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1. Atherosclerosis in youth: are hypertension and other coronary heart disease risk factors already at work?

Pediatr Nephrol 1997 Feb;11(1):99-107
Oalmann MC, Strong JP, Tracy RE, Malcom GT
Department of Pathology, Louisiana State University Medical Center, New Orleans 70112, USA.

The purposes of this review were to describe the natural history of
atherosclerosis in youth, discuss the role of adult coronary heart disease (CHD) risk factors in the development of atherosclerosis-particularly in the young- and present the relationship between atherosclerosis and hypertension. Evidence is presented that, by age 15 years, 100% of the youth have aortic atherosclerosis and about one-half have coronary atherosclerosis. Risk factors for adult CHD, including lipoproteins, smoking, glycohemoglobin (a marker for diabetes), obesity, and hypertension, are associated with extent and prevalence of atherosclerosis in young people. Hypertension seems to play its role mainly by converting early atherosclerotic lesions (fatty streaks) to more advanced lesions (raised lesions).

2. Aging is associated with endothelial dysfunction in healthy men years before the age-related decline in women.

Celermajer DS, et al.
J Am Coll Cardiol 1994 Aug;24(2):471-6
Celermajer DS, Sorensen KE, Spiegelhalter DJ, Georgakopoulos D, Robinson J, Deanfield JE
Cardiothoracic Unit, Hospital for Sick Children, London.

OBJECTIVES. This study assessed whether aging is associated with progressive endothelial dysfunction, whether the pattern of any age-related decline in vascular health is different in men and women and whether any gender difference is consistent with known changes in hormonal status. BACKGROUND. Coronary and cerebrovascular disease are much less common in young and middle-aged women compared with men, although the gender difference in death from atherosclerosis is less marked after the menopause. Endothelial dysfunction is an early event in atherogenesis and is important in dynamic plaque stenosis in later life. The effect of aging on endothelial function in men and women, however, is not well known. METHODS. We used high resolution ultrasound to study endothelium-dependent and endothelium-independent vascular responses. Brachial artery physiology was investigated in 238 subjects (103 men, 135 women; mean [ SD] age 38 17 years, range 15 to 72) with no known risk factors for atherosclerosis. The responses to reactive hyperemia (flow-mediated dilation, which is endothelium dependent) and to glyceryl trinitrate (an endothelium-independent dilator) were assessed for all the subjects and then for men and women separately. RESULTS. On multivariate analysis for the whole group, reduced flow-mediated dilation was related to older age (r = -0.34, p < 0.0001). In men, flow-mediated dilation was preserved in subjects aged < or = 40 years but declined thereafter at 0.21%/year. In women, flow-mediated dilation was stable until the early 50s, after which it declined at 0.49%/year (p = 0.002 compared with men). In contrast, there was no significant change in the glyceryl trinitrate response with aging in either gender. CONCLUSIONS. Aging is associated with progressive endothelial dysfunction in normal humans, and this appears to occur earlier in men than in women. In women, however, a steep decline commences at around the time of the menopause. This is consistent with a protective effect of estrogens on the arterial wall.

3. Vitamin C protects human vascular smooth muscle cells against apoptosis induced by moderately oxidized LDL containing high levels of lipid hydroperoxides.

Arterioscler Thromb Vasc Biol 1999 Oct;19(10):2387-94
Siow RC, Richards JP, Pedley KC, Leake DS, Mann GE
Centre for Cardiovascular Biology and Medicine, GKT School of Biomedical
Sciences, King's College, London, UK.

