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Experimental Biology and Medicine 231:766-771 (2006)
© 2006 Society for Experimental Biology and Medicine

VASCULAR AND HYPERTENSION

Upregulation of Endothelin Receptor B in Human Endothelial Cells by Low-Density Lipoproteins

Gregor Muller*, Rusan A. Catar*, Bernd Niemann{dagger}, Matthias Barton{ddagger}, Lilla Knels§, Martina Wendel§ and Henning Morawietz*,1

* Department of Vascular Endothelium and Microcirculation, University of Technology Dresden, D-01307 Dresden, Germany; {dagger} Institute of Pathophysiology and Department of Cardiothoracic Surgery, Martin Luther University Halle-Wittenberg, D-06097 Halle, Germany; {ddagger} Medical Policlinic, Department of Medicine, University Hospital, CH-8091 Zürich, Switzerland; and § Department of Anesthesiology and Intensive Care Medicine, University of Technology Dresden, D-01307 Dresden, Germany

1To whom requests for reprints should be addressed at Department of Vascular Endothelium and Microcirculation, Medical Faculty Carl Gustav Carus, University of Technology Dresden, Fetscherstrasse 74, D-01307 Dresden, Germany. E-mail: Henning.Morawietz{at}tu-dresden.de

Abstract

Low-density lipoproteins (LDLs) represent the most important treatable risk factors for coronary artery disease. Although it has been previously shown that hypercholesterolemia stimulates the endothelin system, the effects of increased levels of LDL on endothelial endothelin receptors have not been previously studied. In particular, the influence of native and oxidatively modified LDLs (nLDLs and oxLDLs) and the regulatory mechanisms in endothelial cells are currently unknown. Human endothelial cells almost exclusively express the endothelin receptor type B (ETB). Therefore, the effect of nLDL and oxLDL on the expression of ETB was studied in primary cultures of human umbilical vein endothelial cells (HUVEC). HUVEC were stimulated by nLDL and oxLDL in a time-dependent (1–12 hrs) and dose-dependent (25–100 µg/ml) manner. To analyze signal transduction pathways involved in the regulation of ETB, protein kinase C (PKC) was inhibited using 100 nM Ro-31-8220. The mRNA expression of ETB was determined by quantitative reverse transcription–polymerase chain reaction and ETB protein expression by Western blot. Native LDL induced ETB mRNA after 1 hr (100 µg/ml, 199 ± 35%, n = 15, P < 0.05 vs. control). Stimulation of HUVEC with oxLDL increased ETB mRNA expression (1 hr, 100 µg/ml oxLDL: 308 ± 48%, n = 15, P < 0.05 vs. control) as well. Induction of ETB was also found on the protein level. nLDL was even more potent than oxLDL in inducing ETB protein expression. Induction of ETB expression by oxLDL is mediated by PKC. These data demonstrate that low-density lipoproteins even independent of oxidative modification are potent inducers of ETB receptors at the mRNA and protein level in HUVEC. Given the nitric oxide-releasing capacity of endothelial ETB receptors, this effect may represent a possible vasoprotective mechanism.

Key Words: endothelin-1 • endothelin receptor B • endothelium • low-density lipoprotein

Introduction

Low-density lipoproteins (LDLs) represent the most important treatable risk factors for coronary artery disease (1). Increased levels of native low-density lipoprotein (nLDL) can promote the influx of lipoproteins into the intima, leading to fatty streak formation (2, 3). The modification of nLDL by reactive oxygen species to oxidized low-density lipoprotein (oxLDL) can further promote the local progression of atherosclerosis (4). However, how different lipoproteins modulate the regulation of components of the endothelin system is still not well understood (5).

Endothelin is expressed in the vascular wall in endothelial cells and vascular smooth muscle cells as well as in macrophages accumulating in atherosclerotic plaques (6). Endothelin-1 (ET-1) binds to G-protein–coupled endothelin receptors A or B (ETA, ETB) and activates the phospholipase C phosphatidylinositol 1,4,5-trisphosphate pathway and Ca2+, promoting vasoconstriction (7). Human umbilical vein endothelial cells (HUVEC) almost exclusively express ETB (8, 9), causing in intact endothelial cells mainly nitric oxide (NO) release.

