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PubMed1999

Cardiovascular morbidity and endothelial dysfunction in chronic haemodialysis patients: is homocyst(e)ine the missing link?

BACKGROUND: Haemodialysis patients exhibit an excessive burden of atherothrombotic disease, which is not explained adequately by traditional risk factors. Hyperhomocyst(e)inaemia, a consistent finding in uraemic patients, is now widely recognized as an independent risk factor for vascular disease. The aim of this study was to examine the hypothesis that hyperhomocyst(e)inaemia is associated with cardiovascular complications in dialysed patients. METHODS: In a cohort of 63 stable chronic haemodialysis patients, we examined the causal relationship between hyperhomocyst(e)inaemia and vascular endothelial and haemostatic function. All their markers were determined before and after an 8-week course of a 10 mg per day oral folate supplementation, a manoeuvre known to decrease hyperhomocyst(e)inaemia in uraemic patients. RESULTS: History of at least one cardiovascular atherothrombotic event was present in 47.6% of the haemodialysed patients, and radiographic evidence of vascular calcifications in 70%. Hyperhomocyst(e)inaemia was found in all patients, averaging 3.5-fold the upper limit of normal values (P<0.001), despite the lack of clinical and biological evidence of malnutrition. Fibrinogen, von Willebrand factor and plasminogen activator inhibitor type 1, but not endothelin 1, were significantly higher in haemodialysis patients than in controls. After adjustment for all variables, past history of cardiovascular events was independently associated with higher levels of homocyst(e)inaemia only (odds ratio (OR) 1.06; 95% confidence interval (CI) 1.01-1.12; P<0.026). The presence of aortic calcifications was independently and significantly associated with age (OR 1.37; 95% CI 1.07-1.75; P<0.025), homocyst(e)inaemia (OR 1.14; 95% CI 1.02-1.27; P<0.05) and fibrinogen concentration only (OR 9.74; 95% CI 1.25-75.2; P<0.05). None of the endothelial haemostatic factors was, however, related to homocyst(e)ine levels. Mid-term folate supplementation decreased plasma homocyst(e)ine levels significantly without achieving normal values. No significant change of endothelial-haemostatic markers was observed, however, despite the drop in plasma homocyst(e)ine. CONCLUSIONS: Hyperhomocyst(e)inaemia is associated with increased cardiovascular risk in haemodialysis patients. Folate supplementation was partially effective in lowering hyperhomocyst(e)inaemia, but its usefulness in terms of reduction in cardiovascular morbidity and mortality remains to be determined in prospective trials.

Aged↗

PubMed1992

Myocardial and endothelial dysfunction after multiple, brief coronary occlusions: role of oxygen radicals.

The major objective of the present study was to determine the effect of multiple, brief periods of coronary artery occlusion and reperfusion on postischemic contractile function (sonomicrometry) and endothelium-dependent vasodilator responses in isolated conduit coronary artery rings obtained from anesthetized dogs. The role of oxygen-derived free radicals was also investigated. Dogs were subjected to four 5-min episodes of left anterior descending coronary occlusion interspersed with 5 min of reperfusion followed by a final 60-min reperfusion period. The multiple occlusion-reperfusion protocol resulted in regional segment dysfunction (37 +/- 15% of preocclusion values at 60 min of reperfusion) and attenuated endothelium-dependent responses to acetylcholine, bradykinin, and the calcium ionophore, A23187. Responses to the endothelium-independent vasodilator, sodium nitroprusside, were unaffected. Infusion of superoxide dismutase (5,000 U/kg) and catalase (55,000 U/kg) markedly improved the recovery of myocardial function at 30 and 60 min of reperfusion and completely protected against vascular endothelial damage. These results suggest an important role for oxygen-derived free radicals in the myocardial and endothelial injury that occurs in this model of multiple stunned myocardium.

Animals↗

PubMed2006

Effects of Astragalus membranaceus and its main components on the acute phase endothelial dysfunction induced by homocysteine.

