title: Nitroxyl (HNO) reduces endothelial and monocyte activation and promotes M2 macrophage polarization.
abstract: Nitroxyl anion (HNO) donors are currently being assessed for their therapeutic utility in several cardiovascular disorders including heart failure. Here, we examine their effect on factors that precede atherosclerosis including endothelial cell and monocyte activation, leucocyte adhesion to the endothelium and macrophage polarization. Similar to the NO donor glyceryl trinitrate (GTN), the HNO donors Angeli's salt (AS) and isopropylamine NONOate (IPA/NO) decreased leucocyte adhesion to activated human umbilical vein endothelial cells (HUVECs) and mouse isolated aorta. This reduction in adhesion was accompanied by a reduction in intercellular adhesion molecule-1 (ICAM-1) and the cytokines monocyte chemoattractant protein 1 (MCP-1) and interleukin 6 (IL-6) which was inhibitor of nuclear factor κB (NFκB) α (IκBα)- and subsequently NFκB-dependent. Intriguingly, the effects of AS on leucocyte adhesion, like those on vasodilation, were found to not be susceptible to pharmacological tolerance, unlike those observed with GTN. As well, HNO reduces monocyte activation and promotes polarization of M2 macrophages. Taken together, our data demonstrate that HNO donors can reduce factors that are associated with and which precede atherosclerosis and may thus be useful therapeutically. Furthermore, since the effects of the HNO donors were not subject to tolerance, this confers an additional advantage over NO donors.
authors.affiliation: Vascular Pharmacology Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria 3004, Australia Cardiovascular Disease Program and Department of Pharmacology, Biomedical Discovery Institute, Monash University, Clayton, Victoria 3800, Australia karen.andrews@monash.edu.
authors.forename: Karen L
authors.initials: KL
authors.lastname: Andrews
authors.affiliation: Vascular Pharmacology Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria 3004, Australia.
authors.forename: Amanda K
authors.initials: AK
authors.lastname: Sampson
authors.affiliation: Vascular Pharmacology Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria 3004, Australia.
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: Irvine
authors.affiliation: Vascular Pharmacology Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria 3004, Australia Cardiovascular Disease Program and Department of Pharmacology, Biomedical Discovery Institute, Monash University, Clayton, Victoria 3800, Australia.
authors.forename: Waled A
authors.initials: WA
authors.lastname: Shihata
authors.affiliation: Vascular Pharmacology Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria 3004, Australia.
authors.forename: Danielle L
authors.initials: DL
authors.lastname: Michell
authors.affiliation: Vascular Pharmacology Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria 3004, Australia.
authors.forename: Natalie G
authors.initials: NG
authors.lastname: Lumsden
authors.affiliation: Vascular Pharmacology Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria 3004, Australia.
authors.forename: Chloe
authors.initials: C
authors.lastname: Lim
authors.affiliation: Vascular Pharmacology Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria 3004, Australia.
authors.forename: Olivier
authors.initials: O
authors.lastname: Huet
authors.affiliation: Cardiovascular Disease Program and Department of Pharmacology, Biomedical Discovery Institute, Monash University, Clayton, Victoria 3800, Australia.
authors.forename: Grant R
authors.initials: GR
authors.lastname: Drummond
authors.affiliation: Cardiovascular Disease Program and Department of Pharmacology, Biomedical Discovery Institute, Monash University, Clayton, Victoria 3800, Australia.
authors.forename: Barbara K
authors.initials: BK
authors.lastname: Kemp-Harper
authors.affiliation: Vascular Pharmacology Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria 3004, Australia Cardiovascular Disease Program and Department of Pharmacology, Biomedical Discovery Institute, Monash University, Clayton, Victoria 3800, Australia.
authors.forename: Jaye P F
authors.initials: JP
authors.lastname: Chin-Dusting
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000276:immunology / Q000503:physiopathology; D050197:Atherosclerosis / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D016764:Cell Polarity / Q000187:drug effects*; D018932:Chemokine CCL2 / Q000276:immunology; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000276:immunology; D015850:Interleukin-6 / Q000276:immunology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000166:cytology* / Q000187:drug effects* / Q000276:immunology; D009589:Nitrogen Oxides / Q000008:administration & dosage*
chemical_list: D018932:Chemokine CCL2; D015850:Interleukin-6; D009589:Nitrogen Oxides; D018799:Intercellular Adhesion Molecule-1; C039900:nitroxyl
keywords: inflammation; leucocyte adhesion; nitrate tolerance; nitric oxide; nitroxyl