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Elevated plasma levels of HDL cholesterol or apolipoprotein A-I, the major protein moiety of HDL particles, are protective against coronary artery disease. HDL particles remove cholesterol from peripheral cells and transfer it to the liver for bile acid synthesis. The interaction between lipoproteins is not mediated through simple contact between 2 phospholipid membranes but involves specific protein-receptor interactions, charged phospholipid-phospholipid contact, and activation of cellular signaling pathways. These lead to regulation of genes or the modification of proteins involved in vasomotor function, platelet activation, thrombosis and thrombolysis, cell adhesion, apoptosis and cell proliferation, and cellular cholesterol homeostasis.
We tested whether trans fatty acids and saturated fatty acids had different effects on flow-mediated vasodilation (FMD), a risk marker of coronary heart disease (CHD). Consumption of trans fatty acids is related to increased risk of CHD, probably through effects on lipoproteins. Trans fatty acids differ from most saturated fatty acids because they decrease serum high-density lipoprotein (HDL) cholesterol, and this may increase the risk of CHD. We fed 29 volunteers 2 controlled diets in a 2x4-week randomized crossover design. The "Trans-diet" contained 9.2 energy percent of trans fatty acids; these were replaced by saturated fatty acids in the "Sat-diet." Mean serum HDL cholesterol after the Trans-diet was 0.39 mmol/L (14.8 mg/dL), or 21% lower than after the Sat-diet (95% CI 0.28 to 0.50 mmol/L). Serum low density lipoprotein and triglyceride concentrations were stable. FMD+SD was 4.4+/-2.3% after the Trans-diet and 6.2+/-3.0% after the Sat-diet (difference -1.8%, 95% CI -3.2 to -0.4). Replacement of dietary saturated fatty acids by trans fatty acids impaired FMD of the brachial artery, which suggests increased risk of CHD. Further studies are needed to test whether the decrease in serum HDL cholesterol caused the impairment of FMD.
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Excess vascular oxidative stress and the local formation of oxidized LDL (ox-LDL) have been implicated in the development of impaired endothelium-dependent arterial relaxation in hypercholesterolemia and atherosclerosis. Dietary antioxidants limit LDL oxidation in vitro and treatment of cholesterol-fed rabbits with dietary antioxidants preserves endothelium-derived relaxing factor (EDRF) action. To investigate the mechanism(s) responsible for these observations, we examined EDRF action, vascular oxidative stress, and antioxidant protection in male New Zealand White rabbits using four dietary treatments. Animals consumed standard chow (chow group) or chow supplemented with: (a) 0.5% cholesterol (0.5% cholesterol group); (b) 1% cholesterol (1% cholesterol group); or (c) 1% cholesterol and 1% probucol (probucol group). After 28 d of dietary treatment, segments of thoracic aorta from the 0.5 and 1% cholesterol groups demonstrated impairment of acetylcholine-mediated endothelium-dependent arterial relaxation compared to chow-fed animals (57 +/- 11% and 45 +/- 9% vs 78 +/- 3%, respectively; P < 0.05). In contrast, vessels from the probucol group demonstrated normal relaxation to acetylcholine (83 +/- 5%). Plasma cholesterol levels and the extent of atherosclerosis were similar among all cholesterol-fed groups. Probucol treatment was associated a threefold increase in LDL resistance to copper-induced oxidative modification (P < 0.05) and a reduction in tissue lipid peroxidation (as assessed by thiobarbituric acid-reactive substances; P < 0.05) compared to animals fed cholesterol alone. Most importantly, both of these changes were strongly correlated with preserved EDRF action. Moreover, cholesterol feeding was associated with a dose-dependent increase in vascular superoxide generation and lysophosphatidylcholine content, both of which were prevented by probucol treatment. From these findings, we conclude that probucol, a lipid-soluble antioxidant, preserves EDRF action in cholesterol-fed rabbits in association with limiting vascular oxidative stress and superoxide generation.
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BACKGROUND: Impaired flow mediated dilatation (FMD) and increased wall thickness (WT) of the brachial artery have been associated with atherosclerosis and its risk factors. In this study we sought to determine brachial artery wall thickness in chronic smokers and the instantaneous effect of smoking on brachial artery endothelium dependent vasodilator function in smokers and non-smokers. METHOD AND RESULTS: Using a high-resolution ultrasound, WT of posterior brachial artery wall, the diameter of brachial artery at rest and during reactive hyperemia (FMD %), as well as after sublingual administration of nitroglycerine (nitroglycerine mediated dilatation (NMD) %) was measured in 20 smokers and 20 non-smokers. Wall thickness (WT) of the posterior brachial artery wall and the wall index (WI) were greater in smokers than non-smokers. The baseline brachial artery diameter was comparable in smokers and non-smokers. Flow mediated dilation (FMD) was found to be less in smokers than non-smokers. The NMD in smokers also did not differ significantly from that in non-smokers. Flow mediated dilation significantly reduced after smoking compared to baseline in both groups. However, NMD remained unchanged after smoking in both groups. CONCLUSIONS: Increased WT and impaired endothelium-dependent dilatation of brachial artery suggests that cigarette smoking disrupts vessel wall morphology long before atherosclerosis is manifest.