OBJECTIVE: This study was designed to investigate the effects of Astragalus membranaceus (AM) and its main components, astragalus saponin (ASP), astragalus polysaccharide (APS) and aminobutyric acid (GABA), on homocysteine (Hcy) induced acute impairment of vascular tone and to explore whether the antioxidant mechanism was involved in AM protective effect. METHODS: Inhibitory effects of Hcy and protective effects of AM and its main components on endothelium-dependent relaxation of aortic rings were determined by isometric tension recordings and nitric oxide signaling was assayed with 125I-cGMP RIA Kit. Furthermore, generation of reactive oxygen species (ROS) in endothelial cells was detected using 5-(6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate (CM-H2DCF-DA). RESULTS: Hcy significantly inhibited endothelium-dependent relaxation to acetylcholine (ACh) in a dose-dependent manner, and decreased cGMP levels increased by ACh in aorta. Furthermore, superoxide dismutase (SOD), AM, and ASP markedly attenuated inhibition of vasorelaxation and downregulation of cGMP level by Hcy, and APS exerted a tendency to reverse both of the depressive responses, while GABA had no similar effects. Additionally, partially impaired relaxation by Hcy was completely blocked due to the presence of N(omega)-nitro-L-arginine-methyl ester (L-NAME), which could not be further altered by treatment with AM, ASP, APS or GABA. Finally, Hcy significantly increased intracellular ROS levels in endothelial cells as measured by CM-H2DCF-DA fluorescence. SOD, AM, ASP, and APS, but not GABA, inhibited Hcy-stimulated ROS generation. CONCLUSION: This study demonstrated that AM and ASP, potently protected endothelium-dependent relaxation against the acute injury from Hcy through nitric oxide regulatory pathways, in which antioxidation played a key role.

Acetylcholine↗

PubMed2000

Hemodynamic stresses induce endothelial dysfunction and remodeling of pulmonary artery in experimental compensated heart failure.

BACKGROUND: We hypothesized that, in compensated heart failure (HF), hemodynamic perturbations and their consequences exist in pulmonary artery (PA) despite the absence of any perturbation in thoracic aorta (TA). METHODS AND RESULTS: The left coronary artery was ligated in 20 male Wistar rats with compensated HF. Four months after ligation, these rats were compared with 20 sham-operated control rats. Blood pressure, velocity, viscosity, luminal diameter, and wall tensile and shear stresses were determined in PA and TA. Arterial rings were mounted in a myograph for ex vivo study. Endothelial nitric oxide synthase (eNOS) mRNA expression was determined in lung and aorta. Sections of PA and TA were used for histomorphometric study. In PA from rats with compensated HF, (1) blood pressure and wall tensile stress increased, whereas blood velocity and wall shear stress decreased; (2) contractions to KCl were not altered, but maximal contraction to phenylephrine and EC(50) decreased; (3) endothelium-dependent relaxation to acetylcholine and basal NO activity were blunted, whereas endothelium-independent relaxation was preserved; (4) eNOS mRNA levels and eNOS transcription in lung nuclei decreased; and (5) medial cross-sectional area, thickness, smooth muscle cell number, elastin, and collagen contents increased. Conversely, no such changes were found in TA from rats with compensated HF. CONCLUSIONS: In compensated HF induced by small myocardial infarction, hemodynamics, vascular wall function, and structure are altered in PA but preserved in TA. These results indicate that the pulmonary vascular bed is an early target of regional circulatory alterations in HF.

Animals↗

PubMed2004

Protective effects of Danshensu from the aqueous extract of Salvia miltiorrhiza (Danshen) against homocysteine-induced endothelial dysfunction.

Homocysteine (Hcy) is a by-product of methionine metabolism. An imbalance of Hcy in the body may lead to hyperhomocysteinemia, a condition with elevated Hcy concentration in blood that may be one of the risk factors responsible for the development of several vascular diseases (thromboembolism, atherosclerosis, stroke, vascular diseases and dementia). Radix Salvia miltiorrhiza (Danshen), a well-known Chinese medicinal herb that can activate and improve blood microcirculation, is noticeable for its beneficial effect in treating cardiovascular diseases. The present study is to demonstrate the protective effect of Danshen extract against the homocysteine-induced adverse effect on human umbilical vein endothelial cell (HUVEC). Homocysteine (5 mM) not only decreased the cell viability but also caused the disruption of capillary-like structure formation in vitro. The protective effect of Danshen aqueous extract and its active compounds on endothelial cell function were demonstrated through an in vitro tube formation assay, which mimics the new blood vessel formation. To identify the active components in the aqueous extract of Danshen, the content was characterized by instrumental analysis using high performance liquid chromatography with diode array detector (DAD) and electrospray tandem mass spectrometry (ESI-MS/MS). Interestingly, Danshen extract and its pure compounds showed different effectiveness in protecting HUVEC against Hcy-induced injury according to the following descending order: Danshen aqueous extract, 3-(3,4-dihydroxy-phenyl)-2-hydroxy-propionic acid (Danshensu), protocatechuic acid, catechin and protocatechualdehyde. We believed that such findings might provide evidence in understanding the beneficial effects of Danshen on the cardiovascular system.