Vascular cell death is a key feature of atherosclerotic lesions and may
contribute to the plaque "necrotic" core, cap rupture, and thrombosis.
Oxidatively modified low-density lipoproteins (LDLs) are implicated in the
pathogenesis of atherosclerosis, and dietary antioxidants are thought to protect
the vasculature against LDL-induced cytotoxicity. Because LDL oxidative
modification may vary within atherosclerotic lesions, we examined the effects of
defined, oxidatively modified LDL species on human arterial smooth muscle cell apoptosis and the cytoprotective effects of vitamin C. Moderately oxidized LDL (0 to 300 microg protein/mL), which has the highest content of lipid
hydroperoxides, induced smooth muscle cell apoptosis within 6 hours, whereas
native LDL and mildly and highly oxidized LDL had no effect. Moderately oxidized LDL increased cellular DNA fragmentation, release of fragmented DNA into the culture medium, and annexin V binding and decreased mitochondrial dehydrogenase activity and expression of the antiapoptotic mediator Bcl-x(L). Treatment of cells with native LDL together with the lipid hydroperoxide 13(S)-hydroperoxyoctadeca-9Z,11E-dienoic acid (HPODE, 200 micromol/L, 6 to 24 hours) also induced apoptotic cell death. Pretreatment of smooth muscle cells with vitamin C (0 to 100 micromol/L, 24 hours) attenuated the cytotoxicity and apoptosis induced by both moderately oxidized LDL and HPODE. Our findings suggest that moderately oxidized LDL, with its high lipid hydroperoxide content, rather than mildly or highly oxidized LDL, causes apoptosis of human smooth muscle cells and that vitamin C supplementation may provide protection against plaque instability in advanced atherosclerosis.

4. On the role of vitamin C and other antioxidants in atherogenesis and vascular

Proc Soc Exp Biol Med 1999 Dec;222(3):196-204
Frei B
Linus Pauling Institute, Oregon State University, Corvallis, OR 97331-6512, USA.

Oxidative stress has been implicated as an important etiologic factor in atherosclerosis and vascular dysfunction. Antioxidants may inhibit atherogenesis and improve vascular function by two different mechanisms. First, lipid-soluble antioxidants present in low-density lipoprotein (LDL), including alpha-tocopherol, and water-soluble antioxidants present in the extracellular fluid of the arterial wall, including ascorbic acid (vitamin C), inhibit LDL oxidation through an LDL-specific antioxidant action. Second, antioxidants present in the cells of the vascular wall decrease cellular production and release of reactive oxygen species (ROS), inhibit endothelial activation (i.e., expression of adhesion molecules and monocyte chemoattractants), and improve the biologic activity of endothelium-derived nitric oxide (EDNO) through a cell- or tissue-specific antioxidant action. alpha-Tocopherol and a number of thiol antioxidants have been shown to decrease adhesion molecule expression and monocyte-endothelial interactions. Vitamin C has been demonstrated to potentiate EDNO activity and normalize vascular function in patients with coronary artery disease and associated risk factors, including hypercholesterolemia,
hyperhomocysteinemia, hypertension, diabetes, and smoking.

.5. Induction of antioxidant stress proteins in vascular endothelial and smooth muscle cells: protective action of vitamin C against atherogenic lipoproteins.

Free Radic Res 1999 Oct;31(4):309-18
Siow RC, Sato H, Leake DS, Ishii T, Bannai S, Mann GE
Centre for Cardiovascular Biology and Medicine, GKT School of Biomedical
Sciences, King's College London, UK.

Elevated levels of lipid peroxidation and increased formation of reactive oxygen species within the vascular wall in atherosclerosis can overwhelm cellular antioxidant defence mechanisms. Accumulating evidence implicates oxidatively modified low density lipoproteins (LDL) in vascular dysfunction in atherosclerosis and oxidized LDL have been localized with in atherosclerotic lesions. We here report that human oxidatively modified LDL induce expression of 'antioxidant-like' stress proteins in vascular cells, involving increases in the activity of L-cystine transport, glutathione synthesis, heme oxygenase-1 and the murine stress protein MSP23. Moreover, treatment of human arterial smooth muscle cells with the dietary antioxidant vitamin C markedly attenuates adaptive increases in endogenous antioxidant gene expression and affords protection against smooth muscle cell apoptosis induced by moderately oxidized LDL. As vascular cell death is a key feature of atherosclerotic lesions and may contribute to the plaque 'necrotic' core, cap rupture and thrombosis, our findings suggest that the cytoprotective actions of vitamin C could limit plaque instability in advanced atherosclerosis.

