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PubMed2004

Molecular basis for arsenic-induced alteration in nitric oxide production and oxidative stress: implication of endothelial dysfunction.

Accumulated epidemiological studies have suggested that prolonged exposure of humans to arsenic in drinking water is associated with vascular diseases. The exact mechanism of how this occurs currently unknown. Nitric oxide (NO), formed by endothelial NO synthase (eNOS), plays a crucial role in the vascular system. Decreased availability of biologically active NO in the endothelium is implicated in the pathophysiology of several vascular diseases and inhibition of eNOS by arsenic is one of the proposed mechanism s for arsenic-induced vascular diseases. In addition, during exposure to arsenic, overproduction of reactive oxygen species (ROS) can occur, resulting in oxidative stress, which is another major risk factor for vascular dysfunction. The molecular basis for decreased NO levels and increased oxidative stress during arsenic exposure is poorly understood. In this article, evidence for arsenic-mediated alteration in NO production and oxidative stress is reviewed. The results of a cross-sectional study in an endemic area of chronic arsenic poisoning and experimental animal studies to elucidate a potential mechanism for the impairment of NO formation and oxidative stress caused by prolonged exposure to arsenate in the drinking water are also reviewed.

Animals↗

PubMed1998

Klotho protein protects against endothelial dysfunction.

Arteriosclerosis caused by aging is recognized to be a crucial risk factor of cardiovascular disease. We recently established klotho mouse which causes age-related disorders including arteriosclerosis. However, no information on endothelial function of klotho mouse or the physiological role of klotho protein as a circulating factor is available. In this report, we demonstrate that 50% effective dose of aortic relaxation in response to acetylcholine in heterozygous klotho mice is significantly greater (4 x 10(-5) M) than in wild-type mice (8 x 10(-6) M, n = 7, p < 0.05) and that the vasodilator response of arterioles to acetylcholine is significantly attenuated in heterozygous (20% effective dose; 2 x 10(-6) M) and homozygous klotho mice (>1 x 10(-5) M) as compared with wild-type mice (1 x 10(-7) M, n = 7, p < 0.05). Nitric oxide metabolites (NO-2 and NO-3) in urine are significantly lower in heterozygous klotho mice (142 +/- 16 nmol/day) than wild-type mice (241 +/- 28 nmol/day, n = 13, p < 0.05). Parabiosis between wild-type and heterozygous klotho mice results in restoration of endothelial function in heterozygous klotho mice. We conclude that the klotho protein protects the cardiovascular system through endothelium-derived NO production by humoral pathways.

Acetylcholine↗

PubMed2002

Insulin causes endothelial dysfunction in humans: sites and mechanisms.

BACKGROUND: Insulin resistance is often accompanied by hyperinsulinemia and may predispose to atherosclerosis. Endothelium plays a central role in atherogenesis. The in vivo effects of hyperinsulinemia on endothelial function of large conduit arteries are unknown. METHODS AND RESULTS: Twenty-five healthy subjects were enrolled for study. In study A (n=9), subjects underwent both a time-control saline study and a euglycemic low-dose insulin (insulin approximately 110 pmol/L) clamp for 6 hours. Study B (n=5) was identical to study A except that the euglycemic clamp was performed at high physiological insulin concentrations (approximately 440 pmol/L). In study C (n=7), subjects underwent two 4-hour euglycemic insulin (approximately 110 pmol/L) clamps with and without the concomitant infusion of an antioxidant (vitamin C). In study D (n=4), two saline time-control studies were performed with and without the concomitant infusion of vitamin C. In all studies, both at baseline and throughout the experimental period, endothelium-dependent (flow-mediated) and endothelium-independent (nitroglycerin-induced) vasodilation was assessed in femoral and brachial arteries by echo Doppler. Both low (study A) and high physiological (study B) hyperinsulinemia abolished endothelium-dependent vasodilation, whereas endothelium-independent vasodilation was unaffected. Vitamin C fully restored insulin-impaired endothelial function without affecting endothelium-independent vasodilation (study C). Vitamin C had no effects on endothelium-dependent or endothelium-independent vasodilation during saline control studies (study D). CONCLUSIONS: Modest hyperinsulinemia, mimicking fasting hyperinsulinemia of insulin-resistant states, abrogates endothelium-dependent vasodilation in large conduit arteries, probably by increasing oxidant stress. These data may provide a novel pathophysiological basis to the epidemiological link between hyperinsulinemia/insulin-resistance and atherosclerosis in humans.

