can directly interact with human platelets, resulting in their activation. Its action is mediated by OH· formation and involves PKC activity. Our findings provide an additional contribution to the understanding of the mechanism(s) by which iron overload might promote atherosclerosis and coronary artery disease.
KW - Free radicals
KW - Platelets
KW - Protein kinase C
KW - Thromboxane
UR - https://www.scopus.com/pages/publications/0033594957
U2 - 10.1161/01.CIR.99.24.3118
DO - 10.1161/01.CIR.99.24.3118
M3 - Article
C2 - 10377074
AN - SCOPUS:0033594957
SN - 0009-7322
VL - 99
SP - 3118
EP - 3124
JO - Circulation
JF - Circulation
IS - 24
ER -
