title: A-FABP and oxidative stress underlie the impairment of endothelium-dependent relaxations to serotonin and the intima-medial thickening in the porcine coronary artery with regenerated endothelium.
abstract: Experiments were designed to determine the cause of the selective dysfunction of G(i) proteins, characterized by a reduced endothelium-dependent relaxation to serotonin (5-hydroxytryptamine), in coronary arteries lined with regenerated endothelial cells. Part of the endothelium of the left anterior descending coronary artery of female pigs was removed in vivo to induce regeneration. The animals were treated chronically with vehicle (control), apocynin (antioxidant), or BMS309403 (A-FABP inhibitor) for 28 days before functional examination and histological analysis of segments of coronary arteries with native or regenerated endothelium of the same hearts. Isometric tension was recorded in organ chambers and cumulative concentration-relaxation curves obtained in response to endothelium-dependent [serotonin (G(i) protein mediated activation of eNOS) and bradykinin (G(q) protein mediated activation of eNOS)] and independent [detaNONOate (cGMP-mediated), isoproterenol (cAMP-mediated)] vasodilators. The two inhibitors tested did not acutely affect relaxations of preparations with either native or regenerated endothelium. In the chronically treated groups, however, both apocynin and BMS309403 abolished the reduction in relaxation to serotonin in segments covered with regenerated endothelium and prevented the intima-medial thickening caused by endothelial regeneration, without affecting responses to bradykinin or endothelium-independent agonists (detaNONOate and isoproterenol). Thus, inhibition of either oxidative stress or A-FABP likely prevents both the selective dysfunction of G(i) protein mediated relaxation to serotonin and the neointimal thickening resulting from endothelial regeneration.
authors: Department of Pharmacology and Pharmacy, University of Hong Kong, Hong Kong, China.
authors: Calvin K
authors: CK
authors: Chan
authors: Yingzi
authors: Y
authors: Zhao
authors: Song Yan
authors: SY
authors: Liao
authors: Yue Lin
authors: YL
authors: Zhang
authors: Mary Y K
authors: MY
authors: Lee
authors: Aimin
authors: A
authors: Xu
authors: Hung Fat
authors: HF
authors: Tse
authors: Paul M
authors: PM
authors: Vanhoutte
mesh_terms: D000098:Acetophenones / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology; D001920:Bradykinin / Q000378:metabolism; D003331:Coronary Vessels / Q000187:drug effects*; D004730:Endothelium, Vascular / Q000187:drug effects; D050556:Fatty Acid-Binding Proteins / Q000037:antagonists & inhibitors*; D005260:Female; D019204:GTP-Binding Proteins / Q000494:pharmacology; D009126:Muscle Relaxation / Q000187:drug effects*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology*; D011720:Pyrazoles / Q000494:pharmacology; D012038:Regeneration / Q000187:drug effects; D012701:Serotonin / Q000494:pharmacology*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D034421:Sus scrofa; D017539:Tunica Intima / Q000187:drug effects
chemical_list: C559288:2-(2'-(5-ethyl-3,4-diphenyl-1H-pyrazol-1-yl)biphenyl-3-yloxy)acetic acid; D000098:Acetophenones; D000975:Antioxidants; D001713:Biphenyl Compounds; D050556:Fatty Acid-Binding Proteins; D011720:Pyrazoles; D017366:Serotonin Receptor Agonists; D012701:Serotonin; C056165:acetovanillone; D052250:Nitric Oxide Synthase Type III; D019204:GTP-Binding Proteins; D001920:Bradykinin