Adult↗

PubMed2001

Vasopeptidase inhibition restores renovascular endothelial dysfunction in salt-induced hypertension.

Renovascular hemodynamics plays a pivotal role in the regulation of BP. The effect of the vasopeptidase inhibitor omapatrilat (O) and the ACE-inhibitor captopril (C) on endothelial function in the renal circulation in salt-induced hypertension were investigated. Dahl salt-sensitive rats (n = 6 per group) on standard or salt-enriched chow were treated for 8 wk with O (36 +/- 4 mg/kg per d), C (94 +/- 2 mg/kg per d), or placebo. Renal arteries were suspended in organ chambers for isometric tension recording. Vascular hypertrophy was assessed by determination of standardized heart weight and aortic weight, and morphologic analysis of glomerular injury was performed. Systolic BP of salt-fed, placebo-treated animals increased to 196 +/- 6 mmHg, which was reduced by O (162 +/- 5 mmHg; P < 0.05) and C (164 +/- 7 mmHg; P < 0.05) to a comparable degree. In salt-induced hypertension, endothelium-dependent relaxations in renal arteries (56 +/- 6 versus 100 +/- 6%; P < 0.05) as well as contractions to endothelin-1 (ET-1) (98 +/- 5% versus 128 +/- 5%; P < 0.05) and big ET-1 (47 +/- 6% versus 116 +/- 7%; P < 0.05) were markedly reduced as compared with control animals, whereas standardized aortic weight and heart weight (4.9 +/- 0.4 versus 3.2 +/- 0.3 g/kg; P < 0.05) increased. Treatment with O restored endothelium-dependent relaxations (88 +/- 6%; P < 0.05 versus C) and contractions to ET-1 (120 +/- 6%) and big ET-1 (98 +/- 9%). O prevented vascular hypertrophy (0.23 +/- 0.019 mg/mm(2) versus 0.31 +/- 0.018 mg/mm(2) in high-salt diet; P < 0.05), but, in contrast to C, it only had a modest effect on glomerular injury. In conclusion, O restored renovascular endothelial function and prevented vascular hypertrophy in salt-induced hypertension and therefore may advance as a beneficial approach in the therapy of various forms of hypertension.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed2002

Heat stress increases endothelium-dependent relaxations and prevents reperfusion-induced endothelial dysfunction.

1. Heat stress has been widely used to stimulate the expression of stress proteins and is associated with various cardiovascular changes, including anti-ischaemic effects. However, the effect of heat stress on endothelial function is less clear. 2. Heat stress was induced in anaesthetized rats by increasing body temperature to 42 degrees C for 15 min. Twenty-four hours later, segments of rat aorta and mesenteric and coronary arteries were mounted in organ chambers. 3. Heat stress markedly increased relaxation to acetylcholine (ACh) in all three blood vessels studied, without affecting the response to the nitric oxide (NO) donor sydnonimine-1. 4. Heat stress also increased aortic relaxation to histamine and the calcium ionophore A23187. 5. In the aorta, an inhibitor of NO synthesis abolished the response to ACh in both control and heat stressed-rings, whereas a cyclo-oxygenase inhibitor had no effect. 6. Heat stress also prevented completely the impaired response to ACh in coronary arteries isolated from rats subjected to myocardial ischaemia and reperfusion. 7. Thus, heat stress increases the stimulated release of NO the rat aorta and mesenteric and coronary arteries and prevents reperfusion-induced injury at the level of the coronary endothelium.

Animals↗

PubMed2001

Na(+)/H(+) exchange inhibition prevents endothelial dysfunction after I/R injury.

