Nitric oxide and atherosclerosis: An update (original) (raw)
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Nitric oxide and arterial disease
Journal of Vascular Surgery, 2004
Nitric oxide (NO) is a molecule that has gained recognition as a crucial modulator of vascular disease. NO has a number of intracellular effects that lead to vasorelaxation, endothelial regeneration, inhibition of leukocyte chemotaxis, and platelet adhesion. Its role in vascular disease has been intensively investigated and further elucidated over the past two decades. It is important in the pathogenesis of many cardiovascular diseases, including atherosclerosis, intimal hyperplasia, and aneurysmal disease. In addition, NO has been used as a therapeutic tool to treat diseases that range from recurrent stenosis to inhibiting thrombotic events. Many commonly used medications have their therapeutic actions through the production of NO. This review highlights the vascular biologic characteristics of NO, its role in the pathogenesis of cardiovascular disease processes, and its potential therapeutic applications.
Reduced Endothelial Nitric Oxide Synthase Expression and Production in Human Atherosclerosis
Circulation, 1998
Background —NO regulates vascular tone and structure, platelets, and monocytes. NO is synthesized by endothelial NO synthase (eNOS). Endothelial dysfunction occurs in atherosclerosis. Methods and Results —With a porphyrinic microsensor, NO release was measured in atherosclerotic human carotid arteries and normal mammary arteries obtained during surgery. eNOS protein expression was analyzed by immunohistochemistry. In normal arteries, the initial rate of NO release after stimulation with calcium ionophore A23187 (10 μmol/L) was 0.42±0.05 (μmol/L)/s (n=10). In contrast, the initial rate of NO release was markedly reduced in atherosclerotic segments, to 0.08±0.04 (μmol/L)/s (n=10, P <0.0001). NO peak concentration in normal arteries was 0.9±0.09 μmol/L (n=10) and in atherosclerotic segments, 0.1±0.03 μmol/L (n=10, P <0.0001). Reduced NO release in atherosclerotic segments was accompanied by marked reduction of immunoreactive eNOS in luminal endothelial cells, although specific en...
NITRIC OXIDE IN ATHEROSCLEROSIS: VASCULAR PROTECTOR OR VILLAIN?
Clinical and Experimental Pharmacology and Physiology, 1998
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.
The role of nitric oxide in cardiovascular diseases
Nitric oxide (NO) is a gaseous lipophilic free radical cellular messenger generated by three distinct isoforms of nitric oxide synthases (NOS), neuronal (nNOS), inducible (iNOS) and endothelial NOS (eNOS). NO plays an important role in the protection against the onset and progression of cardiovascular disease. Cardiovascular disease is associated with a number of different disorders including hypercholesterolaemia, hypertension and diabetes. The underlying pathology for most cardiovascular diseases is atherosclerosis, which is in turn associated with endothelial dysfunctional. The cardioprotective roles of NO include regulation of blood pressure and vascular tone, inhibition of platelet aggregation and leukocyte adhesion, and prevention smooth muscle cell proliferation.
Nitric oxide in the pathogenesis of vascular disease
The Journal of Pathology, 2000
Nitric oxide (NO) is synthesized by at least three distinct isoforms of NO synthase (NOS). Their substrate and cofactor requirements are very similar. All three isoforms have some implications, physiological or pathophysiological, in the cardiovascular system. The endothelial NOS III is physiologically important for vascular homeostasis, keeping the vasculature dilated, protecting the intima from platelet aggregates and leukocyte adhesion, and preventing smooth muscle proliferation. Central and peripheral neuronal NOS I may also contribute to blood pressure regulation. Vascular disease associated with hypercholesterolaemia, diabetes, and hypertension is characterized by endothelial dysfunction and reduced endothelium-mediated vasodilation. Oxidative stress and the inactivation of NO by superoxide anions play an important role in these disease states. Supplementation of the NOS substrate L-arginine can improve endothelial dysfunction in animals and man. Also, the addition of the NOS cofactor (6R)-5,6,7, 8-tetrahydrobiopterin improves endothelium-mediated vasodilation in certain disease states. In cerebrovascular stroke, neuronal NOS I and cytokine-inducible NOS II play a key role in neurodegeneration, whereas endothelial NOS III is important for maintaining cerebral blood flow and preventing neuronal injury. In sepsis, NOS II is induced in the vascular wall by bacterial endotoxin and/or cytokines. NOS II produces large amounts of NO, which is an important mediator of endotoxin-induced arteriolar vasodilatation, hypotension, and shock.
