3-nitrotyrosine and Coronary-Thrombosis

Recent studies have demonstrated that inflammatory cells are a component that plays a role in thrombus formation in ST-elevation myocardial infarction (STEMI). 3-nitrotyrosine (3-NO2-Tyr), a specific marker for protein modification by nitric oxide-derived oxidants, is increased in human atherosclerotic lesions. The purpose of this study was to determine the possible association of inflammatory markers of coronary thrombi with nitroxidative stress. Intracoronary thrombus (n=51) and blood from the systemic circulation were obtained by thromboaspiration in 138 consecutive STEMI patients presenting for primary percutaneous coronary intervention (PCI). Each blood and intracoronary thrombus were measured simultaneously the following biomarkers: C-reactive protein (CRP), 3-NO2-Tyr, soluble CD 40 ligand (sCD40L), vascular cellular adhesion molecule-1 (VCAM-1) and haemoglobin content (only in coronary thrombus). Time delay in minutes from symptom onset to PCI was 244 ± 324. Serum CRP was positively correlated to CRP content in the thrombus (r= 0.395; p = 0.02) and serum sCD40L was negatively correlated to sCD40L in the thrombus (r= -0.394; p = 0.02). Patients were divided into tertiles according to thrombi 3-NO2-Tyr concentration: 1(st)tertile (<0.146ng/mg), 2(nd)tertile (0.146-0.485ng/mg) and 3(rd)tertile (>0.485ng/mg). Thus, thrombus in the highest tertile had significantly higher levels of CRP (p=0.002), VCAM-1 (p=0.003) and haemoglobin (p=0.002). In conclusion, the present study demonstrated that coronary thrombi with higher levels of 3-NO2-Tyr content often contain more inflammatory markers which could have a direct impact on the efficacy of drugs or devices used for coronary reperfusion.

Topics: Aged; Biomarkers; C-Reactive Protein; CD40 Ligand; Coronary Thrombosis; Enzyme-Linked Immunosorbent Assay; Female; Hemoglobins; Humans; Inflammation; Male; Middle Aged; Myocardial Infarction; Oxidative Stress; Percutaneous Coronary Intervention; Tyrosine; Vascular Cell Adhesion Molecule-1

Platelet-derived nitric oxide inhibits platelet aggregation via constitutive NO synthase (NOS). Tetrahydrobiopterin (BH(4)), a cofactor of NOS, augments NO formation, whereas its deficiency decreases NO bioactivity and increases superoxide generation by NOS. The roles of intraplatelet BH(4) in platelet aggregation and thrombus formation, however, are unknown. Accordingly, we investigated whether intraplatelet BH(4) is involved in regulating cyclic flow variations (CFVs) and platelet aggregation in a canine model with stenosed and endothelium-injured coronary arteries that mimics acute coronary syndromes in humans.. After developing CFVs, dogs received saline or BH(4) (10 or 30 mg/kg) intravenously. Intraplatelet BH(4) and cGMP levels were decreased and intraplatelet nitrotyrosine production was increased during CFVs. ADP- and U46619-induced ex vivo platelet aggregation and platelet P-selectin expression were augmented during CFVs. BH(4) administration restored intraplatelet BH(4) and cGMP levels and decreased intraplatelet nitrotyrosine production, resulting in reduced CFVs and inhibited ex vivo platelet aggregation and platelet P-selectin expression. CFVs again developed after N(G)-monomethyl-L-arginine, an inhibitor of NOS, in BH(4)-treated dogs. Ex vivo platelet NOS activity at baseline, during CFVs, and after BH(4) administration did not differ.. Intraplatelet BH(4) may play an important role in regulating thrombus formation by modulating platelet-derived nitric oxide and superoxide generation by platelet NOS.

Topics: Animals; Biopterins; Blood Platelets; Coronary Thrombosis; Cyclic GMP; Dogs; Enzyme Inhibitors; Hemodynamics; Nitric Oxide; Nitric Oxide Synthase; omega-N-Methylarginine; P-Selectin; Platelet Aggregation; Superoxides; Tyrosine