Whereas inhibition of the Na(+)/H(+) exchanger (NHE) has been demonstrated to reduce myocardial infarct size in response to ischemia-reperfusion injury, the ability of NHE inhibition to preserve endothelial cell function has not been examined. This study examined whether NHE inhibition could preserve endothelial cell function after 90 min of regional ischemia and 180 min of reperfusion and compared this inhibition with ischemic preconditioning (IPC). In a canine model either IPC, produced by one 5-min coronary artery occlusion (1 x 5'), or the specific NHE-1 inhibitor eniporide (EMD-96785, 3.0 mg/kg) was administered 15 min before a 90-min coronary artery occlusion followed by 3 h of reperfusion. Infarct size (IS) was determined by 2,3,5-triphenyl tetrazolium chloride staining and expressed as a percentage of the area-at-risk (IS/AAR). Endothelial cell function was assessed by measurement of coronary blood flow in response to intracoronary acetylcholine infusion at the end of reperfusion. Whereas neither control nor IPC-treated animals exhibited a significant reduction in IS/AAR or preservation of endothelial cell function, animals treated with the NHE inhibitor eniporide showed a marked reduction in IS/AAR and a significantly preserved endothelial cell function (P < 0.05). Thus NHE-1 inhibition is more efficacious than IPC at reducing IS/AAR and at preserving endothelial cell function in dogs.

Acetylcholine↗

PubMed2001

Heterogenous nature of flow-mediated dilatation in human conduit arteries in vivo: relevance to endothelial dysfunction in hypercholesterolemia.

Flow-mediated dilatation (FMD) of conduit arteries is dependent on an intact endothelium, although the mechanisms are not fully understood. Using high-resolution ultrasound, we examined the role of endothelial mediators in radial artery dilatation in response to transient (short period of reactive hyperemia) and sustained (prolonged period of reactive hyperemia, hand warming, or an incremental infusion of acetylcholine into the distal radial artery) hyperemia. After short episodes of reactive hyperemia, FMD was abolished by local infusion of the nitric oxide synthesis inhibitor N:(G)monomethyl-L-arginine (5.3+/-1.2% versus 0.7+/-0.7%, P:<0.001). In contrast, basal vessel diameter and dilatation after prolonged episodes of reactive hyperemia, hand warming, and distal infusion of acetylcholine were not attenuated by nitric oxide synthesis inhibition. Inhibition of cyclooxygenase or local autonomic nervous system blockade also had no effect on FMD. Patients with hypercholesterolemia exhibited reduced FMD in response to transient hyperemia, but the response to sustained hyperemia was normal. These data suggest heterogeneity of endothelial responses to blood flow that are dependent on the characteristics of the flow stimulus. Dilatation after brief episodes of hyperemia is mediated by release of nitric oxide, whereas dilatation during sustained hyperemia is unaffected by NO synthesis inhibition. Hypercholesterolemia seems to differentially affect these pathways with impairment of the nitric oxide-dependent pathway and preservation of non nitric oxide-mediated dilatation to sustained flow stimuli.

Acetylcholine↗

PubMed1993

[Clinical significance of endothelial dysfunction: studies of human coronary circulation in vivo].

One of the most fascinating findings concerning our knowledge on the physiology of the cardiovascular system, especially the coronary circulation, concerns the modulating capacity of the endothelial cells on the tone of smooth muscle cells. This phenomenon was described for the first time in the aorta of a rabbit in 1980 by Furchgott and Zawadzki using acetylcholine as stimulator. Later, however, it became clear that other substances that are likewise of interest in the context of coronary heart disease, like thrombin, serotonin and histamine, have the same effect on endothelial cells. These effects can also be demonstrated in the human coronary circulation during cardiac catheterization. While normal coronary segments show a vasodilatation (corresponding to the endothelial relaxation in vitro) in arteriosclerotic coronary segments, vasoconstriction is induced by acetylcholine and serotonin. A disturbance of this vasomotor process mediated by endothelial vasomotor processes may be of particular importance in instable angina pectoris and for the development of myocardial infarction.

Blood Platelets↗

PubMed2001

Attenuation of vascular endothelial dysfunction by testosterone receptor blockade after trauma and hemorrhagic shock.