Benzaldehydes↗

PubMed2007

Increased arginase activity and endothelial dysfunction in human inflammatory bowel disease.

Nitric oxide (.NO) generation from conversion of l-arginine to citrulline by nitric oxide synthase isoforms plays a critical role in vascular homeostasis. Loss of .NO is linked to vascular pathophysiology and is decreased in chronically inflamed gut blood vessels in inflammatory bowel disease (IBD; Crohn's disease and ulcerative colitis). Mechanisms underlying decreased .NO production in IBD gut microvessels are not fully characterized. Loss of .NO generation may result from increased arginase (AR) activity, which enzymatically competes with nitric oxide synthase for the common substrate l-arginine. We characterized AR expression in IBD microvessels and endothelial cells and its contribution to decreased .NO production. AR expression was assessed in resected gut tissues and human intestinal microvascular endothelial cells (HIMEC). AR expression significantly increased in both ulcerative colitis and Crohn's disease microvessels and submucosal tissues compared with normal. TNF-alpha/lipopolysaccharide increased AR activity, mRNA and protein expression in HIMEC in a time-dependent fashion. RhoA/ROCK pathway, a negative regulator of .NO generation in endothelial cells, was examined. The RhoA inhibitor C3 exoenzyme and the ROCK inhibitor Y-27632 both attenuated TNF-alpha/lipopolysaccharide-induced MAPK activation and blocked AR expression in HIMEC. A significantly higher AR activity and increased RhoA activity were observed in IBD submucosal tissues surrounding microvessels compared with normal control gut tissue. Functionally, inhibition of AR activity decreased leukocyte binding to HIMEC in an adhesion assay. Loss of .NO production in IBD microvessels is linked to enhanced levels of AR in intestinal endothelial cells exposed to chronic inflammation in vivo.

ADP Ribose Transferases↗

PubMed1998

Role of angiotensin-converting enzyme inhibition in reversal of endothelial dysfunction in coronary artery disease.

Angiotensin-converting enzyme (ACE) inhibitors have shown unexpected benefits in the prevention of ischemic events in patients with hypertension and congestive heart failure. In addition to these clinical observations, there is a growing body of knowledge about the molecular and cellular effects of ACE inhibitors. For example, ACE inhibition prevents stimulation of smooth muscle cell angiotensin II receptors, thereby blocking both contractile and proliferative actions. Angiotensin II blockade also diminishes the production of superoxide anion, which inactivates ambient nitric oxide. ACE inhibition of kininase II inhibits the breakdown of bradykinin, a direct stimulant of nitric oxide release from the intact endothelial cell. Thus, at the cellular level within the vasculature, ACE inhibition shifts the balance of ongoing mechanisms in favor of those promoting vasodilatory, antiaggregatory, antithrombotic, and antiproliferative effects. These effects underlie the potential benefits of ACE inhibition in the therapy of ischemia and atherosclerosis. Some data is available in humans to show that these effects can be sustained for months, thereby maintaining improved endothelial function and, presumably, allowing the initiation of steps that might alter the progression of atherosclerosis. Definitive information is not yet available in humans to show that ACE inhibition clearly alters the progression of atherosclerosis or diminishes coronary events in uncomplicated coronary disease. This promising area of investigation is, however, the subject of multiple clinical trials, which should provide clarification of this important question in coming years.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1997

Endothelial dysfunction exacerbates the impairment of relaxation by lysophosphatidylcholine in porcine coronary artery.

