nitrophenols and Atherosclerosis

Via the solvothermal reaction between Zn(II) or Mn(II) salts and 5-(3,4-dicarboxylphenoxy)nicotinic acid (H

Topics: Animals; Atherosclerosis; Coordination Complexes; Cytokines; Endothelial Cells; Enzyme-Linked Immunosorbent Assay; Hemolysis; Humans; Ligands; Manganese; NF-kappa B; Niacin; Nitrophenols; Polymers; Real-Time Polymerase Chain Reaction; Signal Transduction; Spectrometry, Fluorescence; Zinc

People with diabetes are at a significantly higher risk of cardiovascular disease, in part, due to accelerated atherosclerosis. Diabetic subjects have increased number of platelets that are activated, more reactive, and respond suboptimally to antiplatelet therapies. We hypothesized that reducing platelet numbers by inducing their premature apoptotic death would decrease atherosclerosis. Approach and Results: This was achieved by targeting the antiapoptotic protein Bcl-x. These studies suggest that selectively reducing circulating platelets, by targeting Bcl-x

Topics: Animals; Apoptosis; Atherosclerosis; Biphenyl Compounds; Blood Platelets; Diabetes Mellitus, Experimental; Diabetic Angiopathies; Female; Humans; Leukocytes; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Nitrophenols; Piperazines; Platelet Count; Receptors, LDL; Risk Factors; Sulfonamides

Paraoxonase 1 (PON 1) is an enzyme that is promiscuous in its ability to hydrolyze various types of substrates. It hydrolyzes aryl esters, phosphate esters, lactones, and reduces lipid peroxides to hydroxides. Aspirin is an aryl ester with a short plasma half life. We hypothesized that aspirin would be effectively hydrolyzed by PON 1 and many of its anti-atherogenic effects, at least in part, could be accounted for by its antioxidant product, salicylic acid. In this study, we determined the ability of human plasma and PON 1-rich HDL to hydrolyze acetyl ester of salicylic acid (aspirin). The ability of aspirin to compete for the hydrolysis of paraoxon and p-nitrophenylacetate was determined. In addition, nitrated aspirin was synthesized and tested directly for hydrolysis. Aspirin competed for the hydrolysis of paraoxon and p-nitrophenylacetate by HDL in a dose-dependent manner. Human plasma and HDL were also able to hydrolyze nitroaspirin and aspirin and release nitrosalicylic acid and salicylic acid, respectively. These findings suggest that salicylic acid might be generated in the plasma from aspirin. The ability of long-term treatment with aspirin to retard atherosclerosis might be dependent on the generation of free salicylic acid, a scavenger of free radicals.

Topics: Adult; Antioxidants; Aryldialkylphosphatase; Aspirin; Atherosclerosis; Binding, Competitive; Biotransformation; Humans; Hydrolysis; In Vitro Techniques; Nitrophenols; Paraoxon; Platelet Aggregation Inhibitors; Salicylic Acid

Calcium channel blockers (CCBs) are widely used in clinical practice, and have been reported to be effective in preventing the progression of atherosclerosis. We examined whether various types of calcium channel blockers affected the expression of ATP binding cassette transporter A1 (ABCA1), a factor contributing to anti-atherogenesis. Undifferentiated monocytic cell line, THP-1 cells were maintained in RPMI 1640 medium and treated with different kinds of calcium channel blockers. Among the calcium channel blockers tested, aranidipine and efonidipine increased ABCA1 protein expression without an increase in ABCA1 mRNA expression, whereas other calcium channel blockers (eg, nifedipine, amlodipine, and nicardipine) or T-type calcium channel blockers (eg, mibefradil and nickel chloride) failed to upregulate ABCA1 expression. H89, a protein kinase A inhibitor inhibited the aranidipine-induced ABCA1 protein expression, whereas genistein (a tyrosine kinase inhibitor), or AG490 (a JAK-2 inhibitor) had no effects. Neither of these inhibitors suppressed the efonidipine-induced ABCA1 protein expression. Intracellular cAMP levels were elevated only by aranidipine, but not by efonidipine. In conclusion, aranidipine and efonidipine have the ability to induce ABCA1 protein by distinct mechanisms; protein kinase A is involved in the aranidipine-induced ABCA1 upregulation. This non-class effect of calcium channel blockers may potentially offer beneficial action in the treatment of hypertensive subjects with atherosclerosis.

Topics: Atherosclerosis; ATP Binding Cassette Transporter 1; ATP-Binding Cassette Transporters; Calcium Channel Blockers; Cells, Cultured; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Dihydropyridines; Humans; Hypertension; Janus Kinase 2; Nitrophenols; Organophosphorus Compounds; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; RNA, Messenger

Topics: 2,4-Dinitrophenol; Arteriosclerosis; Atherosclerosis; Dinitrophenols; Nitrophenols; Thyroxine