Circulating and Tissue Endothelin Immunoreactivity in Advanced Atherosclerosis

Lerman, Amir; Edwards, Brooks S.; Hallett, John W.; Heublein, Denise M.; Sandberg, Sharon M.; Burnett, John C.

doi:10.1056/nejm199110033251404

Cited by 902 publications

(453 citation statements)

References 28 publications

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“…Coronary artery ET immunoreactivity is increased in experimental hypercholesterolemia in pigs 8 and in humans with atherosclerosis. 24 It is thus possible that acetylcholine causes a local increase in ET levels, which is of much greater magnitude than the rise in circulating levels. Indeed, circulating concentrations of ET have been shown to correlate poorly with local concentrations because ET is secreted primarily abluminally.…”

Section: Discussionmentioning

confidence: 99%

Acute Endothelin-Receptor Inhibition Does Not Attenuate Acetylcholine-Induced Coronary Vasoconstriction in Experimental Hypercholesterolemia

Hasdai

Best

Cannan

et al. 1998

ATVB

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Abstract-Endothelin (ET) may mediate the enhanced coronary vasoconstriction associated with hypercholesterolemia. We hypothesized that short-term inhibition of ET receptors attenuates the coronary epicardial vasoconstrictor response to acetylcholine in experimental hypercholesterolemia. ET-1 (group I, nϭ5; 5 ng ⅐ kg Ϫ1 ⅐ min Ϫ1 ) and acetylcholine (group III, nϭ7; 10 Ϫ6 to 10 Ϫ4 mol/L) were given by intracoronary infusion in pigs. ET-1 and acetylcholine were also infused with the specific ETA-receptor blocker FR-139317 (5 g ⅐ kg Ϫ1 ⅐ min Ϫ1 ; group II, nϭ6; group IV, nϭ6). Acetylcholine was also infused with the combined ET-receptor blocker, bosentan (0.5 mg/kg plus 1 mg ⅐ kg Ϫ1 ⅐ h Ϫ1 , group V, nϭ5). The ETB-receptor agonist sarafotoxin 6c (5 ng ⅐ kg Ϫ1 ⅐ min Ϫ1 ; nϭ4) was also infused. The percentage change in coronary artery diameter (%⌬CAD) to the infusions was measured at baseline and after 10 weeks of high-cholesterol diet in all animals. Sarafotoxin 6c mildly reduced %⌬CAD at baseline and 10 weeks (Ϫ10Ϯ2% and Ϫ12Ϯ3%, respectively). FR-139317 did not attenuate the epicardial vasoconstrictor response to ET-1 at baseline (%⌬CAD Ϫ18Ϯ8% for group I versus Ϫ12Ϯ6% for group II; PϭNS) but did at 10 weeks (%⌬CAD Ϫ77Ϯ14% for group I versus Ϫ14Ϯ6% for group II; PϽ.05). FR-139317 did not affect the response to acetylcholine at baseline (%⌬CAD 5Ϯ2% for group III versus 7Ϯ3% for group IV, PϭNS) or at 10 weeks (%⌬CAD Ϫ23Ϯ12% for group III versus Ϫ19Ϯ7% for group IV; PϭNS). Bosentan did not affect the response to acetylcholine at baseline or 10 weeks. The ETA receptor is expressed in vascular smooth muscle, whereas the ETB receptor is localized to endothelial and smooth muscle cells. 4 Coronary vasoconstriction is mediated by both receptors. 1 We 5 recently reported that intracoronary infusion of ET-1 at pathophysiological concentrations results in coronary epicardial vasoconstriction in dogs, which was presumed to be mediated predominantly via the ETA receptor.Hypercholesterolemia is a pathophysiological state characterized by impaired coronary endothelium-dependent arterial relaxation to the endothelium-dependent vasodilator acetylcholine. 6,7 In a porcine model of diet-induced hypercholesterolemia, plasma concentrations of ET are elevated, and coronary tissue ET immunoreactivity is enhanced. 8 Moreover, intracoronary infusion of acetylcholine causes vasoconstriction and further increases plasma ET concentrations. 8 Similarly, humans with coronary endothelial dysfunction have enhanced ET immunoreactivity in the coronary circulation, with an additional rise in coronary ET levels during intracoronary infusion of acetylcholine. 9 These prior studies implicate ET as a potential mediator of endothelial dysfunction in hypercholesterolemia, possibly through stimulation of the ET receptor. The present study was designed to examine the hypothesis that selective inhibition of the ET receptor attenuates the coronary epicardial vasoconstrictor response to acetylcholine in experimental hypercholesterolemia.