1. Current evidence suggests that lysophosphatidylcholine (LPC), a component found in oxidized low-density lipoprotein (Ox-LDL), inhibits endothelium-dependent relaxation (EDR) mediated by endothelium-derived relaxing factor (EDRF) and endothelium-derived hyperpolarizing factor (EDHF). An objective of the present study was to characterize the roles of the different elements of EDR in LPC-induced impairment within the porcine coronary artery. Concomitantly, we sought to determine whether impairment of one component of EDR would increase the sensitivity of the endothelium to LPC. 2. Bradykinin (0.1 nmol/L -0.3 mumol/L) relaxed U46,619 (30 nmol/L)-precontracted porcine coronary artery rings in a concentration-dependent manner. A reduction in the bradykinin-elicited response was observed in NG-nitro-L-arginine methyl ester (L-NAME; 300 mumol/L)- and ouabain (50 mumol/L)-treated rings. Pretreatment with LPC (20 mumol/L), which on its own had no effect on normal endothelial relaxation, resulted in further inhibition of EDRF- and EDHF-induced relaxations. 3. Our results demonstrate that EDRF and EDHF are the primary mediators of EDR in the porcine coronary artery. Our data also show that while a low concentration of LPC (20 mumol/L) does not impair EDR, it can evoke vascular dysfunction following blockade of either the effects of EDRF or EDHF. Therefore, these data suggest that the partially damaged vascular endothelium could be more sensitive to threshold levels of this atherogenic phospholipid.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed2005

Vasculopathy in Turner syndrome: arterial dilatation and intimal thickening without endothelial dysfunction.

CONTEXT: Women with Turner syndrome (TS) have an increased cardiovascular mortality rate from both structural and ischemic heart disease, especially aortic dissection. OBJECTIVE: We hypothesized that TS women have a fundamental arterial wall defect that may be due to genetic factors or estrogen deficiency. DESIGN, SETTING, AND PATIENTS: TS women (n = 93) were compared with normal controls (n = 25) and women with 46,XX primary amenorrhea (PA) (n = 11) with a similar history of estrogen deficiency. Clinical parameters, aortic root diameter, extraaortic arterial structure [common carotid (CD), brachial artery diameter, and carotid intima-media thickness (IMT)], arterial stiffness (pulse-wave velocity, augmentation index), and endothelial function (flow-mediated dilatation) were assessed. MAIN OUTCOME MEASURES: These included arterial diameters and vascular physiology parameters. RESULTS: Differences in arterial structure were observed among TS, normal controls, and 46,XX PA women: IMT (0.61 +/- 0.07 vs. 0.55 +/- 0.06 vs. 0.60 +/- 0.05 mm, respectively; P < 0.001), CD (5.71 +/- 0.64 vs. 5.27 +/- 0.34 vs. 5.22 +/- 0.38 mm; P < 0.001), and brachial artery diameter (3.29 +/- 0.44 vs. 3.06 +/- 0.36 vs. 2.97 +/- 0.30 mm; P = 0.006). Aortic root diameter was greater in TS than normal control women. TS status, height, weight, and IMT were independently associated with increased CD after multivariate adjustment (P < 0.05). TS status, age, diastolic blood pressure, and CD remained independently associated with increased IMT after multivariate adjustment (P < 0.05). Pulse-wave velocity and flow-mediated dilatation were similar among the three groups. CONCLUSION: Women with TS have greater IMT and conduit artery diameters than normal controls. Similarly, increased IMT in TS and 46,XX PA women suggests that estrogen deficiency contributes to intimal thickening. Interventional studies are required to determine the extent to which blood pressure and estrogen deficiency may be appropriate therapeutic targets to reduce cardiovascular risk in TS.

Adult↗

PubMed2004

Endothelial dysfunction and hypercontractility of vascular myocytes are ameliorated by fluvastatin in obese Zucker rats.