In hypercholesterolemic patients, endothelin-1 release is increased (10, 11). In experimental studies, hypercholesterolemic stimuli activate the endothelin system in endothelial cells (12, 13) and vascular smooth muscle cells (14). However, the effects of increased levels of LDL on endothelial ETB receptor have not been previously studied. In particular, the influence of nLDL, oxLDL, and the regulatory mechanisms in endothelial cells are currently unknown. Moreover, the potential role of protein kinase C for the regulation has not been studied. Therefore, the effect of nLDL and oxLDL on the expression of ETB and the role of protein kinase C (PKC) in this process was analyzed in primary cultures of HUVEC.

Materials and Methods

Cell Culture.
All cell culture reagents and chemicals were purchased from Sigma-Aldrich (Munich, Germany) unless otherwise specified. Primary cultures of HUVEC were isolated using collagenase IV. To minimize variations of primary cultures, different batches of primary isolates were pooled and cultured on gelatine-coated plates in medium M199 (Invitrogen, Karlsruhe, Germany) supplemented with 10% fetal calf serum.

Stimulation of HUVEC with nLDL and oxLDL.
nLDLs and oxLDLs were isolated as previously described (15). Confluent primary cultures of HUVEC were stimulated with nLDL or oxLDL in a time-dependent (1–12 hrs) and concentration-dependent (25–100 µg/ml) manner. Each experiment was accompanied by a control from the same HUVEC preparation incubated for the same period of time without lipoproteins.

Quantitation of mRNA Expression by Reverse Transcription–Polymerase Chain Reaction (RT-PCR).
Total RNA from endothelial cells was isolated by guanidinium isothiocyanate/cesium chloride centrifugation. RNA concentration was determined spectrophotometrically. Human ETB mRNA expression was quantified by RT-PCR and normalized to 18S rRNA (16). In brief, 500 ng RNA was reverse transcribed using random hexamer primers and SuperScript II RNase H– reverse transcriptase (Invitrogen) at 42°C for 1 hr. PCR was performed using 400 nM of specific sense and antisense primers, 1xTaq reaction buffer, and 20 nM each of dNTP and 1 U rTaqDNA polymerase (Amersham Biosciences Europe, Freiburg, Germany). After denaturation at 95°C for 2 mins, PCR was performed using the following protocol: 30 secs at 95°C, 30 secs at specific annealing temperature, and 30 secs at 72°C. After final extension at 72°C for 3 min, PCR products were separated by standard agarose gel electrophoresis with ethidium bromide. Optical density of amplified PCR fragments was quantified using AIDA software (Raytest; Isotopenmessgeraete GmbH, Berlin, Germany) and normalized to the density of 18S rRNA PCR fragments. To confirm the specificity of the ETB PCR primers, amplified fragments were cloned and sequenced (data not shown).

Protein Isolation and Western Blot.
After stimulation with nLDL or oxLDL, cells were washed twice with phosphate-buffered saline, and the membrane protein fraction was isolated as previously described (17). The protein concentration was determined with BCA Protein Assay Reagent (Perbio Science, Bonn, Germany). Equal amounts of membrane protein (20 µg/lane) were separated by sodium dodecyl sulfate–polyacrylamide gel electrophoresis (SDS-PAGE) and transferred to polyvinylidene fluoride membranes (Roth, Karlsruhe, Germany). Membranes were incubated with a polyclonal ETB antibody (18) and secondary horseradish peroxidase-linked rabbit Ig (Amersham Biosciences Europe). Protein expression was detected with ECL Western blotting detection reagent (Amersham Biosciences Europe) and quantified by densitometry.

Inhibitor Studies.
Protein kinase C was inhibited using 100 nM Ro-31-8220 (Calbiochem, San Diego, CA) as described (16). After preincubation with or without inhibitor for 1 hr, lipoproteins were applied on HUVEC for the time indicated. Each experiment was accompanied by two controls from the same HUVEC preparation incubated for the same period of time without lipoproteins: (i) without inhibitor, and (ii) with inhibitor at identical concentrations. From these experiments, ETB mRNA expression was determined by RT-PCR.

Statistics.
Data are given as mean ± SEM; n indicates the number of independent experiments. Statistical analysis was performed by Student’s t test, Mann-Whitney Rank Sum test, or ANOVA followed by Bonferroni’s method (multiple comparisons) when appropriate (Sigma Stat software; SPSS Inc., San Rafael, CA, USA). P < 0.05 was considered statistically significant.