HYPOTHESIS: The salutary effects of the testosterone receptor antagonist flutamide on the depressed immune and cardiovascular functions after hemorrhage and resuscitation are related to improved endothelial cell function, which can subsequently lead to an increase in organ blood flow, oxygen delivery, and tissue oxygen consumption. DESIGN, INTERVENTIONS, AND MAIN OUTCOME MEASURES: Male adult rats underwent a 5-cm midline laparotomy (ie, trauma) and were bled to and maintained at a mean systemic arterial pressure of 40 mm Hg until 40% maximal blood-out volume was returned in the form of Ringer lactate). The animals were then resuscitated with 4 times the total volume of shed blood with Ringer lactate for 60 minutes. Flutamide (25 mg/kg) or an equivalent volume of the vehicle propanediol was injected subcutaneously 15 minutes before the end of resuscitation. At 20 hours after resuscitation, aortic rings (approximately 2.5 mm in length) were isolated and mounted in an organ chamber. Dose responses for an endothelium-dependent vasodilator (acetylcholine chloride) and endothelium-independent vasodilator (nitroglycerine) were determined. Organ blood flow was measured using strontium 85-labeled microspheres. Total hemoglobin and oxygen content in the femoral artery and portal, hepatic, and renal veins were determined. Oxygen delivery and consumption in liver, small intestine, and kidneys were calculated. RESULTS: Administration of flutamide after trauma-hemorrhage attenuated the depressed endothelial function. Furthermore, flutamide treatment restored the reduced blood flow and oxygen delivery and consumption in all organs tested after trauma-hemorrhage and resuscitation. CONCLUSION: Flutamide appears to be a useful adjunct for improving vascular endothelial function and regional hemodynamics after trauma-hemorrhage and resuscitation.

Acetylcholine↗

PubMed2005

Amelioration of vascular endothelial dysfunction in obstructive sleep apnea syndrome by nasal continuous positive airway pressure--possible involvement of nitric oxide and asymmetric NG, NG-dimethylarginine.

BACKGROUND: Asymmetric NG,NG-dimethylarginine (ADMA) is an endogenous inhibitor of endothelial nitric oxide (NO) synthase and its plasma concentration is elevated in patients with cardiovascular risk factors, including hyperlipidemia, hypertension, diabetes, and hyperhomocysteinemia. Obstructive sleep apnea syndrome (OSAS) has been attracting attention as a risk factor for cardiovascular disorders because it often accompanies hypertension, obesity, glucose impairment, and dyslipidemia, all of which are factors in metabolic syndrome and risk factors for cardiovascular disease. METHODS AND RESULTS: In the present study, flow-mediated vasodilatation (FMD) of the brachial artery and plasma concentrations of ADMA were measured before and after nasal continuous positive airway pressure (nCPAP) therapy, which abrogates apnea, in 10 male patients aged 36-69 years old, who were given a diagnosis of OSAS by polysomnography. The percent FMD (%FMD) improved significantly from 3.3+/-0.3% to 5.8+/-0.4% (p<0.01) and 6.6+/-0.3% (p<0.01), before, 1 week, and 4 weeks after nCPAP, respectively. At the same time, the plasma NOx concentrations, metabolites of NO, tended to increase, but the plasma ADMA concentration decreased inversely to %FMD and NOx. A negative correlation between %FMD and plasma ADMA concentration, and a positive correlation between %FMD and plasma NOx concentrations were observed. CONCLUSION: Nasal CPAP improves endothelial function, in part by the decreasing ADMA concentration, thereby potentiating NO production.

Adult↗

PubMed1998

ET(A) receptor blockade prevents increased tissue endothelin-1, vascular hypertrophy, and endothelial dysfunction in salt-sensitive hypertension.