Nitric Oxide and its Role in Cardiovascular Diseases
Open Nitric Oxide …, 2011
Nitric oxide synthases (NOS) are the enzymes responsible for nitric oxide (NO) generation. NO is a free radical which reacts with various molecules to cause multiple biological effects. It is clear that the generation and actions of NO under physiological and pathophysiological conditions are exquisitely regulated and extend to almost every cell type and function within the circulation. While the molecule mediates many physiological functions, an excessive presence of NO is toxic to cells. The enzyme NOS, constitutively or inductively, catalyses the production of NO in several biological systems. NO is derived not only from NOS isoforms but also from NOS-independent sources. In mammals, to date, three distinct NOS isoforms have been identified: neuronal NOS (nNOS), inducible NOS (iNOS), and endothelial NOS (eNOS). The molecular structure, enzymology and pharmacology of these enzymes have been well defined, and reveal critical roles for the NOS system in a variety of important physiological processes. This review focuses on recent advances in the understanding of the interactions between NOS enzymes and pathophysiology of cardiovascular diseases (CVD) and the role of NO agonists as potential therapeutic agents in treatment of CVD.
Nitric oxide and the endothelium: History and impact on cardiovascular disease
Vascular Pharmacology, 2006
There are few discoveries with the magnitude of the impact that NO has had on biology during the 25 years since its discovery. There is hardly a disease today not associated with altered NO homeostasis. In fact, despite numerous other endothelial functions, endothelial dysfunction has become synonymous with reduced biological activity of NO.
Insight into oxidative stress mediated by nitric oxide synthase (NOS) isoforms in atherosclerosis
The principle product of each NOS is nitric oxide. However, under conditions of substrate and cofactor deficiency the enzymes directly catalyze superoxide formation. Considering this alternative chemistry of each NOS, the effects of each single enzyme on key events of atherosclerosis are difficult to predict. Here, we evaluate nitric oxide and superoxide production by all three NOS isoforms in atherosclerosis. ESR measurements of circulating and vascular wall nitric oxide production showed significantly reduced nitric oxide levels in apoE/eNOS double knockout (dko) and apoE/iNOS dko animals but not in apoE/nNOS dko animals suggesting that eNOS and iNOS majorly contribute to vascular nitric oxide production in atherosclerosis. Pharmacological inhibition and genetic deletion of eNOS and iNOS reduced vascular superoxide production suggesting that eNOS and iNOS are uncoupled in atherosclerotic vessels. Though genetic deletion of nNOS did not alter superoxide production, acute inhibition...
Cardiology, 2010
and thus exerts antiatherogenic properties . According to available studies, impaired NO synthesis and subsequent worsening of endothelial functioning and vasoconstriction have been observed in patients with atherosclerosis or its risk factors and are thought to be independent predictors of cardiovascular events . However, in pathological conditions (inflammation, aging, hypertension, hypercholesterolemia, diabetes mellitus, shortage of cofactors, or hypoxia), NO readily reacts with abundant reactive oxygen species, resulting in the formation of reactive dinitrogen trioxide and peroxynitrite (ONOO -), which in turn leads to a considerable diminishing of the amount of NO involved in its typical reactions, such as vasodilation or platelet adhesion inhibition . The amount of NO may also be decreased due to the presence of polymorphisms within NOS leading to the formation of protein having little or no activity (dysfunctional protein) . Numerous studies have suggested that the presence of some polymorphisms within the eNOS gene may be associated with an increased risk of cardiovascular disease [9] , ischemic heart disease [10] , coronary spasm [11] , hypertension [12] and in-stent restenosis .