Impairment of endothelium-dependent arterial relaxation by lysolecithin in modified low-density lipoproteins

Kugiyama, Kiyotaka; Kerns, Scott; Morrisett, Joel D.; Roberts, Robert; Henry, Philip D.

doi:10.1038/344160a0

Cited by 827 publications

(416 citation statements)

References 20 publications

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“…In contrast, no significant correlation was observed between the HDL fructosamine:total protein ratio or PON activity and Emax (ox-LDL+HDL) in type 2 diabetic patients or control subjects. The inhibitory effect of ox-LDL and some of their specific compounds such as derivatives of cholesterol oxidised in position 7 or lysophophatidylcholine on endothelium-dependent vasorelaxation is mainly related to a decreased bioavailability of NO [13][14][15][16][17]. HDL are likely to counteract the inhibitory effect of ox-LDL on endotheliumdependent vasorelaxation both by a direct and an indirect way.…”

Section: Discussionmentioning

confidence: 99%

Inability of HDL from type 2 diabetic patients to counteract the inhibitory effect of oxidised LDL on endothelium-dependent vasorelaxation

et al. 2006

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Aims/hypothesis: In healthy normolipidaemic and normoglycaemic control subjects, HDL are able to reverse the inhibition of vasodilation that is induced by oxidised LDL. In type 2 diabetic patients, HDL are glycated and more triglyceride-rich than in control subjects. These alterations are likely to modify the capacity of HDL to reverse the inhibition of vasodilation induced by oxidised LDL. Subjects and methods: Using rabbit aorta rings, we compared the ability of HDL from 16 type 2 diabetic patients and 13 control subjects to suppress the inhibition of vasodilation that is induced by oxidised LDL. Results: Oxidised LDL inhibited endothelium-dependent vasodilation (maximal relaxation [Emax]=58.2± 14.6 vs 99.3±5.2% for incubation without any lipoprotein, p<0.0001). HDL from control subjects significantly reduced the inhibitory effect of oxidised LDL on vasodilatation (Emax=77.6±12.9 vs 59.5±7.7%, p<0.001), whereas HDL from type 2 diabetic patients had no effect (Emax=52.4±20.4 vs 57.2±18.7%, NS). HDL triglyceride content was significantly higher in type 2 diabetic patients than in control subjects (5.3±2.2 vs 3.1±1.4%, p<0.01) and was highly inversely correlated to Emax for oxidised LDL+HDL in type 2 diabetic patients (r=−0.71, p<0.005). Conclusions/interpretation: In type 2 diabetes mellitus, the ability of HDL to counteract the inhibition of endothelium-dependent vasorelaxation induced by oxidised LDL is impaired and is inversely correlated with HDL triglyceride content. These findings suggest that HDL are less atheroprotective in type 2 diabetic patients than in control subjects.

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Section: Discussionmentioning

confidence: 99%

Inability of HDL from type 2 diabetic patients to counteract the inhibitory effect of oxidised LDL on endothelium-dependent vasorelaxation

et al. 2006

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“…18 Oxidized low-density lipoprotein (LDL) inhibits vascular smooth muscle relaxation through endothelial cells. 19 Also, high LDL-cholesterol level may influence the severity of ED. 20 Indeed, atherosclerotic biomarkers for endothelial function, thrombosis and dyslipidemia are associated with the degree of ED.…”

Section: Introductionmentioning

confidence: 99%

Atorvastatin improves the response to sildenafil in hypercholesterolemic men with erectile dysfunction not initially responsive to sildenafil

et al. 2009

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Despite the initial enthusiasm, the significant number of patients in whom sildenafil is contraindicated or ineffective is a major challenge to all urologists. Our aim was to determine the safety and efficacy of adjunctive atorvastatin in restoring normal erectile function in hypercholesterolemic (low-density lipoprotein (LDL) cholesterol 4120 mg per 100 ml) sildenafil nonresponders. The study comprised 131 men with ED not responding to sildenafil citrate. They were randomized either to 40 mg atorvastatin daily (n ¼ 66, group 1) or matching placebo (n ¼ 65, group 2) for 12 weeks while they were taking on-demand 100 mg sildenafil. Erectile function was subjectively assessed using the 5-item version of the International Index of Erectile Function (IIEF-5) questionnaire and response to the global efficacy question (GEQ). Serum biochemical and lipid profile (total cholesterol, triglycerides, LDL cholesterol and high-density lipoprotein cholesterol) analyses were performed at baseline and repeated at post-treatment weeks 6 and 12. Compared with the placebo group (59 patients, mean age ± s.d. 61.9 ± 6.1, mean years ED 3.9 ± 1.8), the atorvastatin group (59 patients, mean age±s.d. 63.9±6.9, mean years ED 3.7±1.6) had significantly greater improvements in all IIEF-5 questions (P ¼ 0.01) and GEQ (P ¼ 0.001). Subgroup analyses did reveal trends in the atorvastatin group to indicate that a change in the IIEF-5 score is affected by age, severity of ED and baseline serum levels of LDL. Patients with moderate (r ¼ 0.28, P ¼ 0.01) and severe (r ¼ 0.20, P ¼ 0.01) ED had better positive response rates to adjunctive atorvastatin than patients with mild to moderate ED. None of the patients taking atorvastatin achieved a response of 5 to the IIEF-5 questions and none of the patients regained normal erectile function as defined by the IIEF-5 score 421. Subjects experienced a statistically significant but modest improvement in erectile function. Further investigation is needed to test the usefulness of long-term atorvastatin administration to restore erectile function in sildenafil nonresponders.