Sodium plays an important role in the pathogenesis and therapy of hypertension, a major risk factor for cardiovascular disease. This study investigated the involvement of endothelin in vascular alterations in salt-induced Dahl hypertension. Salt-sensitive (DS) and salt-resistant (DR) Dahl rats were treated with a high-sodium diet (NaCl 4%) with or without ET(A) receptor antagonist LU135252 for two months, and effects of treatments on systolic blood pressure, vascular endothelin-1 (ET-1) protein content, aortic hypertrophy, and vascular reactivity of isolated aortic rings were studied. In DS rats, a high-sodium diet increased systolic pressure (190+/-4 versus 152+/-2 mm Hg, P<.05) and aortic ET-1 protein content (4.2-fold, P<.0001) and induced aortic hypertrophy as assessed by tissue weight (P<.0001). Sodium diet markedly reduced NO-mediated endothelium-dependent relaxations to acetylcholine (49+/-4% versus 81+/-4%, P<.0001) and contractions to ET-1 (92+/-7 versus 136+/-8% of KCl, P=.0011). ET-1 tissue levels were highly and inversely correlated with endothelium-dependent relaxations (r=0.931, P<.0001) and contractions to ET (r=0.77, P=.0007). LU135252 treatment reduced systolic blood pressure only in part (168+/-3 versus 190+/-4 mm Hg, P<.05) but normalized sodium-induced changes of vascular reactivity, tissue ET-1 protein content, and vascular structure (P<.001 versus sodium). None of these effects were observed in DR rats. These results suggest that ET-1 acts as a local mediator of vascular dysfunction and aortic hypertrophy in Dahl salt-induced hypertension. ET(A) receptor antagonism may have therapeutic potential for lowering vascular ET-1 content, improving endothelial function, and preventing structural changes in salt-sensitive hypertension.

Acetylcholine↗

PubMed2004

Dexamethasone blocks hypoxia-induced endothelial dysfunction in organ-cultured pulmonary arteries.

We assessed the effects of dexamethasone (DEX) on hypoxia-induced dysfunction of the pulmonary endothelium using organ-cultured rabbit intrapulmonary arteries; 3-microM DEX inhibited the 7-day hypoxia (5% oxygen)-induced impairments of endothelial-dependent relaxation, cGMP accumulation, and increase in intracellular Ca(2+) level under substance P-stimulated conditions. Treatment with DEX over the final 3 days of the 7-day hypoxic exposure period also restored the decreased endothelium-dependent relaxation. Although chronic hypoxia did not change the mRNA expression of endothelial nitric oxide synthase (eNOS), 3 microM of DEX increased eNOS mRNA expression in both the hypoxic and normoxic (20% oxygen) pulmonary endothelium. On the other hand, eNOS protein expression was not changed in any of the arteries. We next assessed the effects of DEX on the eNOS activation pathway. Chronic hypoxia impaired eNOS phosphorylation and Akt phosphorylation under both the nonstimulated and substance P-stimulated conditions, and 3-microM DEX restored these phosphorylations. Morphologic study revealed that 3-microM DEX inhibited chronic hypoxia-induced atrophy of endothelial cells and eNOS protein condensation into plasma membranes. These results suggest that DEX exerts beneficial effects on chronic hypoxia-induced impairments of nitric oxide-mediated arterial relaxation by increasing eNOS mRNA expression and inhibiting hypoxia-induced impairments in eNOS activation pathway with atrophy of endothelial cells.

Animals↗

PubMed2002

New mechanisms of LDL-cholesterol induced endothelial dysfunction; correction by statins.

High LDL-cholesterol is a risk factor for atherosclerosis and cardiovascular events. Dysfunction of the endothelium, e.g. the impairment of its capacity to produce nitric oxide (NO) is an early step in atherogenesis. We identified a mechanism of endothelial toxicity of LDL-cholesterol that alters the activity of the endothelial isoform of nitric oxide synthase (eNOS) in the absence of changes in its expression (abundance). This effect involves the transcriptional activation of the gene encoding caveolin-1, a structural protein of caveolae that acts as a negative allosteric regulator of eNOS. The effect is proportional to the increase in intracellular cholesterol that modulates caveolin-1 gene transcription, through the Sterol Regulatory Element Binding Protein (SREBP). Treatment of endothelial cells with statins (inhibitors of cholesterol synthesis) abrogates caveolin-1 upregulation and restores eNOS activity in vitro and in vivo in genetically apoE-deficient, hypercholesterolemic mice.

Animals↗

PubMed2000

IL-10 deficiency increases superoxide and endothelial dysfunction during inflammation.

