Nitric Oxide in Atherosclerosis: Vascular Protector or Villain?

Abstract

1. Nitric oxide (NO) has important roles in physiological vasodilatation, cytotoxicity and vascular disease. Nitric oxide and prostacyclin (PGIz), both released from the endothelium, act synergistically to inhibit platelet aggregation and adhesion. These autacoids also inhibit the adhesion and migration of leucocytes and, in some arteries, they synergize in terms of vasodilatation.2. The development of atherosclerosis and hyperlipaemiaper se is accompanied by impairment of endothelium-dependent vasodilatation.3. Atherosclerosis is associated with marked changes in the activity of isoforms of NO synthase (NOS) in the artery wall, including increased expression of the NOS2 (inducible) isoform in complex human lesions as well as in the neointima of experimental animal models.4. Failure of NO release from the endothelium with normal physiological stimuli, which has been attributed to a defect in the operation of the endothelial NOS (NOS3), provides conditions propitious for leucocyte adhesion, vasospasm, thrombosis and, in addition, may promote increased proliferation of intimal cells.5. Nitric oxide and superoxide anions generated by inflammatory cells in atherosclerosis react to form cytodestructive peroxynitrite radicals, potentially causing injury to the endothelium and myocytes, and this may be a factor in apoptosis of cells leading to plaque rupture. 6. We have been able to reverse these NO defects with therapeutic agents, including angiotensin-converting enzyme inhibitors, antagonists of platelet-activating factor and NO donor compounds, all offering promise in protecting against some manifestations of vascular disease.

Antioxidative Properties of Acetylsalicylic Acid on Vascular Tissues From Normotensive and Spontaneously Hypertensive Rats

“…11 The present study showed that ASA treatment significantly restored the impaired vasorelaxant response to Ach only in SHRs characterized by high aortic O 2 Ϫ production, but did not modify the vasorelaxation in normotensive WKY rats. These data strongly suggest that ASA treatment improved endothelium-dependent vasorelaxant functions in SHRs mainly by its antioxidant properties, thus increasing the bioavailability of NO in response to Ach.…”

D-4F Induces Heme Oxygenase-1 and Extracellular Superoxide Dismutase, Decreases Endothelial Cell Sloughing, and Improves Vascular Reactivity in Rat Model of Diabetes

“…49 Superoxidemediated impairment of NO may result in vascular smooth muscle cell proliferation and migration and the expression of proinflammatory molecules, which contribute to atherosclerosis. 47,50 It is hypothesized that the elevated superoxide seen in the diabetic animals in the present study was vascular in origin, because EC-SOD is primarily vascular in nature. This hypothesis is supported by prior study showing that the apolipoprotein A1 mimetic L-4F can attenuate O 2 Ϫ production in cultured endothelial cells.…”

Deficiency in Inducible Nitric Oxide Synthase Results in Reduced Atherosclerosis in Apolipoprotein E-Deficient Mice

“…Production of NO in the vasculature may have beneficial effects related to the development of atherosclerosis, and these have been extensively reviewed (25)(26)(27)(28)(29)(30)(31). NO output by the constitutive form of NOS, ecNOS, expressed in endothelial cells, helps in maintaining vascular tone.…”