Results

Induction of ETB by Native and Oxidized Low-Density Lipoprotein in Human Endothelial Cells.
HUVEC were stimulated by nLDL and oxLDL in a time-dependent (1–12 hrs) and dose-dependent (25–100 µg/ml) manner. The mRNA expression of ETB was determined by quantitative RT-PCR and ETB protein expression by Western blot. Native LDL induced ETB mRNA after 1 hr (100 µg/ml, 199 ± 35%, n = 15, P < 0.05 vs. control; Fig. 1AGo). Stimulation of HUVEC with oxLDL increased ETB mRNA expression (1 hr, 100 µg/ml oxLDL: 308 ± 48%, n = 15, P < 0.05 vs. control) as well (Fig. 1BGo). Induction of ETB mRNA by nLDL and oxLDL returned to baseline after 12 hrs. The induction of ETB by lipoproteins was also found on the protein level after 2 hrs of stimulation (Fig. 2Go). Native LDL was even more potent than oxLDL in inducing ETB protein expression.


Figure 1
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  		Figure 1. Induction of ETB receptor mRNA expression by nLDL and oxLDL in human endothelial cells. Human umbilical vein endothelial cells (HUVEC) were exposed to increasing concentrations (25–100 µg/ml) of nLDL (A) and oxLDL (B) for 1 hr. ETB mRNA was determined in equal amounts of RNA by RT-PCR, and normalized to 18S rRNA expression. All samples were normalized to internal controls (con) incubated in parallel for the same period of time. Values are given as mean ± SEM in relative units; n ≥ 5; *P < 0.05 vs. control.

 

Figure 2
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  		Figure 2. Effects of low-density lipoproteins on ETB protein expression in human umbilical vein endothelial cells. Cells were exposed to 100 µg/ml nLDL and oxLDL for 2 hrs. Samples were normalized to internal control (con) incubated in parallel for the same period of time without lipoprotein. The protein expression of ETB was determined by Western blot (Lane M, marker; Lane con, control; Lane nLDL, HUVEC stimulated with nLDL; Lane oxLDL, HUVEC stimulated with oxLDL (A). Values are given as mean ± SEM in relative units; n = 6; *P < 0.05 (B).

 
Effect of Protein Kinase C Inhibition on Lipid-Induced ETB Expression.
To determine potential signaling mechanisms involved in the lipoprotein-dependent upregulation of ETB, inhibitor studies were performed. HUVEC were exposed to 100 µg/ml nLDL or oxLDL for 1 hr in the presence or absence of the nonisoform selective PKC inhibitor Ro-31-8220 (100 nM). The corresponding data are shown in Figure 3Go. The increased ETB expression in response to oxLDL was reduced with PKC inhibition (P < 0.05 vs. lipoprotein-induced expression). In contrast, PKC inhibitor Ro-31-8220 had no significant effect on nLDL-induced ETB expression (not shown).


Figure 3
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  		Figure 3. Induction of the ETB receptor by oxidized low-density lipoprotein involves protein kinase C. HUVEC were exposed to 100 µg/ml oxLDL for 1 hr. PKC was inhibited by 100 nM Ro-31-8220 (Ro), and ETB mRNA expression was determined in equal amounts of RNA by RT-PCR and normalized to 18S rRNA expression. All samples exposed to lipoproteins were normalized to internal controls (con) incubated in parallel for the same period of time without or with the corresponding inhibitor concentration. Values are given as mean ± SEM in relative units; n ≥ 3; *P < 0.05.

