NYMC Faculty Publications

Elevated 20-HETE Impairs Coronary Collateral Growth in Metabolic Syndrome Via Endothelial Dysfunction

First Page

00561

Last Page

00561

Document Type

Article

Publication Date

12-23-2016

Department

Pharmacology

Abstract

Coronary collateral growth (CCG) is impaired in metabolic syndrome (MetS). microRNA-145 (miR-145-Adv) delivery to our rat model of metabolic syndrome (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, 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.

Comments

Please see the work itself for the complete list of authors.

Publisher's Statement

Originally published in American Journal of Physiology.Heart and Circulatory Physiology. https://doi.org/10.1152/ajpheart.00561.2016

Link to Full Text

Share

COinS