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Section: Discussionmentioning

confidence: 99%

Acute Endothelin-Receptor Inhibition Does Not Attenuate Acetylcholine-Induced Coronary Vasoconstriction in Experimental Hypercholesterolemia

Hasdai

Best

Cannan

et al. 1998

ATVB

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“…ET-1 acts as a potent mitogenic agent, which promotes neointima formation and proliferation of smooth muscle cells [79]. ET-1 is found to be elevated in patients with severe atherosclerosis [80]. Statins inhibit the expression of preproET-1 [81] and downregulate endothelin and angiogensin subtype 1 receptors [82,83] in a RhoA-dependent manner.…”

Section: Statins and Vascular Dysfunctionmentioning

confidence: 99%

Pleiotropic effects of statin therapy: molecular mechanisms and clinical results

Wang

Liu

Liao

2008

Trends in Molecular Medicine

537

394

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Statins inhibit the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, which is required for cholesterol biosynthesis, and are beneficial in the primary and secondary prevention of cardiovascular disease. Most of the benefits of statin therapy are owing to the lowering of serum cholesterol levels. However, by inhibiting HMG-CoA reductase, statins can also inhibit the synthesis of isoprenoids, which are important lipid attachments for intracellular signaling molecules, such as Rho, Rac and Cdc42. Therefore, it is possible that statins might exert cholesterol-independent or 'pleiotropic' effects through direct inhibition of these small GTP-binding proteins. Recent studies have shown that statins might have important roles in diseases that are not mediated by cholesterol. Here, we review data from recent clinical trials that support the concept of statin pleiotropy and provide a rationale for their clinical importance. [6], have demonstrated the beneficial effects of statin therapy for primary and secondary prevention of cardiovascular disease. Because 60-70% of serum cholesterol is derived from hepatic synthesis and HMG-CoA reductase is the crucial, rate-limiting enzyme in the cholesterol biosynthetic pathway, inhibition of this enzyme by statins results in a dramatic reduction in circulating low-density lipoprotein (LDL)-cholesterol (Figure 1). In addition, reduction of LDL-cholesterol leads to upregulation of the LDL receptor and increased LDL clearance. The lowering of serum cholesterol levels is therefore thought to be the primary mechanism underlying the therapeutic benefits of statin therapy in cardiovascular disease [1]. Pleiotropy of statins: beyond cholesterol loweringStatins, however, might also exert cholesterol-independent or pleiotropic effects. By inhibiting the conversion of HMG-CoA to L-mevalonic acid, statins prevent the synthesis of important isoprenoids, such as farnesylpyrophosphate (FPP) and geranylgeranylpyrophosphate (GGPP), which are precursors of cholesterol biosynthesis [7] (Figure 1). These intermediates serve as important lipid attachments for the post-translational modification of proteins, such as nuclear lamins, Ras, Rho, Rac and Rap [8]. These isoprenylated proteins constitute approximately 2% of total cellular proteins [9]. Protein isoprenylation (see Glossary) enables proper subcellular localization and trafficking of intracellular proteins. Given that isoprenylated proteins might

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“…It is well known that increased ET-1 levels are present in insulinresistant subjects, in Type 2 diabetic hyperlipidemic patients, and in atherosclerosis and cardiovascular disease (16,20,32). Moreover, in patients with coronary artery disease, a marked increase of ET-1 release was observed during exercise, in the presence of increased FFA levels (11).…”