 
Discussion

This is the first study showing that lipoproteins induce transcription and protein expression of the ETB receptor in human endothelial cells. We tested in detailed dose-response experiments the impact of native and oxidized LDL on ETB expression in endothelial cells. Our data suggest that a certain threshold of both lipoproteins is necessary before the mRNA expression of ETB is significantly induced. This could correspond to an initially limited number of LDL or oxLDL receptors on native endothelial cells, which have to be activated by their agonists, or a threshold of intracellular signaling to activate transcription factors to stimulate ETB mRNA expression. We recently analyzed the effect of native and oxidized LDL on endothelin-converting enzyme-1, preproendothelin-1 and endothelin-1 peptide release in endothelial cells. Comparing the effects of both lipoproteins on other components of the endothelin system, oxLDL had a stronger effect on induction of ppET-1 mRNA. However, even as oxLDL showed a nonsignificant trend to stimulate the release of ET-1 stronger than nLDL, both lipoproteins were finally equally potent in the induction of the endothelin system in human endothelial cells (19). nLDL and oxLDL showed similar potencies to induce ETB mRNA expression. However, nLDL induced ETB on the protein level much more strongly than did oxLDL. This augmented ETB protein level in response to nLDL might involve additional mechanisms on the posttranscriptional level, e.g., by increasing protein stability or inhibiting degradation. To our knowledge, no experimental data addressing this specific topic have been published so far. Differential effects of nLDL and oxLDL have been described in earlier studies. nLDL has been shown to induce genes like the angiotensin II type 1 receptor in vascular smooth muscle cells (20), whereas oxLDL had no such effect (21). In macrophages, nLDL and oxLDL differentially induce macrophage scavenger receptors and reduce macrophage lipoprotein lipase secretion and mRNA expression by mechanisms involving mRNA stability (22, 23). Recently, a regulation of the LDL receptor on the level of mRNA stability has been demonstrated involving the extracellular signal-regulated protein kinase (ERK) signaling pathway through interactions of cis-regulatory sequences of 3' UTR and mRNA binding proteins (24). Which of these mechanisms is involved in the observed differential regulation of the ETB receptor in our study will be the focus of future studies.

Only a few studies have described an upregulation of endothelial ETB so far. Our group has previously reported that laminar shear stress upregulates ETB mRNA by a PKC-dependent mechanism (16). The induction of ETB by oxLDL in this study seems to involve a PKC-dependent pathway as well. Furthermore, PKC was critically involved in the expression of ETB in organ culture of rat basilar arteries (25). PKC plays also a role in the endothelial release of ET-1 and the enhanced arterial myogenic tone in response to oxLDL, but not nLDL (26). Therefore, our findings further support a role of PKC in the activation of endothelin system in response to hypercholesterolemia (27).

In vascular smooth muscle cells, ETB was upregulated by nLDL and oxLDL as well (14). The clinical relevance of this finding is supported by enhanced vasoconstrictor response to ETB stimulation in patients with atherosclerosis suggesting an upregulation of vascular smooth muscle ETB receptors in atherosclerosis (28). Binding studies in vitro suggest that ETB receptors are upregulated in the tunica media of atherosclerotic human coronary arteries (29, 30). In patients with other risk factors for coronary heart disease such as hypertension (31) and in patients with atherosclerosis (32) dual ETA/ETB receptor blockade improved endothelium-dependent vasodilatation, suggesting increased bioavailability of nitric oxide when blocking both receptors.

The endothelial ETB receptor has been reported to mediate NO release (33) and ET-1–mediated survival of endothelial cells (34). Furthermore, ETB could serve as a clearance receptor of augmented circulating ET-1 serum concentration and locally increased vascular ET-1 immunoreactivity in coronary endothelial dysfunction and atherosclerosis (35–37). Therefore, the induction of ETB by lipoproteins, especially by nLDL, might be considered as a compensatory atheroprotective mechanism. This concept is further supported by the finding that chronic ETA antagonism even while leading to increased ET-1 plasma levels preserves coronary endothelial function and increases NO most probably by an ETB-mediated mechanism in hypercholesterolemia (38).

In conclusion, our data demonstrate that low-density lipoproteins even independent of oxidative modification are potent inducers of ETB receptors at the mRNA and protein level in HUVEC. Given the NO-releasing capacity of endothelial ETB receptors, this effect may represent a possible vasoprotective mechanism.

Footnotes

This study was supported by the Doktor Robert Pfleger-Stiftung Bamberg, Deutsche Forschungsgemeinschaft (SFB/TR2 C1: MO 839/S1-1), the Wilhelm Roux Program of the Medical Faculty of the Martin Luther University Halle-Wittenberg (FKZ: 1/25), the German Federal Ministry of Education and Research (BMBF) program NBL3 of the University of Technology Dresden, Professorship of Vascular Endothelium and Microcirculation (all to H.M.); and the Swiss National Foundation (SCORE 32.58421.99, 32-58426.99/I and 32-108258) and the Hanne-Liebermann-Stiftung (all to M.B.).

