title: Elevated 20-HETE impairs coronary collateral growth in metabolic syndrome via endothelial dysfunction.
abstract: Coronary collateral growth (CCG) is impaired in metabolic syndrome (MetS). microRNA-145 (miR-145-Adv) delivery to our rat model of MetS (JCR) completely restored and neutrophil depletion significantly improved CCG. We determined whether low endogenous levels of miR-145 in MetS allowed for elevated production of 20-hydroxyeicosatetraenoic acid (20-HETE), which, in turn, resulted in excessive neutrophil accumulation and endothelial dysfunction leading to impaired CCG. Rats underwent 0-9 days of repetitive ischemia (RI). RI-induced cardiac CYP4F (neutrophil-specific 20-HETE synthase) expression and 20-HETE levels were increased (4-fold) in JCR vs. normal rats. miR-145-Adv and 20-HETE antagonists abolished and neutrophil depletion (blocking antibodies) reduced (~60%) RI-induced increases in CYP4F expression and 20-HETE production in JCR rats. Impaired CCG in JCR rats (collateral-dependent blood flow using microspheres) was completely restored by 20-HETE antagonists [collateral-dependent zone (CZ)/normal zone (NZ) flow ratio was 0.76 ± 0.07 in JCR + 20-SOLA, 0.84 ± 0.05 in JCR + 20-HEDGE vs. 0.11 ± 0.02 in JCR vs. 0.84 ± 0.03 in normal rats]. In JCR rats, elevated 20-HETE was associated with excessive expression of endothelial adhesion molecules and neutrophil infiltration, which were reversed by miR-145-Adv. Endothelium-dependent vasodilation of coronary arteries, endothelial nitric oxide synthase (eNOS) Ser1179 phosphorylation, eNOS-dependent NO·-production and endothelial cell survival were compromised in JCR rats. These parameters of endothelial dysfunction were completely reversed by 20-HETE antagonism or miR-145-Adv delivery, whereas neutrophil depletion resulted in partial reversal (~70%). We conclude that low miR-145 in MetS allows for increased 20-HETE, mainly from neutrophils, which compromises endothelial cell survival and function leading to impaired CCG. 20-HETE antagonists could provide viable therapy for restoration of CCG in MetS.NEW & NOTEWORTHYElevated 20-hydroxyeicosatetraenoic acid (20-HETE) impairs coronary collateral growth (CCG) in metabolic syndrome by eliciting endothelial dysfunction and apoptosis via excessive neutrophil infiltration. 20-HETE antagonists completely restore coronary collateral growth in metabolic syndrome. microRNA-145 (miR-145) is an upstream regulator of 20-HETE production in metabolic syndrome; low expression of miR-145 in metabolic syndrome promotes elevated production of 20-HETE.
authors.affiliation: Department of Pharmacology, New York Medical College, Valhalla, New York.
authors.forename: Gregory
authors.initials: G
authors.lastname: Joseph
authors.affiliation: Department of Pharmacology, New York Medical College, Valhalla, New York.
authors.forename: Amanda
authors.initials: A
authors.lastname: Soler
authors.affiliation: Department of Pharmacology, New York Medical College, Valhalla, New York.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Hutcheson
authors.affiliation: Department of Pharmacology, New York Medical College, Valhalla, New York.
authors.forename: Ian
authors.initials: I
authors.lastname: Hunter
authors.affiliation: Department of Biology, Tuskegee University, Tuskegee, Alabama.
authors.forename: Chastity
authors.initials: C
authors.lastname: Bradford
authors.affiliation: Department of Pharmacology, New York Medical College, Valhalla, New York.
authors.forename: Brenda
authors.initials: B
authors.lastname: Hutcheson
authors.affiliation: Department of Pharmacology, New York Medical College, Valhalla, New York.
authors.forename: Katherine H
authors.initials: KH
authors.lastname: Gotlinger
authors.affiliation: Department of Pharmacology, New York Medical College, Valhalla, New York.
authors.forename: Houli
authors.initials: H
authors.lastname: Jiang
authors.affiliation: Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas; and.
authors.forename: John R
authors.initials: JR
authors.lastname: Falck
authors.affiliation: Metabolic and Cardiovascular Diseases Laboratory, Alberta Institute for Human Nutrition, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Spencer
authors.initials: S
authors.lastname: Proctor
authors.affiliation: Department of Pharmacology, New York Medical College, Valhalla, New York.
authors.forename: Michal Laniado
authors.initials: ML
authors.lastname: Schwartzman
authors.affiliation: Department of Pharmacology, New York Medical College, Valhalla, New York; petra_rocic@nymc.edu.
authors.forename: Petra
authors.initials: P
authors.lastname: Rocic
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology; D001160:Arterioles / Q000187:drug effects; D002196:Capillaries / Q000187:drug effects; D015815:Cell Adhesion Molecules / Q000096:biosynthesis; D003097:Collateral Circulation / Q000187:drug effects*; D003331:Coronary Vessels / Q000187:drug effects* / Q000254:growth & development* / Q000473:pathology; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology*; D006893:Hydroxyeicosatetraenoic Acids / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008297:Male; D024821:Metabolic Syndrome / Q000378:metabolism / Q000473:pathology*; D017202:Myocardial Ischemia / Q000378:metabolism / Q000473:pathology; D009504:Neutrophils / Q000187:drug effects; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D019138:Antibodies, Blocking; D015815:Cell Adhesion Molecules; D006893:Hydroxyeicosatetraenoic Acids; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat
keywords: 20-HETE; arteriogenesis; endothelial dysfunction; miR-145; neutrophils