Activation of vascular endothelial nitric oxide synthase and heme oxygenase-1 expression by electrophilic nitro-fatty acids.
Reactive oxygen species mediate a decrease in nitric oxide (NO) bioavailability and endothelial dysfunction, with secondary oxidized and nitrated by-products of these reactions contributing to the pathogenesis of numerous vascular diseases. While oxidized lipids and lipoproteins exacerbate inflammatory reactions in the vasculature, in stark contrast the nitration of polyunsaturated fatty acids and complex lipids yields electrophilic products that exhibit pluripotent anti-inflammatory signaling capabilities acting via both cGMP-dependent and -independent mechanisms. Herein we report that nitro-oleic acid (OA-NO(2)) treatment increases expression of endothelial nitric oxide synthase (eNOS) and heme oxygenase 1 (HO-1) in the vasculature, thus transducing vascular protective effects associated with enhanced NO production. Administration of OA-NO(2) via osmotic pump results in a significant increase in eNOS and HO-1 mRNA in mouse aortas. Moreover, HPLC-MS/MS analysis showed that NO(2)-FAs are rapidly metabolized in cultured endothelial cells (ECs) and treatment with NO(2)-FAs stimulated the phosphorylation of eNOS at Ser(1179). These posttranslational modifications of eNOS, in concert with elevated eNOS gene expression, contributed to an increase in endothelial NO production. In aggregate, OA-NO(2)-induced eNOS and HO-1 expression by vascular cells can induce beneficial effects on endothelial function and provide a new strategy for treating various vascular inflammatory and hypertensive disorders.
Department of Pharmacology and Chemical Biology, E1314 BST, University of Pittsburgh, Pittsburgh, PA 15261, USA. nkhoo@pitt.edu
Nicholas K H
NK
Khoo
Volker
V
Rudolph
Marsha P
MP
Cole
Franca
F
Golin-Bisello
Francisco J
FJ
Schopfer
Steven R
SR
Woodcock
Carlos
C
Batthyany
Bruce A
BA
Freeman
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D002417:Cattle; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000473:pathology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D004789:Enzyme Activation / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006973:Hypertension; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism*; D009574:Nitro Compounds / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D019301:Oleic Acid / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D014652:Vascular Diseases
D009574:Nitro Compounds; D019301:Oleic Acid; D052250:Nitric Oxide Synthase Type III; D051547:Heme Oxygenase-1