Elevated 20-HETE impairs coronary collateral growth in metabolic syndrome via endothelial dysfunction
| Autor: | Brenda Hutcheson, Petra Rocic, Spencer D. Proctor, Rebecca Hutcheson, Michal L. Schwartzman, Houli Jiang, Amanda Soler, John R. Falck, Chastity Bradford, Ian Hunter, Gregory Joseph, Katherine H. Gotlinger |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Male medicine.medical_specialty Nitric Oxide Synthase Type III Physiology Neutrophils Myocardial Ischemia Collateral Circulation 030204 cardiovascular system & hematology Biology Rats Sprague-Dawley 03 medical and health sciences 0302 clinical medicine Physiology (medical) Internal medicine Hydroxyeicosatetraenoic Acids medicine Animals Endothelial dysfunction Antibodies Blocking Metabolic Syndrome medicine.disease Coronary Vessels Capillaries Rats Arterioles 030104 developmental biology Endocrinology Apoptosis cardiovascular system lipids (amino acids peptides and proteins) Arteriogenesis Endothelium Vascular Metabolic syndrome Cardiology and Cardiovascular Medicine Cell Adhesion Molecules circulatory and respiratory physiology Research Article |
| Popis: | 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 & NOTEWORTHY Elevated 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. |
| Databáze: | OpenAIRE |
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