title: trans-Arachidonic acids induce a heme oxygenase-dependent vasorelaxation of cerebral microvasculature.
abstract: Nitrative stress is an important regulator of vascular tone. We have recently described that trans-arachidonic acids (TAA) are major products of NO(2)(.)-mediated isomerization of arachidonic acid in cell membranes and that nitrative stress increases TAA levels leading to neural microvascular degeneration. In the present study, we explored whether TAA exert acute effects on neuromicrovascular tone and investigated potential mechanisms thereof. TAA induced an endothelium-dependent vasorelaxation of rat brain pial microvasculature. This vasorelaxation was independent of nitric oxide, prostanoids, lipoxygenase products, and CYP(450) metabolite trans-hydroxyeicosatetraenoic acids. However, inhibition of heme oxygenase (using zinc protoporphyrin IX) and of dependent soluble guanylate cyclase (sGC; using ODQ) significantly diminished (by approximately 70%) the TAA-induced vasorelaxation. Consistent with these findings, TAA stimulated heme oxygenase (HO)-2-dependent bilirubin (using siRNA HO-2) and cGMP formation, and the HO product carbon monoxide (using CO-releasing CORM-2) reproduced the sGC-dependent cGMP formation and vasorelaxation. Further exploration revealed that TAA-induced vasorelaxation and bilirubin formation (HO activation) were nearly abrogated by large-conductance calcium-dependent potassium channels (BK(Ca)) (using TEA and iberiotoxin). Opening of BK(Ca) with the selective activator NS1619 induced a concentration-dependent vasorelaxation, which was inhibited by HO and sGC inhibitors. Coimmunoprecipitation suggested a molecular complex interaction between BK(Ca) and HO-2 (but not HO-1). Collectively, these findings identify new properties of TAA, specifically cerebral vasorelaxation through interactive activation of BK(Ca) with HO-2 and, in turn, sGC. Our findings provide new insights into the characterization of nitrative stress-derived TAA products, by showing they can act as acute mediators of nitrative stress on neurovascular tone.
authors: Department of Paediatrics, Research Center of Hôpital Ste-Justine, Montréal, Quebec, Canada.
authors: Amna
authors: A
authors: Kooli
authors: Elsa
authors: E
authors: Kermorvant-Duchemin
authors: Florian
authors: F
authors: Sennlaub
authors: Michela
authors: M
authors: Bossolasco
authors: Xin
authors: X
authors: Hou
authors: Jean-Claude
authors: JC
authors: Honoré
authors: Phyllis A
authors: PA
authors: Dennery
authors: Przemyslaw
authors: P
authors: Sapieha
authors: Daya
authors: D
authors: Varma
authors: Pierre
authors: P
authors: Lachapelle
authors: Tang
authors: T
authors: Zhu
authors: Sophie
authors: S
authors: Tremblay
authors: Pierre
authors: P
authors: Hardy
authors: Kavita
authors: K
authors: Jain
authors: Michael
authors: M
authors: Balazy
authors: Sylvain
authors: S
authors: Chemtob
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000737:chemistry / Q000494:pharmacology*; D001663:Bilirubin / Q000378:metabolism; D002478:Cells, Cultured; D002560:Cerebrovascular Circulation / Q000187:drug effects* / Q000502:physiology; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism*; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; D009573:Nitrites / Q000378:metabolism; D015221:Potassium Channels / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013237:Stereoisomerism; D014664:Vasodilation / Q000187:drug effects*
chemical_list: D001095:Arachidonic Acids; C494842:Kcnma1 protein, rat; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; D009573:Nitrites; D015221:Potassium Channels; D012333:RNA, Messenger; D000242:Cyclic AMP; D006419:Heme Oxygenase (Decyclizing); D006152:Cyclic GMP; D001663:Bilirubin