24 research outputs found
Editorial [Hot topic: New Perspectives in Cardiovascular Medicine (Executive Editor: Jaye P.F. Chin-Dusting)]
No full textMetabolic health, obesity and 9-year incidence of peripheral arterial disease: The D.E.S.I.R. study
No full textMichael R. Skilton, Jaye P.F. Chin-Dusting, Anthony M. Dart, Laima Brazionis, Olivier Lantieri, Kerin O'Dea, Beverley Balkau, for the D.E.S.I.R. Study Grou
Endothelium-dependent relaxation by acetylcholine is impaired in hypertriglyceridemic humans with normal levels of plasma LDL cholesterol
No full textAbstractOBJECTIVESPatients with high triglyceride (of which very low density lipoproteins [VLDL] are the main carriers), but with normal low density lipoprotein (LDL) cholesterol levels, were examined for in vivo endothelium function status.BACKGROUNDVery low density lipoproteins inhibit endothelium-dependent, but not -independent, vasorelaxation in vitro.METHODSThree groups were studied: 1) healthy volunteers (n = 10; triglyceride 1.24 ± 0.14 mmol/liter, LDL cholesterol 2.99 ± 0.24 mmol/liter); 2) hypertriglyceridemic (n = 11; triglyceride 6.97 ± 1.19 mmol/liter,∗ LDL cholesterol 2.17 ± 0.2 mmol/liter, ∗p < 0.05); and 3) hypercholesterolemic (n = 10; triglyceride 2.25 ± 0.29 mmol/liter,∗ LDL cholesterol 5.61 ± 0.54 mmol/liter∗; ∗p < 0.05) patients. Vasoactive responses to acetylcholine, sodium nitroprusside, noradrenaline, NG-monomethyl-l-arginine and postischemic hyperemia were determined using forearm venous occlusion plethysmography.RESULTSResponses to acetylcholine (37 μg/min) were significantly dampened both in hypercholesterolemic (% increase in forearm blood flow: 268.2 ± 62) and hypertriglyceridemic patients (232.6 ± 45.2) when compared with controls (547.8 ± 108.9; ANOVA p < 0.05). Responses to sodium nitroprusside (at 1.6 μg/min: controls vs. hypercholesterolemics vs. hypertriglyceridemic: 168.7 ± 25.1 vs. 140.6 ± 38.9 vs. 178.5 ± 54.5% increase), noradrenaline, NG-monomethyl-l-arginine and postischemic hyperemic responses were not different among the groups examined.CONCLUSIONSAcetylcholine responses are impaired in patients with pathophysiologic levels of plasma triglycerides but normal plasma levels of LDL cholesterol. The impairment observed was comparable to that obtained in hypercholesterolemic patients. We conclude that impaired responses to acetylcholine normally associated with hypercholesterolemia also occur in hypertriglyceridemia. These findings identify a potential mechanism by which high plasma triglyceride levels may be atherogenic independent of LDL cholesterol levels
Dietary supplementation with l-arginine fails to restore endothelial function in forearm resistance arteries of patients with severe heart failure
No full textObjectives.We sought to examine the efficacy of dietary supplementation of l-arginine on endothelium-dependent vasodilation in patients with congestive heart failure.Background.Endothelial dysfunction, as evidenced by a diminished response to such vasodilators as acetylcholine, is well defined in patients with heart failure. These responses are improved by intraarterial infusion with l-arginine. Because l-arginine is a semiessential amino acid, we investigated the effects of dietary l-arginine on endothelium-dependent vasodilation in these patients.Methods.Twenty patients with heart failure (New York Heart Association functional class III/IV, mean [±SE] age 51.3 ± 1.7 years) and seven healthy control subjects (mean age 52.6 ± 3.3 years) were studied. All patients continued taking their usual treatment. Responses to acetylcholine and sodium nitroprusside were determined using forearm plethysmography. Patients with heart failure received either l-arginine (20 g/day every day for 28 days) or placebo (vehicle syrup in equal amounts) in a double-blind protocol. The calculated power of the study was between 62% and 80% to detect a 30% to 40% change in area under the dose-response (forearm vascular resistance) curve.Results.Responses to acetylcholine, but not to sodium nitroprusside, were significantly attenuated in patients with heart failure compared with control subjects (mean area under curve [Auc], control subjects vs. patients with heart failure: 1,125.4 ± 164.5 vs. 617.3 ± 116.6 U, p < 0.05, by Student t test). A significant increase in urea and aspartate transaminase levels in patients receiving active l-arginine treatment was observed. Responses to acetylcholine (AUC; before vs. after l-arginine: 641.5 ± 126.7 vs. 695.9 ± 151.9 U) and sodium nitroprusside were not affected by either l-arginine or placebo.Conclusions.Endothelial dysfunction was apparent in patients with heart failure despite rigorous vasoactive treatment. Oral administration with l-arginine was ineffective in influencing endothelial function in these patients
Neutrophil Activation Is Attenuated by High-Density Lipoprotein and Apolipoprotein A-I in In Vitro and In Vivo Models of Inflammation
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Objective—
Neutrophils play a key role in the immune response but can undesirably exacerbate inflammation. High-density lipoproteins (HDL) are antiinflammatory particles, exerting beneficial cardiovascular influences. We determined whether HDL exerts antiinflammatory effects on neutrophils and explored the mechanisms by which these occur.