To study the mechanisms of vascular dysfunction in diabetes mellitus, we examined the responses of the aorta to adrenomedullin (AM) and ANG II in obese Zucker (OZ), lean Zucker (LZ), and OZ rats administered fluvastatin (OZ + Flu). AM-induced endothelium-dependent vasorelaxation was impaired in OZ rats compared with LZ rats, and fluvastatin restored AM-induced, endothelium-dependent vasorelaxation (%Deltatension at 10(-7) mol/l AM; LZ, -85.1 +/- 3.1%; OZ, -50.7 +/- 2.5%; OZ + Flu, -75.6 +/- 2.7%). Expression of endothelial nitric oxide synthase (eNOS) and Akt phosphorylation in response to AM (10(-7) mol/l) were also diminished in OZ rats. Fluvastatin restored the eNOS expression and Akt phosphorylation [eNOS expression (relative intensity): LZ, 2.3 +/- 0.4; OZ, 1.0 +/- 0.2; OZ + Flu, 1.8 +/- 0.3; Akt phosphorylation (relative intensity): LZ, 2.3 +/- 0.2; OZ, 1.0 +/- 0.3; OZ + Flu, 1.9 +/- 0.2]. ANG II-induced vasoconstriction was enhanced in the aortic rings of OZ rats compared with LZ rats, and this enhanced vasoconstriction was partially normalized by fluvastatin and was abolished when the aorta of OZ rats was preincubated with the Rho kinase inhibitor Y-27632. GTPgammaS-induced contraction of permeabilized aortic smooth muscle cells, which is an indicator of the Rho-dependent Ca(2+) sensitization of contraction, was enhanced in OZ rats compared with LZ rats, and this enhanced contraction was suppressed in OZ + Flu rats. These results suggested that endothelium-dependent vasorelaxation was impaired, Ca(2+) sensitization of contraction was augmented in blood vessels of OZ rats and that fluvastatin restored vascular function by activating the Akt-dependent pathway and inhibiting the Rho-dependent pathway.

Adrenomedullin↗

PubMed2000

Hyperhomocysteinemia, vascular pathology, and endothelial dysfunction.

Hyperhomocysteinemia has been associated with premature atherothrombotic vascular disease. It is not known whether hyperhomocysteinemia induces a distinct type of vascular disease. Its interaction, if any, with traditional risk factors also remains unclear. The pathophysiological mechanisms linking hyperhomocysteinemia to vascular disease have been extensively studied in vitro and in animals. From these studies, it has been suggested that homocysteine limits the bioavailability of nitric oxide (NO), increases oxidative stress, stimulates smooth cell proliferation, and alters elastic wall properties. The relevance of these proposed mechanisms in vivo is unclear, because clinical studies have yielded controversial results with regard to the relation between plasma homocysteine levels and indices of endothelial function, such as brachial artery flow-mediated vasodilatation and plasma levels of endothelium-derived marker proteins. Up till now, there have been no controlled data on the effects of homocysteine-lowering treatment on vascular function or clinical end points. The precise mechanisms (if any) by which homocysteine mediates its adverse vascular effects are in fact unknown but may relate to impaired endothelial and smooth muscle cell function.

Adult↗

PubMed2003

Organic nitrate tolerance and endothelial dysfunction: role of folate therapy.

Tolerance to organic nitrates has been demonstrated in patients with acute coronary syndromes following continuous, long-term therapy, and has been shown to occur within 24 to 48 h after administration of a nitrate preparation. Dosing schedules that include a nitrate-free period often fail to ameliorate the development of nitrate tolerance, and, in fact, can result in an increase in rebound ischemia. Several mechanisms have been suggested to explain the phenomenon of nitrate tolerance, notably, nitrate-mediated depletion of intracellular thiols, and enhanced reactive oxygen species formation. Recently, increased superoxide production, owing to the un-coupling of the endothelial isoform of nitric oxide synthase (eNOS) and/or increased NAD(P)H oxidase activity, has been implicated in the development of nitrate tolerance. Based on these observations, strategies to overcome tachyphylaxis to nitrates have been designed to modulate the production of reactive oxygen species. Folic acid and its derivatives have been shown to prevent nitrate tolerance by preventing eNOS uncoupling, and, thereby, eNOS-mediated superoxide production resulting in improved endothelial function. Folic acid, which has a benign side-effect profile, may, therefore, be a simple pharmacological intervention to prevent nitrate tolerance and may have broad application in the treatment of atherothrombotic vascular disease.

Animals↗

PubMed2006

Temporary coronary artery occlusion during off-pump coronary artery bypass grafting with the new poloxamer P407 does not cause endothelial dysfunction in epicardial coronary arteries.

