Evaluation of Fibrinolytic Inhibitors: Alpha-2-Antiplasmin and Plasminogen Activator Inhibitor 1 in Patients with Obstructive Sleep Apnoea.

Obstructive sleep apnoea (OSA) induces thrombophilia and reduces fibrinolysis. Alpha-2-antiplasmin (a-2-AP) and plasminogen activator inhibitor 1 (PAI-1) are major inhibitors of the fibrinolytic system. Increased concentrations of these factors are associated with a higher risk of cardiovascular diseases. The aim of this study was to assess plasma a-2-AP and PAI-1 in patients with OSA and evaluate correlations with the polysomnographic record and selected risk factors of cardiovascular diseases. The study group comprised 45 patients with OSA, and the control group consisted of 19 patients who did not meet the diagnostic criteria of OSA. Plasma a-2-AP and PAI-1 concentrations were assessed by enzyme-linked immunosorbent assay (ELISA). In the study group, the median value of plasma a-2-AP was higher than that of the control group (157.34 vs. 11.89 pg/ml, respectively, P<0.0001). A-2-AP concentration increased proportionally to the severity of OSA. The concentration of a-2-AP was positively correlated with the apnoea-hypopnoea index (AHI), apnoea index (AI), respiratory disturbances time (RDT), and desaturaion index (DI), and negatively correlated with mean and minimal oxygen saturation (SpO2 mean, SpO2 min, respectively). The median value of PAI-1 was higher in the study group than the control group (12.55 vs. 5.40 ng/ml, respectively, P = 0.006) and increased along with OSA severity. PAI-1 concentration was positively correlated with AHI, AI, RDT, DI, and body mass index (BMI) and negatively correlated with SpO2 mean and SpO2 min. Higher plasma concentrations of a-2-AP and PAI-1 in patients with OSA indicated that these patients had increased prothrombotic activity. OSA increases the risk of cardiovascular complications as it enhances prothrombotic activity.

Modulation of paraoxonase 1 (PON1) activity and protein N-homocysteinylation by bisphosphonates in rats.

BACKGROUND AND AIM: Bisphosphonates are potent antiresorptive agents commonly used in the treatment of osteoporosis. As osteoporosis and atherosclerosis share some common risk factors and frequently coexist in the same patients, we examined the effect of bisphosphonates on paraoxonase 1 (PON1) - the high density lipoprotein-associated enzyme with potent anti-atherosclerotic activity. MATERIAL AND METHODS: Bisphosphonates were administered orally to male adult rats for 4 weeks and then PON1 activity and some related biochemical parameters were measured in plasma. RESULTS: Clodronate, alendronate, ibandronate and pamidronate reduced PON1 activity toward synthetic (paraoxon, phenyl acetate) and natural (homocysteine thiolactone) substrates. The most marked effect was observed in animals receiving ibandronate. In contrast, risedronate increased PON1 activity toward these 3 substrates and zoledronate increased PON1 activity toward phenyl acetate but had no effect on its activity toward paraoxon and homocysteine thiolactone. Bisphosphonates had no effect on total plasma homocysteine and protein-bound homocysteine thiolactone. In addition, total plasma cholesterol, HDL-cholesterol, plasma triglycerides and alanine aminotransferase activity did not differ between groups. CONCLUSIONS: Bisphosphonates have differential effects on PON1 activity. Risedronate could be particularly useful in patients with high cardiovascular risk and PON1 deficiency. Bisphosphonates have no effect on plasma homocysteine and protein N-homocysteinylation as well as on the lipid profile.

Effects of antiretroviral treatment on paraoxonase 1 (PON1) activity in rats.

Highly active antiretroviral therapy (HAART), especially protease inhibitors (PIs), commonly used in HIV-infected patients, effectively suppresses a viral replication. However, it is frequently associated with significant side effects, including fat redistribution, lipodystrophy, hyperlipidemia, insulin resistance and diabetes mellitus. Currently, metabolic complications and atherosclerosis resulting from them become the major cause of mortality in HIV-infected patients receiving HAART. Paraoxonase 1 (PON1) is the HDL-bound esterase, which inhibits development of atherosclerosis by decomposing lipid peroxidation products and hydrolyzing homocysteine thiolactone. The aim of this study was to characterize the effects of HIV protease inhibitors on PON1 activity, total plasma homocysteine and protein-bound homocysteine thiolactone as well as lipid profile in rats. The study was performed on seven groups of male Wistar rats: (1) control; (2) and (3) receiving ritonavir (RTV) at doses of 10 and 50 mg/kg, respectively; (4) and (5) receiving atazanavir (ATV) at 10 and 100 mg/kg, respectively; (6) and (7) receiving saquinavir (SQV) at 10 and 50 mg/kg, respectively. All drugs were administered orally for 4 weeks. Compared to control animals, rats receiving PIs had significantly higher concentration of triglycerides and total cholesterol, but the levels of HDL-cholesterol were not different between groups. PON1 activity toward paraoxon was decreased in groups receiving PIs (control: 149 ± 5 U/ml; PIs-treated: RTV at doses 10 mg/kg 133 ± 9.5 â€ŠU/ml, RTV at doses 50 mg/kg 134 ± 10.8 U/ml, SQV at doses 10 mg/kg 131 ± 9.2 U/ml, ATV at doses 10 mg/kg 132 ± 11.8 U/ml, ATV at doses 100 mg/kg 108 ± 7.8 U/ml). ATV reduced total homocysteine level around 25-28%, whereas other PIs had no effect on its concentration. In contrast, 10-15% increase in protein-bound homocysteine thiolactone was observed in PIs-receiving groups, such as RTV10, RTV50, SQV50, ATV10. In conclusion, dyslipidemia induced by PIs is associated with reduced PON1 activity as well as increased protein homocysteinylation. PON1 deficiency may contribute to increased risk of atherosclerosis in these patients.