6. Role of oxidant stress in endothelial dysfunction produced by experimental
hyperhomocyst(e)inemia in humans.

Circulation 1999 Sep 14;100(11):1161-8
Kanani PM, Sinkey CA, Browning RL, Allaman M, Knapp HR, Haynes WG
Departments of Pediatrics, University of Iowa College of Medicine, Iowa City,
Iowa 52242, USA.

BACKGROUND: Moderate elevations in plasma homocyst(e)ine concentrations are associated with atherosclerosis and hypertension. We tested the hypothesis that experimental perturbation of homocysteine levels produces resistance and conduit vessel endothelial dysfunction and that this occurs through increased oxidant stress. METHODS AND RESULTS: Oral administration of L-methionine (100 mg/kg) was used to induce moderate hyperhomocyst(e)inemia ( approximately 25 micromol/L) in healthy human subjects. Endothelial function of forearm resistance vessels was assessed by use of forearm vasodilatation to brachial artery administration of the endothelium-dependent dilator acetylcholine. Conduit vessel endothelial function was assessed with flow-mediated dilatation of the brachial artery. Forearm resistance vessel dilatation to acetylcholine was significantly impaired 7 hours after methionine (methionine, 47782%; placebo, 673110%; P=0.016). Methionine did not alter vasodilatation to nitroprusside and verapamil. Flow-mediated dilatation was significantly impaired 8 hours after methionine loading (0.32.7%) compared with placebo (8. 21.6%, P=0.01). Oral administration of the antioxidant ascorbic acid (2 g) prevented methionine-induced endothelial dysfunction in both conduit and resistance vessels (P=0.03). CONCLUSIONS: Experimentally increasing plasma homocyst(e)ine concentrations by methionine loading rapidly impairs both conduit and resistance vessel endothelial function in healthy humans. Endothelial dysfunction in conduit and resistance vessels may underlie the reported associations between homocysteine and atherosclerosis and hypertension. Increased oxidant stress appears to play a pathophysiological role in the deleterious endothelial effects of homocysteine.

.7. Long-term ascorbic acid administration reverses endothelial vasomotor dysfunction in patients with coronary artery disease.

Circulation 1999 Jun 29;99(25):3234-40
Gokce N, Keaney JF Jr, Frei B, Holbrook M, Olesiak M, Zachariah BJ, Leeuwenburgh
C, Heinecke JW, Vita JA
Evans Memorial Department of Medicine, Cardiology Section, and Whitaker
Cardiovascular Institute, Boston University School of Medicine, Boston, MA, USA.

BACKGROUND: Loss of endothelium-derived nitric oxide (EDNO) contributes to the clinical expression of coronary artery disease (CAD). Increased oxidative stress has been linked to impaired endothelial vasomotor function in atherosclerosis, and recent studies demonstrated that short-term ascorbic acid treatment improves endothelial function. METHODS AND RESULTS: In a randomized, double-blind, placebo-controlled study, we examined the effects of single-dose (2 g PO) and long-term (500 mg/d) ascorbic acid treatment on EDNO-dependent flow-mediated dilation of the brachial artery in patients with angiographically established CAD. Flow-mediated dilation was examined by high-resolution vascular ultrasound at baseline, 2 hours after the single dose, and 30 days after long-term treatment in 46 patients with CAD. Flow-mediated dilation improved from 6.63.5% to 10.15.2% after single-dose treatment, and the effect was sustained after long-term treatment (9. 03.7%), whereas flow-mediated dilation was 8.64.7% at baseline and remained unchanged after single-dose (7.84.4%) and long-term (7.94.5%) treatment with placebo (P=0.005 by repeated-measures ANOVA). Plasma ascorbic acid concentrations increased from 41.412. 9 to 115.934.2 micromol/L after single-dose treatment and to 95. 036.1 micromol/L after long-term treatment (P<0.001). CONCLUSIONS: In patients with CAD, long-term ascorbic acid treatment has a sustained beneficial effect on EDNO action. Because endothelial dysfunction may contribute to the pathogenesis of cardiovascular events, this study indicates that ascorbic acid treatment may benefit patients with CAD.

8. The key role of histamine in the development of atherosclerosis and coronary heart disease.

Med Hypotheses 1999 Jan;52(1):1-8
Clemetson CA Tulane University School of Medicine, New Orleans, LA, USA.

