Abstract 15863: The Vasoprotective Actions of Nitroxyl, but not Nitric Oxide, are Maintained in Atherosclerotic Mice
Objective: The redox siblings NO. and nitroxyl (HNO) both serve as endothelium-derived vasodilators, inhibit platelet aggregation and suppress superoxide (O2-) generation. However, unlike NO., HNO is resistant to vascular tolerance development, scavenging by O2- and targets distinct vascular signaling pathways. As such, the vasoprotective actions of HNO are preserved in disease states such as hypercholesterolemia. We tested the hypothesis that the efficacy of endogenous and exogenously generated HNO will be sustained in advanced atherosclerosis.
Methods & Results: The vasorelaxant, anti-aggregatory and vascular O2- limiting effects of the HNO donor, isopropylamine NONOate (IPA/NO) and the NO. donor glyceryl trinitrate (GTN) were compared in carotid arteries and platelets from 26 week-old male, wild-type (WT) and ApoE-/- mice (C57Bl6/J background) all maintained on a high fat diet (21 weeks). ApoE-/- mice displayed a 5-fold higher (P<0.001) plasma cholesterol level, atherosclerotic lesions in carotid arteries and reduced endogenous NO. bioavailability (L-NAME contraction; P<0.01). Whilst, vasorelaxant responses to ACh were similar in both genotypes (WT Rmax= 77±5% vs ApoE-/- Rmax= 83±5%, n=3-7), responses in WT were more susceptible than ApoE-/- to inhibition by the NO. scavenger, hydroxocobalamin. By contrast, the HNO scavenger, L-cysteine attenuated the response to ACh to a greater extent in ApoE-/- (51±10%) than in WT (36±9%) mice (n=6). The vasodilator actions of both IPA/NO (WT: pEC50=5.99±0.10, -logM, n=6) and GTN (WT: pEC50=7.39±0.47, n=6) were preserved in ApoE-/- mice, yet GTN was susceptible to tolerance development. The ability of IPA/NO (3μ M) to inhibit both angiotensin II-stimulated vascular O2- production (WT 61±5% vs ApoE-/- 57±8%; n=4-8) and collagen-induced platelet aggregation (WT 47±6% vs ApoE-/- 38±6%; n=5-8) was maintained in ApoE-/- mice. GTN (10μ M) inhibited vascular O2- production (38±3%; n=3) and platelet aggregation (46±10%; n=5) in WT, however, these effects were abolished in ApoE-/- mice (n=7).
Conclusions: In advanced atherosclerosis, the vasoprotective actions of endogenous and exogenously generated HNO are preserved. Thus, HNO donors may represent a novel therapy for atherothrombotic syndromes.
- © 2012 by American Heart Association, Inc.