Atherogenesis endothelial dysfunction

Inadequate levels of vitamin E and other antioxidants will lead to the loss of PUFA through oxidation and to oxidative damage of key biomolecules. The latter has become accepted as a probable factor in atherogenesis, endothelial dysfunction, and myocardial ischemia, whereas it is rarely considered that the loss of n-3 LC-PUFA could be as impor-... 

Fig. 2.1 Sequence of events in atherogenesis and role of low-density lipoprotein. Native LDL, in the subendothelial space, undergoes progressive oxidation (mmLDL) and activates the expression of MCP-1 and M-CSF in the endothelium (EC). MCP-1 and M-CSF promote the entry and maturation of monocytes to macrophages, which further oxidise LDL (oxLDL). Ox-LDL is specifically recognised by the scavenger receptor of macrophages and, once internalised, formation of foam cells occurs. Both mmLDL and oxLDL induce endothelial dysfunction, associated with changes of the adhesiveness to leukoc)des or platelets and to wall permeability.

The oxysterol 7-ketocholesterol is an important COP involved in atherosclerotic lesions and macrophage foam cells (275). There is no direct evidence in humans that COPs contribute to atherogenesis, but it has been found that COP levels are elevated in LDL subfractions that are considered potentially atherogenic (276). In addition, raised levels of 7p-hydroxycholesterol may be associated with an increased risk of atherosclerosis. Arterial injury by COPs causes endothelial dysfunction and arterial wall cholesterol accumulation (277). Even under normocholesterolemic conditions, COPs can cause endothelial dysfunction, increased macromolecular permeability, and increased cholesterol accumulation. These are all factors believed to be involved in the development of atherosclerotic lesions. The atherogenic potential of COPs has been demonstrated by in vitro cell culture (73, 278), as well as in animal feeding studies (279). Japanese quail fed either purified cholesterol or oxidized cholesterol exhibited greater plasma and liver cholesterol concentrations in association with increased severity of atherosclerotic lesions when fed the oxidized cholesterol (279). 

A corollary of the oxidation hypothesis of atherogenesis is that antioxidants may reduce the progression of the disease (114). Antioxidants present in LDL, including alpha-tocopherol, and antioxidants present in the extracellular fluid of the arterial wall, including ascorbic acid (vitamin C), inhibit LDL oxidation (132), and this action is extended to multiple oxLDL-mediated signaling pathways (133). Vitamin C may potentiate NO activity and normalize vascular function in patients with CHD and classical risk factors (132). Thus, NO may restore endothelial dysfunction and ameliorate vascular remodeling in several clinical correlates to experimental... 

Figure 3.2 Beneficial effects of folic acid on vascular wall. Folic acid circulates in human body as 5-methyltetrahydrofolate (5-MTHF). 5-MTHF lowers circulating homocysteine (Hey) levels, thus reducing systemic oxidative stress and Hcy-induced activation of prothrombotic mechanisms. In addition, vascular 5-MTHF has a favourable effect on intracellular Hey metabolism, attenuating Hcy-induced activation of NADPH oxidase isoforms (NOXs) in the vascular wall. Furthermore vascular 5-MTHF scavenges per se peroxynitrite (ONOO ) radicals in the vascular wall preventing the oxidation of vascular tetrahydrobiopterin (BH4) associated with endothelial nitric oxide synthase (eNOS) uncoupling and diminished vascular nitric oxide (NO) bioavailability. In total through these effects 5-MTHF lowers vascular oxidative and nitrosative stress. Thus by modulating vascular redox, 5-MTHF inhibits activation of proinffammatory pathways which orchestrate vascular wall inflammation and perpetuate endothelial dysfunction and atherogenesis development (unpublished).

Endothelial dysfunction is an early event in atherogenesis. Antioxidants, including a-tocopherol and probucol are reported to restore endothelial function in cholesterol-fed rabbits. This study demonstrated that SM-EW-1, a Sal B-enriched fraction of S. miltiorrhiza, reduces endothelium damage effectively in NZW rabbit model. We suggest that water-soluble antioxidants may on one hand scavenge ROS in blood stream and reduce the direct injury to... 

Hutchison SJ, Sudhir K, Sievers RE, et al. Effects of L-arginine on atherogenesis and endothelial dysfunction due to secondhand smoke. Hypertension 1999 34 44-50. 

Elevation of plasma cholesterol, particularly low-density lipoprotein cholesterol (LDL-C), is positively correlated with coronary heart disease (CHD), a major vascular disease predominantly causing by atherosclerosis (1,2). Recent studies have indicated that LDL oxidation, endothelial dysfunction, and inflammation play important roles in the molecular pathogenesis of atherosclerosis (3). Oxidized LDL (OxLDL) appears in the circulation and tends to infiltrate into the aortic endothelium (4). Antioxidants, which inhibit LDL oxidative modification, may reduce early atherogenesis and slow down the disease progression to an advanced stage (5). 

It is accepted that oxidation of LDL is a key event in endothelial injury and dysfunction. Oxidised LDL (oxLDL) may directly injure the endothelium and trigger the expression of migration and adhesion molecules. Monocytes and lymphocytes interact with oxLDL and the phagocytosis which follows leads to the formation of foam cells, which in turn are associated with the alteration of the expression pattern of growth regulatory molecules, cytokines and pro-inflammatory signals. The proposed role of oxLDL in atherogenesis, based on studies in vitro, is shown in Fig. 2.1. 

I. M. Cybulsky and M. A. Gimbione Jr, Endothelial-leucocyte adhesion molecules in acute inflammation and atherogenesis. In Endothelial Cell Dysfunction... 

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