Little is known about the role of interleukin-10 (IL-10), an anti-inflammatory cytokine, in blood vessels. We used IL-10-deficient mice (IL-10 -/-) to examine the hypothesis that IL-10 protects endothelial function after lipopolysaccharide (LPS) treatment. The responses of carotid arteries were studied in vitro 6 h after injection of a relatively low dose of LPS (10 microgram ip). In IL-10 -/- mice, the maximum relaxation to ACh (3 microM) was 56 +/- 6% (means +/- SE) after LPS injection and 84 +/- 4% after vehicle injection (P < 0.05). Thus endothelium-dependent relaxation was impaired in carotid arteries from IL-10 -/- mice after LPS injection. In contrast, this dose of LPS did not alter relaxation to ACh in vessels from wild-type (IL-10 +/+) mice. Relaxation to nitroprusside and papaverine was similar in arteries from both IL-10 -/- and IL-10 +/+ mice after vehicle or LPS injection. Because inflammation is associated with increased levels of reactive oxygen species, we also tested the hypothesis that superoxide contributes to the impairment of endothelial function by LPS in the absence of IL-10. Results using confocal microscopy and hydroethidine indicated that levels of superoxide are elevated in carotid arteries from IL-10 -/- mice compared with IL-10 +/+ mice after LPS injection. The impaired relaxation of arteries from IL-10 -/- mice after LPS injection was restored to normal by polyethylene glycol-suspended superoxide dismutase (50 U/ml) or allopurinol (1 mM), an inhibitor of xanthine oxidase. These data provide direct evidence that IL-10 protects endothelial function after an acute inflammatory stimulus by limiting local increases in superoxide. The source of superoxide in this model may be xanthine oxidase.

Animals↗

PubMed2003

Surgical radiofrequency ablation induces coronary endothelial dysfunction in porcine coronary arteries.

OBJECTIVES: Surgical radiofrequency ablation is increasingly used during open heart surgery for the treatment of chronic atrial fibrillation. The purpose of this study was to determine the effects of application of radiofrequency on coronary endothelial function and structure and establish the relationship between coronary lesions and distance of radiofrequency application. METHODS: Six Landrace swine (25.9+/-2.0 kg) were included in the study. With the heart kept beating, three epicardial radiofrequency lesions (20 W, 20 s duration, 60 degrees C) 2 cm in length each, were created 1, 5 and 10 mm away from the left anterior descending and the right coronary arteries. The circumflex artery served as control. Coronary rings were placed in organ chambers. After contraction to KCl and prostaglandin F2alpha, endothelium-dependent relaxations to bradykinin were studied. Gomori trichrome and hematoxylin-eosin safran staining were used for histological evaluation. RESULTS: Exposure to radiofrequency 1 mm from the coronary arteries caused a significant decrease in endothelium-independent contractions to KCl and endothelium-dependent relaxations to bradykinin compared to controls (P<0.05). No significant decrease of endothelium-dependent relaxations occurred for rings exposed to radiofrequency at a distance of 5 and 10 mm, compared to controls. Histological examination showed endothelial disruption and medial smooth muscle cells at different stages of necrosis up to 5 mm from the radiofrequency application site. CONCLUSIONS: Radiofrequency may induce coronary endothelial functional and morphological damages when applied less than 5 mm from the artery. Caution must be exerted during left atrial radiofrequency application due to the proximity of the circumflex artery.

Animals↗

PubMed1998

Endothelial dysfunction following thrombolysis in vitro.

OBJECTIVES: Thrombolytic therapy is frequently used to manage vascular graft thrombosis. However, long-term patency after thrombolysis remains poor. The purpose of this study was to characterise the morphological and functional response of endothelial cells (EC) exposed to a thrombus and subsequently lytic therapy. METHODS: Human EC were exposed to human whole blood thrombus for 2, 6, 12, and 24 h. The thrombus was lysed with urokinase. Cell morphology was studied with electron microscopy. Northern blot analyses were performed with human c-DNA probes for endothelin-1, thrombomodulin, tissue factor, tissue plasminogen activator, plasminogen activator inhibitor, and triose phosphate isomerase. RESULTS: EC retraction occurred for each period of incubation. Thrombomodulin expression was increased 2.2-fold at 6 h and 2.4-fold at 24 h. t-PA expression was depressed proportionally to the duration of thrombus exposure. PAI and TF expression transiently increased 1.5-fold at 2 h of exposure and returned to baseline at 6 h. Endothelin expression remained unchanged. CONCLUSIONS: Except for a transient increase in TF expression and reversal of the tPA/PAI ratio, EC exposed to thrombus do not appear to become actively procoagulant. The increase in TM expression may reflect enhanced thromboresistance. However, EC retraction may be responsible for an increase thrombogenicity of saphenous vein graft after thrombosis and Urokinase therapy.

