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Neutrophil‐derived 20‐HETE Is a Major Determinant of Coronary Collateral Growth
Author(s) -
Joseph Gregory,
Hutcheson Brenda,
Hunter Ian,
Soler Amanda,
Gotlinger Katie,
Falck John,
Schwartzman Michal L,
Rocic Petra
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.lb559
Subject(s) - medicine , collateral circulation , cardiology , blood flow , coronary occlusion , endocrinology , ischemia , coronary circulation , artery
Coronary collateral growth (CCG) is an adaptive response to transient, repetitive coronary artery occlusion in normal animals but is markedly impaired in metabolic syndrome. Recent studies in our laboratory have shown that in metabolic syndrome rats (JCR:LA‐cp, JCR) in addition to endothelial cell (EC) dysfunction, neutrophil survival is enhanced, leading to neutrophil accumulation which contributes to compromised CCG in JCR rats. 20‐hydroxyeicosatetraenoic acid (20‐HETE) plays an important role in vascular function. However, the role of 20‐HETE in the regulation of CCG is unknown. We investigated the hypothesis that elevated neutrophil‐derived 20‐HETE promotes EC dysfunction and apoptosis and impairs CCG in metabolic syndrome. In our study, coronary blood flow in Sprague‐Dawley (SD) or JCR rats was measured in the collateral (CZ) and normal zone (NZ) of the heart after 9 days of transient, repetitive LAD occlusion (repetitive ischemia, RI) using microspheres. Collateral growth in the JCR rats was impaired compared to SD rats (CZ/NZ flow ratio was 0.11±0.02 in JCR vs. 0.84±0.02 in SD). Administration of 20‐HETE antagonists, either 20‐SOLA or 20‐HEDGE, fully restored collateral‐dependent blood flow (0.85±0.01 in JCR+20‐SOLA, 0.84±0.01 in JCR+20‐HEDGE), while neutrophil depletion, via neutrophil‐blocking antibodies, partially restored collateral‐dependent blood flow (0.57±0.02) in JCR rats. Neutrophil accumulation was ~3 times higher and persisted for the duration of the RI protocol in the CZ of JCR vs. SD rats, where their infiltration was low and transient. This RI‐induced, elevated neutrophil infiltration in the CZ of JCR rats correlated with a >4‐fold increase in CYP4F (the neutrophil 20‐HETE CYP isoform) expression and a 4‐fold increase in 20‐HETE levels vs. SD rats, which was abolished by administration of neutrophil‐blocking antibodies to JCR rats. Furthermore, coronary microvessels of JCR rats displayed reduced endothelium‐dependent vasodilation after 9 days of RI (20%±1.2% JCR vs. 40%±2.3% SD), which was reversed with neutrophil‐blocking antibodies (37%±2.5% JCR+anti‐CD11b/CD18/CD44). eNOS phosphorylation (p1179) and NO production were likewise decreased (~50%) in the CZ of JCR rays after 9 days of RI, which was reversed after administration of neutrophil‐blocking antibodies. Lastly, RI‐induced EC apoptosis in JCR but not in SD rats (TUNEL). EC viability in JCR rats was almost completely restored by treatment with neutrophil‐blocking antibodies. Taken together, these results indicate that neutrophil‐derived 20‐HETE is a major contributor to impaired EC viability and function, and thus to impaired CCG in metabolic syndrome. Support or Funding Information Support: NIH R01 HL093052.