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“…In the rabbit aorta the effect of OX-LDL is mimicked by lysolecithin (a characteristic component of OX-LDL). 64 ' 65 OX-LDL appears to activate an endothelial receptor distinct from the LDL receptor, such as the scavenger receptor (Figure 8) 63 ' 65 ; indeed, dextran sulfate, a competitive antagonist of modified LDL at this receptor, prevents the endothelial effects of OX-LDL. 63 Because endotheUum-dependent relaxations to serotonin, but not to bradykinin, are inhibited by the lipoproteins, they specifically interfere with endothelial production of nitric oxide, whereas that of other EDRFs does not Vascular smooth muscle cell 65 with permission.…”

Section: Lipoproteins and Hypercholesterolemiamentioning

confidence: 99%

Endothelial Regulation of Vascular Tone and Growth

Lüscher

Tanner

1993

American Journal of Hypertension

101

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The endothelium regulates vascular tone by releasing factors involved in relaxation and contraction, in coagulation and thrombus formation, and in growth inhibition and stimulation. Endothelium-dependent relaxations are elicited by transmitters, hormones, platelet substances, and the coagulation system, and by physical stimuli such as the shear stress from circulating blood. They are mediated by the endothelium-derived relaxing factor, recently identified as nitric oxide, which causes vasodilation and platelet deactivation. Other proposed endothelium-derived relaxing factors include a hyperpolarizing factor, lipooxygenase products, and the cytochrome P450 pathway. Endothelium-derived contracting factors are produced by the cyclooxygenase pathway and by endothelial cells, which produce the peptide endothelin-1, a potent vasoconstrictor that under normal conditions circulates at low levels. The endothelium produces both growth inhibitors-normally dominant-and growth stimuli. Denuded or dysfunctional endothelium leads to a proliferative response and intimal hyperplasia in the vessel wall; moreover, platelets adhere to the site and release potent growth factors. Endothelial dysfunction has numerous causes: Aging is associated with increased formation of contracting factor and decreased relaxing factor; denudation, such as by coronary angioplasty, impairs the capacities of regenerated endothelial cells; oxidized low-density lipoproteins and hypercholesterolemia interfere with nitric oxide production; hypertension morphologically and functionally alters the endothelium; and atherosclerosis markedly attenuates some endothelium-dependent relaxations. For patients with coronary bypass grafts, differences in endotheliumderived vasoactive factors between the internal mammary artery and the saphenous vein may be important determinants of graft function, with the mammary artery having more pronounced relaxations than the saphenous vein and thus a higher patency rate. Am J Hypertens 1993;6:283S-293S KEY WORDS: Endothelial regulation, endothelial dysfunction, vascular tone, endothelium-derived relaxing factors, endothelium-derived contracting factors, nitric oxide.T he endothelium takes part in the regulation of vascular tone 1 by releasing relaxing and contracting factors both under basal conditions and when activated by neurotransmitters, hormones, autacoids, or physical stimuli. In addition, endothelial cells release factors involved in coagulation and thrombus formation and in growth inhibition and stimulation.Owing to its strategic anatomic position, the endothelium is a target organ for hypertension, diabetes, and hyperlipidemia. 1 Alterations in endothelial function may contribute to the pathogenesis as well as to the progression and complications of hypertension and its sequelae such as atherosclerotic vascular disease. ENDOTHELIUM-DEPENDENT REGULATION OF VASCULAR TONERelaxing Factors Endothelium-dependent relaxa tions occur both in vitro and in vivo 2^; transmitters, hormones, substances derived from platelets, and t...

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Impairment of endothelium-dependent arterial relaxation by lysolecithin in modified low-density lipoproteins

Cited by 827 publications

References 20 publications

Inability of HDL from type 2 diabetic patients to counteract the inhibitory effect of oxidised LDL on endothelium-dependent vasorelaxation

Inability of HDL from type 2 diabetic patients to counteract the inhibitory effect of oxidised LDL on endothelium-dependent vasorelaxation

Atorvastatin improves the response to sildenafil in hypercholesterolemic men with erectile dysfunction not initially responsive to sildenafil

Endothelial Regulation of Vascular Tone and Growth

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