Methods and Results—
CD11b on activated human neutrophils was significantly attenuated by apolipoprotein A-I (apoA-I) and HDL. The effects of apoA-I were mediated via ABCA1, whereas the effects of HDL were via scavenger receptor BI. Both were associated with a reduction in the abundance of lipid rafts, and a strong correlation between raft abundance and CD11b activation was observed. ApoA-I and HDL reduced neutrophil adhesion to a platelet monolayer under shear flow, as well as neutrophil spreading and migration. ApoA-I also inhibited leukocyte recruitment to the endothelium in an acute in vivo model of inflammation. Finally, infusion of reconstituted HDL in patients with peripheral vascular disease was demonstrated to significantly attenuate neutrophil activation.
Conclusion—
We describe here a novel role for HDL and apoA-I in regulating neutrophil activation using in vitro, in vivo, and clinical approaches. We also show that these effects of HDL and apoA-I involve a mechanism requiring changes in membrane domain content rather than in cholesterol efflux per se.
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Vascular dysfunction in the stroke-prone spontaneously hypertensive rat is dependent on constrictor prostanoid activity and Y chromosome lineage
No full textVascular dysfunction is a hallmark of hypertension and the strongest risk factor to date for coronary artery disease. As Y chromosome lineage has emerged as one of the strongest genetic predictors of cardiovascular disease risk to date, we investigated if Y chromosome lineage modulated this important facet in the stroke-prone spontaneously hypertensive rat (SHRSP) using consomic strains. Here, we show that vascular dysfunction in the SHRSP is attributable to differential cyclooxygenase (COX) activity with nitric oxide (NO) levels playing a less significant role. Measurement of prostacyclin, the most abundant product of COX in the vasculature, confirmed the augmented COX activity in the SHRSP aorta. This was accompanied by functional impairment of the vasodilatory prostacyclin (IP) receptor, while inhibition of the thromboxane (TP) receptor significantly ameliorated vascular dysfunction in the SHRSP, suggesting this is the downstream target responsible for constrictor prostanoid activity. Importantly, Y chromosome lineage was shown to modulate vascular function in the SHRSP through influencing COX activity, prostacyclin levels and IP dysfunction. Vascular dysfunction in the renal and intrarenal arteries was also found to be prostanoid and Y chromosome dependent. Interestingly, despite no apparent differences in agonist-stimulated NO levels, basal NO levels were compromised in the SHRSP aorta, which was also Y chromosome dependent. Thus, in contrast with the widely held view that COX inhibition is deleterious for the vasculature due to inhibition of the vasodilator prostacyclin, we show that COX inhibition abolishes vascular dysfunction in three distinct vascular beds, with IP dysfunction likely being a key mechanism underlying this effect. We also delineate a novel role for Y chromosome lineage in regulating vascular function through modulation of COX and basal NO levels.</jats:p
Origin of the y chromosome influences intrarenal vascular responsiveness to angiotensin i and angiotensin (1-7) in stroke-prone spontaneously hypertensive rats
No full textThe lineage of the Y chromosome accounts for up to 15 to 20 mm Hg in arterial pressure. Genes located on the Y chromosome from the spontaneously hypertensive rat (SHR) are associated with the renin–angiotensin system. Given the important role of the renin–angiotensin system in the renal regulation of fluid homeostasis and arterial pressure, we hypothesized that the origin of the Y chromosome influences arterial pressure via interaction between the intrarenal vasculature and the renin–angiotensin system. Sixteen-week-old normotensive rats (Wistar Kyoto [WKY]), spontaneously hypertensive stroke-prone rat (SHRSP), and 2 reciprocal Y consomic rat strains, 1 comprising the WKY autosomes and X chromosome with the Y chromosome from the hypertensive rat strain (WKY.SPGlaY) and vice versa (SP.WKYGlaY), were examined. SP.WKYGlaY had lower systolic blood pressure than SHRSP (195±5 versus 227±8 mm Hg; P<0.03), whereas WKY.SPGlaY had higher systolic blood pressure compared with WKY (157±3 versus 148±3 mm Hg; P<0.05), measured by radiotelemetry. Compared with WKY rats, SHRSP had higher plasma angiotensin(1-7) (Ang (1-7)):Ang II ratio (WKY: 0.13±0.01 versus SHRSP: 1.33±0.4; P<0.005), greater angiotensin II receptor type 2 and Mas receptor mRNA expression, and a blunted renal constrictor response to intrarenal Ang I and Ang(1-7) infusions. Introgression of the normotensive Y chromosome into the SHRSP background (SP.WKYGlaY) restored responses in the SHRSP to WKY levels, evidenced by a reduction in plasma Ang(1-7):Ang II ratio (SP.WKYGlaY: 0.24±0.02; P<0.01), angiotensin II receptor type 2, and Mas receptor mRNA expression and an increased vasoconstrictor response to intrarenal Ang I and Ang(1-7) infusion. This study demonstrates that the origin of the Y chromosome significantly impacts the renal vascular responsiveness and therefore may influence the long-term renal regulation of blood pressure
High-density lipoprotein inhibits human M1 macrophage polarization through redistribution of caveolin-1
No full textBackground and PurposeMonocyte-derived macrophages are critical in the development of atherosclerosis and can adopt a wide range of functional phenotypes depending on their surrounding milieu. High-density lipoproteins (HDLs) have many cardio-protective properties including potent anti-inflammatory effects. We investigated the effects of HDL on human macrophage phenotype and the mechanisms by which these occur