OBJECTIVE: The aim of this study was to assess the efficacy of the novel reversible thermosensitive gel poloxamer 407 for occlusion of the coronary vessel necessary for minimally invasive operations and its effects on coronary endothelium. METHODS: Domestic swine were submitted to occlusion of the left anterior descending or right coronary artery using the poloxamer. The left and right internal thoracic arteries were used as grafts to perform coronary artery bypasses. Animals were humanely killed after 3 hours of perfusion (acute; n = 8) or 3 days (subacute; n = 6). The vascular reactivity of coronary artery was evaluated in response to serotonin and bradykinin. Histologic studies were performed to analyze cardiomyocyte necrosis and endothelial coverage. RESULTS: The gel led to an occlusion of 7.8 +/- 2.2 minutes. Concentration-response curves of occluded coronary segments showed no difference of endothelium-dependent relaxations in both operated groups (P < .05 vs control). Histologic studies demonstrated the absence of cardiomyocyte necrosis after coronary artery occlusion in the acute group; a small infarct zone was detected in 1 animal in the subacute group, resulting from an occlusion of the first diagonal branch. The endothelial layer coverage was preserved in both groups. CONCLUSION: The poloxamer 407 represents a promising technique for obtaining hemostasis at the site of anastomosis during construction of bypasses during beating heart coronary artery surgery, without damage to the endothelium or ischemic consequence.

Anastomosis, Surgical↗

PubMed1992

Protective effects of benidipine hydrochloride (KW-3049), a calcium antagonist, against experimental arterial calcinosis and endothelial dysfunction in rats.

Protective effects of benidipine hydrochloride (KW-3049) against arterial calcinosis and its possible mechanisms of action have been investigated. Arterial calcinosis was induced in rats by combined administration of vitamin D2 (1050000 IU/kg, s.c.) and nicotine (12.5 mg/kg, p.o., b.i.d.) for 6 successive days. Calcium antagonists, benidipine or nifedipine, were given orally twice a day during the same period. The aortic calcium content in vitamin D2 and nicotine-treated (control) rats increased to about 25 times that in normal rats, accompanying an increase of serum calcium level. Benidipine (10 mg/kg, p.o., b.i.d.) reduced the aortic calcium content to about 18% of control rats without reducing the serum calcium level. Although the presence of aortic endothelial cells was observed under light microscopy in control rats, their surfaces were degenerated under scanning electron microscopy. Benidipine exerted a protective effect against these degenerative changes. Acetylcholine-induced endothelial dependent relaxation was attenuated in control rats, compared with that in normal rats. Benidipine significantly improved this attenuation of the relaxation. These results suggest that the anticalcinotic effect of benidipine is accompanied by its protective effect on endothelial cells.

Acetylcholine↗

PubMed2003

A novel role for calpains in the endothelial dysfunction of hyperglycemia.

Recent studies have reported that the activity of the calcium-dependent protease calpain is increased in acute inflammatory processes of the cardiovascular system. Because diabetes is associated with vascular inflammation, we hypothesized that increased calpain activity in response to hyperglycemia may play a role in diabetic cardiovascular disease. The effects of calpain inhibition on leukocyte-endothelium interactions induced by hyperglycemia were examined by intravital microscopy. Intraperitoneal administration of the selective calpain inhibitor benzyloxycarbonyl-leucyl-leucinal (5 micromol/L) prevented the up-regulation of leukocyte-endothelium interactions in response to 25 mmol/L D-glucose via a nitric oxide-dependent mechanism. Furthermore, treatment of rats with D-glucose significantly decreased basal endothelial NO release in mesenteric post-capillary venules, a phenomenon prevented by inhibition of calpain activity. Immunoprecipitation studies revealed that glucose induces loss of NO via a calpain-dependent decrease in the association of hsp90 with endothelial nitric oxide synthase. In addition, inhibition of calpain activity decreased endothelial cell surface expression of the pro-inflammatory adhesion molecules ICAM-1 and VCAM-1 during hyperglycemia. These data demonstrate that calpains contribute to important inflammatory events during hyperglycemia and that pharmacological inhibition of calpain activity attenuates leukocyte-endothelium interactions and preserves eNOS function.

Animals↗

PubMed2003

Effect of dietary antioxidants on postprandial endothelial dysfunction induced by a high-fat meal in healthy subjects.

