title: 20-Hydroxyeicosatetraenoic acid inhibition attenuates balloon injury-induced neointima formation and vascular remodeling in rat carotid arteries.
abstract: 20-Hydroxyeicosatetraenoic acid (20-HETE) contributes to the migration and proliferation of vascular smooth muscle cells (VSMC) in vitro, but there are few studies that address its effects on vascular remodeling in vivo. The present study determined whether inhibition of 20-HETE production attenuates intimal hyperplasia (IH) and vascular remodeling after balloon injury (BI). Sprague Dawley rats underwent BI of the common carotid artery and were treated with vehicle, 1-aminobenzotriazole (ABT, 50 mg/kg i.p. once daily), or HET0016 (N-hydroxy-N'-(4-butyl-2-methylphenyl)-formamidine) (2 mg/kg s.c. twice daily) for 14 days. Fourteen days after BI and treatment, the animals underwent carotid angiography, and the arteries were harvested for morphometric, enzymatic and immunohistochemical analysis. There was a 96% reduction of angiographic stenosis in the rats treated with 1-ABT. There was a 61 and 66% reduction of the intima/media area ratios in the 1-ABT and HET0016 treated rats compared with the vehicle-treated group. 20-HETE levels were elevated in BI carotid arteries, and the levels were markedly suppressed in the groups treated with 1-ABT and HET0016 (P < 0.001). Immunostaining revealed that the expression of CYP4A enzyme was markedly increased in the neointima of BI arteries, and it colocalized with the expression of smooth muscle-specific actin, indicating increased proliferation of VSMC. An increase in the expression of CYP4A and the production of 20-HETE contributes to neointimal growth in BI rat carotid arteries. Systemic administration 1-ABT or HET0016 prevents the increase in 20-HETE levels and attenuates VSMC migration and proliferation, resulting in a marked reduction in IH and vascular remodeling after endothelial injury.
authors: Department of Neurosurgery, University of Mississippi Medical Center, 2500 N. State Street, Jackson, MS 39216, USA. lorozco-castillo@umc.edu
authors: Ludwig D
authors: LD
authors: Orozco
authors: Huiling
authors: H
authors: Liu
authors: Eddie
authors: E
authors: Perkins
authors: Daryl A
authors: DA
authors: Johnson
authors: Betty B
authors: BB
authors: Chen
authors: Fan
authors: F
authors: Fan
authors: Rodney C
authors: RC
authors: Baker
authors: Richard J
authors: RJ
authors: Roman
mesh_terms: D000578:Amidines / Q000627:therapeutic use; D015906:Angioplasty, Balloon, Coronary / Q000009:adverse effects; D000818:Animals; D020212:Carotid Artery Injuries / Q000188:drug therapy / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D017536:Carotid Artery, Common / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016893:Carotid Stenosis / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D042926:Cytochrome P-450 CYP4A / Q000037:antagonists & inhibitors* / Q000378:metabolism; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D000072470:Cytochrome P450 Family 4; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006893:Hydroxyeicosatetraenoic Acids / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006965:Hyperplasia; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D058426:Neointima / Q000209:etiology / Q000517:prevention & control*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014230:Triazoles / Q000627:therapeutic use; D017539:Tunica Intima / Q000187:drug effects / Q000293:injuries* / Q000378:metabolism / Q000473:pathology
chemical_list: D000578:Amidines; C465387:Cyp4a1protein, rat; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; C000708209:HET0016; D006893:Hydroxyeicosatetraenoic Acids; D014230:Triazoles; C033020:1-aminobenzotriazole; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; D003577:Cytochrome P-450 Enzyme System; D000072470:Cytochrome P450 Family 4; D042926:Cytochrome P-450 CYP4A; C409986:cytochrome P-450 omega-hydroxylase
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