ENOS expression

Endothelial NO Synthase (eNOS) expression is relatively specific for endothelial cells. However, the isozyme has also been detected in certain neurons of the brain, in syncytiotrophoblasts of human placenta and in LLC-PKi kidney tubular epithelial cells. 

A recent study showed significant increases of expression of eNOS in the brains of rats treated with pyrithia-mine [20]. Increased eNOS expression was apparent prior to the onset of neurological symptoms and was restricted to vulnerable medial thalamus and inferior colliculus. Expression of inducible (iNOS) and neuronal (nNOS) isoforms were minimally altered in brain in thiamine deficiency and it has also been shown that targeted disruption of the eNOS (but not the iNOS or nNOS) gene results in reduced extent of neuropathological damage in thalamus of thiamine deficient animals [21] (Fig. 34-5). 

Nitric Oxide Synthase Expression and Activity Nitric Oxide Synthase Uncoupling. Inhibitory effects of quercetin on the activity or expression of endothelial NO synthases (eNOS and iNOS) has been reported but only at high concentrations (< 50 pM) [Camuesco et al., 2004 Chiesi and Schwaller 1995]. Therefore, direct changes in endothelial NO expression or activity, even when relevant to other polyphenolics, do not appear to be physiologically relevant for quercetin. However, quercetin may restore NOS expression or activity when unpaired by pathological stimuli. In fact, eNOS expression, which is up-regulated in SHR, can be corrected by chronic quercetin administration... 

The nNOS knockout mice provide a unique opportunity to explore many of the postulated functions of NO in the nervous system. In the nNOS null mice LTP induced by weak intensity tetanic stimulation was only slightly reduced (O Dell et al., 1994). This LTP was blocked by NOS inhibitors, just as it is in the wild type (O Dell et al., 1994), suggesting that eNOS expressed in the hippocampus may be more important than nNOS to LTP. 

Markers of inflammation, especially CRP (measured with a highly sensitive technique, referred to as hs-CRP), have become the center of attention in recent years (22). This increased interest stems from several important observations made by Ridker and co-workers. Serum CRP has been shown to be an independent cardiovascular disease risk factor (23,24). High levels predict CAD death in healthy middle-aged men (25) and in patients with unstable CAD (26). In acute coronary syndromes, serum CRP concentrations correlate with the severity of endothelial dysfunction (27). In the CARE trial, subjects with elevated markers of inflammation (CRP and serum amyloid A > 90th percentile) were at high cardiovascular risk and responded best to pravastatin treatment in terms of cardiovascular risk reduction (28). The statin also reduced serum CRP concentrations (29). CRP co-incubated with LDL is readily taken up by macrophages, in contrast to native LDL, suggesting that CRP could promote foam cell formation (30). A link with endothelial dysfunction may be related to the fact that CRP decreases endothelial nitric oxide synthase (eNOS) expression and bioactivity in human aortic endothelial cells (31). 

Venugopal, S.K., Devaraj, S., Yuhanna, L, Shaul, P., and Jialal, I. (2002) Demonstration That C-Reactive Protein Decreases eNOS Expression and Bioactivity in Human Aortic Endothelial Cells, Circulation 106,1439-1441. 

An important link may exist between nitric oxide (NO), a crucial mediator of vascular tone and platelet function, and the activation of COX. It has been reported that there is a NO-mediated increased COX activity in endothelial cells. This has now been attributed to the formation of peroxynitrite (produced from an interaction between NO and superoxide anions) that directly activates COX. However, this interaction is complex and may depend on the quantity and source of NO as well as on the specific COX isoforms (Davidge, 2001). This interplay between prostanoid and NO production appears to be particularly important for the function of the ocular vascular endothelium, where the effect of NO in the eye is largely mediated via PGI, and specific prostanoids have been shown to regulate endothelial nitric oxide synthase (eNOS) expression and activity in the ocular blood vessels (Hardy et al, 2000). 

Endothelial NOS (eNOS) is responsible for producing NO in the vascular wall (reviewed in ref. 58). In rat aortic EC, acute exposure to both estradiol and insulin-like growth factor (IGF)-l was associated with an increase in eNOS activity (59). The presence of abnormal ECM in the vessel wall could be responsible for decreased NO synthesis (60), however, chronic over expression of eNOS accelerates atherosclerosis under hypercholesterolemia. eNOS dysfunction, demonstrated by lower NO production relative to eNOS expression and enhanced superoxide production in the endothelium, appears to play important roles in the progression of atherosclerosis in Apo E KO/eNOS transgenic mice (61). 

Red wine strongly inhibits ET-1 synthesis (125) phenolic acids in wine prevent LDL oxidation in the arterial wall (126), increases eNOS expression in HUVEC (127), inhibits PDGF-P receptor activation (128), and inhibits the proliferation and DNA synthesis in cultured rat VSMC (129). However, alcohol is a complementary component of phenolics in the benefits of red wine in hypercholesterolemic golden Syrian hamsters (130). 

In an animal model of atherosclerosis E2 restores FasL expression, which is suppressed by atherogenic levels of serum cholesterol (328). High levels of Hey diminish with estrogen (reviewed in ref. 329). In HUVEC, E2 caused a decrease in expression of the NADPH oxidase subunit gp91phox, up-regulated eNOS expression, and inhibited the increase in adhesion molecule and chemokine expression in cells exposed to cyclic strain. Cyclic strain enhanced endothelial 02 formation, thereby offsetting the inhibitory effect of NO on the expression of these gene products (330). 

Recombinant AV-driven c-met transduction into diabetic corneas appears to restore HGF signaling, normalize diabetic marker patterns, and accelerate wound healing Fibrin delivery of AdeNOS resulted in enhanced eNOS expression, inflammatory response, and a faster rate of re-epithelialization... 

Because (1) AKT is commonly activated in human eaneers to promote tumorigene-sis, (2) eNOS is activated by AKT, at least in endothelial eeUs, (3) eNOS has been detected in cancer cells, and (4) perturbing eNOS expression in a number of settings disrupts tumor phenotypes, sueh as eeU proliferation, apoptosis, and angiogenesis, we propose that illegitimate activation of AKT in cancer eeUs may act through eNOS to promote mmorigenesis (Fig. 2.1). 

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