Atherosclerosis nitric oxide

Napoli C, Ignarro LJ. 2001. Nitric oxide and atherosclerosis. Nitric Oxide 5 88-97... 

The aggregation of platelets contributes to the development of atherosclerosis and to the formation of acute thrombus. The activated platelets that adhere to the vascular endothelium generate lipid peroxides and oxygen free radicals, inhibiting the endothelial formation of prostacyclin and nitric oxide. 

It should also be mentioned that superoxide and not nitric oxide production by eNOS may have implications for atherosclerosis and septic shock due to imbalance between NO and superoxide formation, for example due to an increase in TNF-a production [164]. These pathophysiological functions of NO synthases will be considered in detail in Chapter 31. 

The disturbance of balance between superoxide and nitric oxide occurs in a variety of common disease states. For example, altered endothelium-dependent vascular relaxation due to a decrease in NO formation has been shown in animal models of hypertension, diabetes, cigarette smoking, and heart failure [21]. Miller et al. [22] suggested that a chronic animal model atherosclerosis closely resembles the severity of atherosclerosis in patients. On the whole, the results obtained in humans, for example, in hypertensive patients [23] correspond well to animal experiments. It is important that endothelium-dependent vascular relaxation in patients may be improved by ascorbic acid probably through the reaction with superoxide. 

NO (molecular weight = 30) is small but plays a big role in physiological regulation, not least in the vasculature where its effects were first seen (see Chapter 4). Endothelium-derived relaxation factor (EDRF) was discovered its ability to cause dilatation of vessels by relaxing the arterial muscle layer. Only much later was EDRF discovered to be a gas, nitric oxide. More recent interest in NO is based on the evidence that it is antiatherogenic. The pathogenesis of atherosclerosis is complex but many of the known effects of NO can be implicated in this common and serious condition. 

The oxidation hypothesis of atherosclerosis states that the oxidative modification of LDL (or other lipoproteins) is important and possibly obligatory in the pathogenesis of the atherosclerotic lesion thus, it has been suggested that inhibiting the oxidation of LDL will decrease or prevent atherosclerosis and clinical sequelae. LDL oxidation also has important implications for vascular health function. High concentrations of LDL may inhibit arterial function in terms of the release of nitric oxide from the endothelium and many of these effects are mediated by lipid oxidation products. Furthermore, oxidized LDL inhibits endothelium-dependent nitric oxide-mediated relaxations in isolated rabbit coronary arter-... 

Heinloth A, Brune B, Fischer B, Galle J. Nitric oxide prevents oxidised LDL-indnced p53 accumulation, cytochrome c translocation and apoptosis in macrophages via guanylate cyclase stimulation. Atherosclerosis 162, 93-101, 2002. 

A study has been undertaken to clarify whether glucocorticoid excess affects endothelium-dependent vascular relaxation in glucocorticoid treated patients and whether dexamethasone alters the production of hydrogen peroxide and the formation of peroxynitrite, a reactive molecule between nitric oxide and superoxide, in cultured human umbilical endothelial cells (7). Glucocorticoid excess impaired endothelium-dependent vascular relaxation in vivo and enhanced the production of reactive oxygen species to cause increased production of peroxynitrite in vitro. Glucocorticoid-induced reduction in nitric oxide availability may cause vascular endothelial dysfunction, leading to hypertension and atherosclerosis. 

Chin-Dusting JP, Boak L, Husband A, Nestel PJ. 2004. The isoflavone metabolite dehydroequol produces vasodilatation in human resistance arteries via a nitric oxide dependent mechanism. Atherosclerosis 176 45-48. 

Squadrito F, Altavilla D, Morabito N, Crisafulli A, D Anna R, Corrado F, Ruggeri P, Campo GM, Calapai G, Caputi AP, Squadrito G. 2002. The effect of the phytoestrogen genistein on plasma nitric oxide concentrations, endothelin-1 levels and endothelium dependent vasodilation in postmenopausal women. Atherosclerosis 163 339-347. 

Atorvastatin calcium possesses an anti-inflammatory property and reduces the accumulation of inflammatory cells in the atherosclerotic plaques. The drug also inhibits the vascular smooth muscle cell proliferation a key event in the atherogenesis. Atorvastatin also inhibits the platelet function, thereby limiting both the atherosclerosis and the superadded thrombosis and also improves the vascular endothelial function, largely through the amplification of nitric oxide (NO) generation [3-5]. 

Normal coronary arteries can dilate in response to ischemia, increasing delivery of oxygen to the myocardium. This is mediated by nitric oxide, which acts upon smooth muscle cells of the arterial media. This function is impaired by atherogenic lipoproteins in several phenotypes of hyperlipidemia, aggravating ischemic manifestations of atherosclerosis. Reducing levels of atherogenic lipoproteins and inhibition of their oxidation helps restore endothelial function. 

Body iron level and iron depletion play an important role in the gender differences seen in death from cardiac disease. There is a better correlation with heart disease mortality in iron levels compared with levels of cholesterol (5). It was found that risk of coronary heart disease (6) and carotid atherosclerosis (7) is associated with increased iron stores. However, impaired endothelium-derived nitric oxide activity may be without overt atherosclerosis in patients with risk factors and may be associated with the presence of atherosclerosis (4). Thus, endothelial dysfunction related to iron activity not only may be an early marker for cardiovascular risk but also may contribute to the pathogenesis of atherosclerosis (2) by the stimulation of low-density lipoproteins (LDL) and membrane lipid peroxidation (I) and may be a key to the understanding of early mechanism in the development of atheroma (7,8). Nakayama et al. (9) showed the role of heme oxygenase induction in the modulation of macrophage activation in atherosclerosis. However, Howes et al. (10) concludes that at the moment, the available evidence on iron hypothesis remains circumstantial. Moreover, Kiechl et al. (7) showed that the adverse effect of iron is hypercholesterolemia, In patients... 

Estrogens have also been found to have direct effects on blood vessels, including increased synthesis of nitric oxide and increased vasodilation (Farhat et al., 1996 McCrohon et al., 1996). The observed decrease in the risk of cardiovascular disease and atherosclerosis by estrogens (Pines et al, 1997 Punnonen et al., 1995 Stampfer and Colditz, 1991) is thought to be due to the combined effects of estrogens on serum lipids and vascular reactivity. 

It is important to note that an elevated and/or altered plasma lipid level is only one of a wide range of risk factors that contribute to the clinical manifestations of cardiovascular disease in humans (Lusis, 2000). Consequently, in some studies, the reduced incidence of atherosclerosis in animals fed CLA was not accompanied by an improvement in the plasma lipid profile during the CLA feeding phase (Wilson et al, 2000). Reasons for these effects are not understood fully. However, atherosclerosis can also be considered as a chronic inflammatory disease (Libby, 2002) and several important anti-inflammatory effects have been associated with the use of RA these include a reduction in the expression of COX-2, PGE2, reduced release of nitric oxide, a decreased production of pro-inflammatory cytokines, and PPARy activation (Urquhart et al, 2002 Yu et al, 2002 Toomey et al, 2003). 

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