Section: Effects Of Type 2 Diabetes Mellitus On Myocardial Insulin Rementioning

confidence: 99%

Myocardial insulin resistance associated with chronic hypertriglyceridemia and increased FFA levels in Type 2 diabetic patients

Monti¹,

Landoni²,

Setola³

et al. 2004

American Journal of Physiology-Heart and Circulatory Physiology

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dial insulin resistance associated with chronic hypertriglyceridemia and increased FFA levels in Type 2 diabetic patients. Am J Physiol Heart Circ Physiol 287: H1225-H1231, 2004. First published May 6, 2004; 10.1152/ajpheart.00629.2003.-We evaluated the influence of chronic hypertriglyceridemia and endothelial dysfunction on myocardial glucose uptake (MGU) in Type 2 diabetic patients without coronary heart disease. Patients were divided into two groups according to fasting triglyceride (TG) levels: 5.4 Ϯ 1.1 and 1.5 Ϯ 0.3 mmol/l for high-and normal-TG groups, respectively. Five subjects were assigned to the high-TG group and 11 to the normal-TG group. Age, gender, body mass index, systolic and diastolic blood pressure, glucose, insulin, HbA1c, cholesterol, and HDL cholesterol were similar in the two groups, whereas free fatty acid (FFA) levels were higher in the high-TG group basally and at the end of the clamp. Furthermore, five healthy subjects were subjected to the same protocol and used as the control group. MGU was assessed by using 18 F-labeled 2-fluoro-2-deoxy-D-glucose under hyperglycemic-hyperinsulinemic conditions. Basal endothelin-1 and nitric oxide levels were significantly higher in the high-TG group than in the normal-TG and control groups, and cGMP and maximal postischemic vasodilation were significantly decreased in the high-TG group compared with the normal-TG and control groups. However, significant alterations were found in the same parameters in the normal-TG group compared with the control group. By the end of the hyperglycemic clamp, in the high-TG group, MGU was ϳ40 and 65% of that in the normal-TG and control groups. MGU negatively correlated with TG, FFA, and endothelin-1, whereas a positive correlation was found with cGMP and maximal postischemic vasodilation. In conclusion, increased TG and FFA levels are risks, in addition to Type 2 diabetes mellitus, for myocardial insulin resistance, endothelial dysfunction, and alteration of nitric oxide/cGMP levels. triglycerides; myocardial glucose uptake; positron emission tomography study; endothelium; free fatty acid FOR MANY YEARS, hypertriglyceridemia was considered a marker of cardiovascular disease only in certain subjects, such as women (5, 12) and patients with Type 2 diabetes (10). The association between triglycerides (TGs), independently of HDL cholesterol levels, and definite cardiovascular disease, such as myocardial infarction or angina, was found in some studies (5) and denied in others, in which the simultaneous association of high TG and low HDL cholesterol was necessary to predict cardiovascular risk (8). This apparent discrepancy is probably related to the fact that it is quite difficult to match for duration and degree of cardiovascular disease in different populations, and, when cardiovascular disease is established, some factors might have lost their primary pathogenic significance. Hypertriglyceridemia occurs frequently in patients with coronary heart disease (CHD) and in survivors of myocardial infarction (5), and, durin...

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Circulating and Tissue Endothelin Immunoreactivity in Advanced Atherosclerosis

Abstract: Endothelin may be a marker for arterial vascular disease. Whether it participates in the atherogenic process or is merely released from damaged endothelial cells is unclear.

Cited by 902 publications

References 28 publications

Acute Endothelin-Receptor Inhibition Does Not Attenuate Acetylcholine-Induced Coronary Vasoconstriction in Experimental Hypercholesterolemia

Acute Endothelin-Receptor Inhibition Does Not Attenuate Acetylcholine-Induced Coronary Vasoconstriction in Experimental Hypercholesterolemia

Pleiotropic effects of statin therapy: molecular mechanisms and clinical results

Myocardial insulin resistance associated with chronic hypertriglyceridemia and increased FFA levels in Type 2 diabetic patients

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