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In the endothelium-denuded arteries cultured in the presence of FBS, morphological (i.e. smooth muscle disorientation and increase in collagen fiber) and phenotypic changes in smooth muscle were observed. Correlated with these changes, contractile force induced by high concentration of KCl and norepinephrine was significantly decreased. In addition, Ca-induced contraction in the permeabilized muscle was also significantly reduced. The reduced contractility in the FBS-treated arteries was partially recovered by the treatment with L-NMMA. In the endothelium-intact arteries cultured in the presence of FBS or PDGF, substance P and ionomycin-mediated, endothelium-dependent relaxation (EDR) was significantly decreased compared to the arteries cultured in serum-free condition. In addition, amounts of NO production and total recoverable eNOS mRNA was reduced in the FBS and PDGF-treated arteries. In these arteries, however, cGMP-dependent relaxation in smooth muscle was not impaired. These results suggest that long-term treatment of vascular tissue with growth-activating agents causes morphological or phenotypic changes nad up-regulation of NO production in smooth muscle, resulting in a reduced contractility. Furthermore, longterm treatment with these agents impairs NO-mediated EDR by decreasing eNOS mRNA and NO production.
Although plasma NOx (NO(2)(-) and NO(3)(-)) has been used as an index of nitric oxide (NO) formation in vivo, many unreasonable results appeared even after active elimination of NOx contamination from laboratory ware. For example, plasma NOx concentrations did not increase during vasodilation mediated by the NO/cGMP pathway or after organ perfusion. A possible shift of NOx from plasma to erythrocytes (RBCs) as a cause of these phenomena has been excluded, leaving the destination of NOx (after leaving plasma) unknown. Kinetic analyses have revealed that steady state NOx concentrations in plasma and whole blood did not correlate with the NOx formation rate, but rather with the NOx elimination rate. Therefore, the supposition that the NO status is directly reflected by plasma NOx concentrations appears untenable. As nitrosothiols (R-SNOs), possible carriers of NO bioactivity, have been flagged as alternative indices of NO status in vivo, efforts have been made to detect these substances. When interference by ultrafiltration was eliminated, low molecular weight R-SNOs such as nitrosocystein and nitrosogluthathione were undetectable. However, a high-molecular weight R-SNO, nitrosoalbumin, was detected in human blood. Further research is required into the significance and practical use of nitrosoalbumin as a marker of NO in vivo.
In hypertension, endothelium-dependent relaxation is attenuated and this attenuation contributes to the increased peripheral resistance. However, the role of endothelium-derived hyperpolarizing factor (EDHF) in the arteries of hypertensive rats remains unclear. Therefore, the aim of this study was to evaluate the role of EDHF in the femoral resistance arteries of hypertensive rats. The femoral resistance arteries were isolated from 5-, 15- and 25-week-old spontaneously hypertensive rats (SHR) and age-matched Wistar Kyoto rats (WKY). Changes in internal diameter were examined with videomicroscopy. EDHF-mediated dilatation was determined by differences between the degree of acetylcholine (ACh)-induced dilatation in the presence of NG-monomethy-L-arginine (L-NMMA) plus a prostaglandin I2 inhibitor (indomethacin) and the degree of such dilatation in the presence of L-NMMA, indomethacin and KCl. Charybdotoxin (CTx) and apamin (a Ca2+-activated K+ channel [KCa] inhibitor)-sensitive EDHF dilatation was also compared between in 5-, 15- and 25-week-old SHR and WKY. ACh-induced vasodilatation was not different between 5-week-old SHR and WKY. There was no difference between NO- and EDHF-mediated vasodilatation in 5-week-old rats. ACh-induced vasodilatation was weaker in 15-week-old SHR than in WKY. NO-mediated vasodilatation did not differ between the two groups. EDHF-mediated dilatation was attenuated in SHR but not in WKY. ACh-induced dilatation was weaker in 25-week-old SHR than in WKY. NO- and EDHF-mediated vasodilatation were attenuated in SHR but not WKY. EDHF-mediated vasodilatation was attenuated before the loss of NO-mediated vasodilatation in the femoral resistance arteries of SHR. The attenuation of this vasodilatation was mediated by the CTx plus apamin-sensitive EDHF.