Vitamin C-deficiency is known to cause a disturbance of cholesterol metabolism. Suboptimal plasma ascorbic acid levels also cause increased blood histamine levels, which are exaggerated by sleep-lack and other forms of stress. Histaminemia causes separation of vascular endothelial cells. It is here suggested that the histaminemia of stress and ascorbate depletion combine to cause damage to the arterial endothelium and predispose to atherosclerosis, the principal cause of myocardial infarction.

9. Vitamin C protects against and reverses specific hypochlorous acid- and chloramine-dependent modifications of low-density lipoprotein.

Biochem J 2000 Mar 1;346 Pt 2:491-9
Carr AC, Tijerina T, Frei B
Linus Pauling Institute, 571 Weniger Hall, Oregon State University, Corvallis,
OR 97331, USA.

Activated phagocytes produce the highly reactive oxidant hypochlorous acid (HOCl) via the myeloperoxidase-catalysed reaction of hydrogen peroxide with chloride ions. HOCl reacts readily with a number of susceptible targets on apolipoprotein B-100 of low-density lipoprotein (LDL), resulting in uncontrolled uptake of HOCl-modified LDL by macrophages. We have investigated the efects of vitamin C (ascorbate), an effective water-soluble antioxidant, on the HOCl- and chloramine-dependent modification of LDL. Co-incubation of vitamin C (25-200 &mgr;M) with LDL resulted in concentration-dependent protection against HOCl (25-200 &mgr;M)-mediated oxidation of tryptophan and lysine residues, formation of chloramines and increases in the relative electrophoretic mobility of LDL. Vitamin C also partially protected against oxidation of cysteine residues by HOCl, and fully protected against oxidation of these residues by the low-molecular-mass chloramines, N(alpha)-acetyl-lysine chloramine and taurine chloramine, and to a lesser extent monochloramine (each at 25-200 &mgr;M). Further, we found that HOCl (25-200 &mgr;M)-dependent formation of chloramines on apolipoprotein B-100 was fully reversed by 200 &mgr;M vitamin C; however, the loss of lysine residues and increase in relative electrophoretic mobility of LDL were only partially reversed, and the loss of tryptophan and cysteine residues was not reversed. Time-course experiments showed that the reversal by vitamin C of HOCl-dependent modifications became less efficient as the LDL was incubated for up to 4 h at 37 degrees C. These data show that vitamin C not only protects against, but also reverses, specific HOCl- and chloramine-dependent modifications of LDL. As HOCl-mediated LDL modifications have been strongly implicated in the pathogenesis of atherosclerosis, our data indicate that vitamin C could contribute to the anti-atherogenic defence against HOCl.

10. Vitamin C prevents the acute atherogenic effects of passive smoking.

Free Radic Biol Med 2000 Feb 1;28(3):428-36
Valkonen MM, Kuusi T
Department of Medicine, University of Helsinki, Helsinki, Finland.

During passive smoking the body is attacked by an excess of free radicals inducing oxidative stress. In nonsmoking subjects even a short period of passive smoking breaks down serum antioxidant defense (TRAP) and accelerates lipid peroxidation leading to accumulation of their low-density lipoprotein (LDL) cholesterol in cultured human macrophages. We now studied whether these acute proatherogenic effects of secondhand smoke could be prevented by an effective free radical scavenger, vitamin C. Blood samples were collected from nonsmoking subjects (n = 10) as they were consecutively exposed to normal air or cigarette smoke during four separate days. During the last 2 d, a single dose of vitamin C (3 g) was given, which doubled its plasma concentration. Vitamin C did not influence the plasma antioxidant defense or the resistance of LDL to oxidation in normal air, but prevented the smoke-induced decrease in plasma TRAP (p <.001), the decrease in the resistance of LDL to oxidation (p <.05), and the accelerated formation of serum thiobarbituric acid reactive substances (TBARS) (p <.05) otherwise observed 1.5 h after the beginning of passive smoking. Vitamin C protected nonsmoking subjects against the harmful effects of free radicals during exposure to secondhand smoke.