Cells, Cultured↗

PubMed2005

Lysophosphatidylcholine and secretory phospholipase A2 in vascular disease: mediators of endothelial dysfunction and atherosclerosis.

Lysophosphatidylcholine (LPC) is the major component of oxidized low density lipoprotein (oxLDL) and it has the ability to initiate or amplify several steps in atherogenesis due to its ability to impair endothelium-dependent vasorelaxation, enhance endothelial proliferation and permeability, stimulate adhesion and activation of lymphocytes, initiate chemotaxis of macrophages, impair migration and proliferation in vascular smooth muscle cells (SMCs), and modify platelet aggregation and coagulation pathways. For many of the LPC-induced effects, protein kinase C-dependent pathways have been implicated. In addition, modulation of ion current activity in the cell membrane, binding to a specific oxLDL receptor or to G-protein coupled receptors, as well as amplification of a highly oxidative state have all been postulated as likely mediating mechanisms. Secretory phopholipase A(2)-II (sPLA(2)-II) is one of the enzymes responsible for LPC production. sPLA(2)-II has been recently recognized as an independent risk factor for coronary artery disease. sPLA(2)-II favors the formation of bioactive lipids, stimulates SMC proliferation, activates macrophages enhancing lipid core formation and cytokine secretion, and binds to proteoglycans in the vessel wall matrix promoting lipid fusion and accumulation. The non-catalytic atherogenic effects of sPLA(2)-II are thought to be related to binding to an M-type receptor. Commonly used medications have been shown to decrease sPLA(2)-II activity generating a legitimate interest in the effects of the sPLA(2)-II pharmacologic antagonism. LPC and sPLA(2)-II are two very important mediators in atherosclerosis. Further research is warranted to clarify the cellular and molecular mechanisms that underlie their actions and to correlate in vitro data with clinical observations.

Animals↗

PubMed2006

Simvastatin improves diabetes-induced coronary endothelial dysfunction.

3-Hydroxy-3-methylglutaryl CoA reductase inhibitors decrease cardiovascular morbidity in diabetic patients, but the mechanism is unclear. We studied the actions of simvastatin (SIM) in enhancing NO bioavailability and reducing oxidative stress in coronary vessels from diabetic rats and in rat coronary artery endothelial cells (RCAEC) exposed to high glucose. Coronary arteries isolated from diabetic rats showed decreases in acetylcholine (ACh)-mediated maximal relaxation from 81.0 +/- 4.5% in controls to 43.5 +/- 7.6% at 4 weeks and 22.3 +/- 0.6% at 10 weeks of diabetes. This effect was associated with oxidative stress in coronary vessels as shown by dichlorofluorescein (DCF) imaging and nitrotyrosine labeling. Diabetes also reduced trans-coronary uptake of [(3)H]l-arginine. Supplemental l-arginine (50 mg/kg/day p.o.) did not improve coronary vasorelaxation to ACh. However, SIM treatment (5 mg/kg/day subcutaneously) improved maximal ACh relaxation to 65.8 +/- 5.1% at 4 weeks and 47.1 +/- 3.9% at 10 weeks. Coronary arteries from rats treated with both SIM and l-arginine demonstrated the same maximal relaxation to ACh (66.1 +/- 3%) as SIM alone. Mevalonate and l-NAME (N(omega)-nitro-l-arginine methyl ester hydrochloride) inhibited the response to ACh in SIM-treated diabetic rats. Coronary arteries from all groups relaxed similarly to sodium nitroprusside. SIM increased endothelial NO synthase protein levels and blocked diabetes-induced increases in DCF and nitrotyrosine labeling in diabetic coronary vessels. SIM treatment restored normal NO levels in media from high-glucose-treated RCAEC and plasma of diabetic rat. Treatment with SIM or the NADPH oxidase inhibitor apocynin also blocked high-glucose-induced increases in reactive oxygen species and superoxide formation in RCAEC. Taken together, these data suggest that SIM improves diabetes-induced coronary dysfunction by reducing oxidative stress and increasing NO bioavailability.

Animals↗