BACKGROUND: Persons following current dietary guidelines have a lower risk of mortality from coronary heart disease. OBJECTIVE: The objective was to compare the short-term effect of a high-fat meal and a high-carbohydrate meal, with and without dietary antioxidants, on vasomotor, antiplatelet, and hemostatic functions of the endothelium in healthy subjects. DESIGN: In an observer-blinded, randomized crossover study, 25 (13 men and 12 women) healthy subjects were given each of 3 meals in random order at 1-wk intervals: a high-fat meal (760 kcal), an isoenergetic high-carbohydrate meal, and a high-fat meal with dietary antioxidants from vegetables (865 kcal). Endothelial functions, as assessed by hemodynamic and rheologic responses to L-arginine--the natural precursor of nitric oxide--were evaluated before and 4 h after each meal. RESULTS: Unlike the high-carbohydrate meal, the high-fat meal increased the plasma concentrations of triacylglycerol (P < 0.01); both meals activated hemostasis. The high-carbohydrate meal did not modify blood pressure, and platelet aggregation decreased in response to the L-arginine load (-7.1 +/- 2.3 mm Hg and -8.5 +/- 4.5%, respectively). After the high-fat meal, the decrease in blood pressure in response to L-arginine was reduced (-1 +/- 0.8 mm Hg), and platelet aggregation showed a paradoxical increase (4.1 +/- 2.1%; P < 0.01 compared with the high-carbohydrate meal). The high-fat meal with antioxidants partially restored the vascular response to L-arginine. CONCLUSION: Compared with a high-carbohydrate meal, a high-fat meal can modify endothelial functions toward a more atherogenetic profile, which is partially prevented by dietary antioxidants.

Adult↗

PubMed2005

Microparticles from apoptotic vascular smooth muscle cells induce endothelial dysfunction, a phenomenon prevented by beta3-integrin antagonists.

Fragile atherosclerotic plaques are rich in apoptotic smooth muscle cells (SMCs) and macrophages, generating microparticules (MPs) which accumulate locally and may be released in blood in case of mechanical or spontaneous plaque disruption. Besides being highly procoagulant, this material may interact with downstream endothelium. Using a model of mouse aorta vaso-reactivity, we have investigated the effects of apoptotic MPs prepared in vitro from Fas-ligand sensitive SMCs. Short-term preincubation of aorta rings with the MPs dose-dependently reduced the vasodilatory response to acetylcholine dependent on the endothelium. This effect was prevented by the addition of abxicimab or eptifibatide, indicating a role for a beta3 integrin in this process. We further investigated its mechanism using cultured endothelial cells. The MPs were found to bind to the cells and to inhibit the production and the release of nitric oxide (NO) in response to bradykinin. This phenomenom was redox sensitive, independent of the generation of activated coagulation proteases, and was abrogated when the MPs were pretreated by trypsin. The metabolic effects of MPs were prevented by the addition of eptifibatide. Taken together, these results suggest a potential, platelet-independent, mechanism for the improvement of microvascular perfusion observed with beta3-integrin antagonists.

Abciximab↗

PubMed2004

Tetrahydrobiopterin improves endothelial dysfunction and vascular oxidative stress in microvessels of intrauterine undernourished rats.

In the present study, we investigated the effects of the exogenous application of tetrahydrobiopterin on the endothelium-dependent vasorelaxation and superoxide anion generation in the mesenteric microvessels of intrauterine undernourished rats. In addition, we investigated the presence of peroxynitrite in these rats by evaluation of nitrotyrosine-containing proteins, a stable end-product of peroxynitrite oxidation. For this, female pregnant Wistar rats were fed either normal or 50% of the normal intake diets during the whole gestational period. Male offspring (16 weeks of age) were studied to assess microvascular reactivity, superoxide production using a hydroethidine staining assay, nitric oxide synthase (NOS) activity and nitric oxide (NO) production. Western blot analysis was used to quantify nitrotyrosine-containing proteins and relative multiplex RT-PCR analysis for endothelial NOS (eNOS) mRNA expression. Superfusion with tetrahydrobiopterin significantly decreased superoxide generation and improved vascular function. Intrauterine malnutrition induced a decrement of NOS activity and NO production without affecting the gene expression of eNOS. However, incubation with tetrahydrobiopterin significantly improved NO production after stimulation with acetylcholine or bradykinin in intrauterine undernourished rats. The fact that the nitrotyrosine-containing proteins were increased could, at first sight, suggest that the peroxynitrite is the mediator responsible for the excessive oxidation and depletion of tetrahydrobiopterin. Our study shows that exogenous application of tetrahydrobiopterin leads to a significant improvement of endothelium-dependent vasodilatation, enhanced NO production and decreased superoxide generation in microvessels of intrauterine undernourished rats. Since we found a decrease in NOS activity without an alteration in the gene expression of eNOS, we suggest that impaired NOS-dependent responses of mesenteric arterioles are related to the impairment of tetrahydrobiopterin pathways.

Animals↗