Received for publication September 13, 2005. Accepted for publication November 10, 2005.

References

  1. Pearson TA. The epidemiologic basis for population-wide cholesterol reduction in the primary prevention of coronary artery disease. Am J Cardiol 94:4F–8F, 2004.[Medline]
  2. Nordestgaard BG, Tybjaerg-Hansen A, Lewis B. Influx in vivo of low density, intermediate density, and very low density lipoproteins into aortic intimas of genetically hyperlipidemic rabbits. Roles of plasma concentrations, extent of aortic lesion, and lipoprotein particle size as determinants. Arterioscler Thromb 12:6–18, 1992.[Abstract/Free Full Text]
  3. Abrams J. Clinical practice. Chronic stable angina. N Engl J Med 352: 2524–2533, 2005.[Free Full Text]
  4. Steinberg D. Oxidative modification of LDL and atherogenesis. Circulation 95:1062–1071, 1997.[Free Full Text]
  5. Barton M, Traupe T, Haudenschild CC. Endothelin, hypercholesterolemia and atherosclerosis. Coron Artery Dis 14:477–490, 2003.[Medline]
  6. Masaki T. Historical review: endothelin. Trends Pharmacol Sci 25:219–224, 2004.[Medline]
  7. Takigawa M, Sakurai T, Kasuya Y, Abe Y, Masaki T, Goto K. Molecular identification of guanine-nucleotide-binding regulatory proteins which couple to endothelin receptors. Eur J Biochem 228: 102–108, 1995.[Medline]
  8. Ogawa Y, Nakao K, Arai H, Nakagawa O, Hosoda K, Suga S, Nakanishi S, Imura H. Molecular cloning of a non-isopeptide-selective human endothelin receptor. Biochem Biophys Res Commun 178:248–255, 1991.[Medline]
  9. Heinroth-Hoffmann I, Vogelsang M, Schiewe P, Morawietz H, Holtz J, Ponicke K, Brodde OE. Mechanism of ETA-receptor stimulation-induced increases in intracellular Ca2+ in SK-N-MC cells. Br J Pharmacol 125:1202–1211, 1998.[Medline]
  10. Rossi GP, Colonna S, Pavan E, Albertin G, Della Rocca F, Gerosa G, Casarotto D, Sartore S, Pauletto P, Pessina AC. Endothelin-1 and its mRNA in the wall layers of human arteries ex vivo. Circulation 99: 1147–1155, 1999.[Abstract/Free Full Text]
  11. Cardillo C, Kilcoyne CM, Cannon RO, 3rd, Panza JA. Increased activity of endogenous endothelin in patients with hypercholesterolemia. J Am Coll Cardiol 36:1483–1488, 2000.[Abstract/Free Full Text]
  12. Boulanger CM, Tanner FC, Bea ML, Hahn AW, Werner A, Luscher TF. Oxidized low density lipoproteins induce mRNA expression and release of endothelin from human and porcine endothelium. Circ Res 70:1191–1197, 1992.[Abstract/Free Full Text]
  13. Horio T, Kohno M, Yasunari K, Murakawa K, Yokokawa K, Ikeda M, Fukui T, Takeda T. Stimulation of endothelin-1 release by low density and very low density lipoproteins in cultured human endothelial cells. Atherosclerosis 101:185–190, 1993.[Medline]
  14. Haug C, Schmid-Kotsas A, Zorn U, Schuett S, Gross HJ, Gruenert A, Bachem MG. Endothelin-1 synthesis and endothelin B receptor expression in human coronary artery smooth muscle cells and monocyte-derived macrophages is up-regulated by low density lipoproteins. J Mol Cell Cardiol 33:1701–1712, 2001.[Medline]
  15. Locher R, Brandes RP, Vetter W, Barton M. Native LDL induces proliferation of human vascular smooth muscle cells via redox-mediated activation of ERK 1/2 mitogen-activated protein kinases. Hypertension 39:645–650, 2002.[Abstract/Free Full Text]
  16. Morawietz H, Talanow R, Szibor M, Rueckschloss U, Schubert A, Bartling B, Darmer D, Holtz J. Regulation of the endothelin system by shear stress in human endothelial cells. J Physiol (Lond) 525:761–770, 2000.[Abstract/Free Full Text]
  17. Wendel M, Petzold A, Koslowski R, Kasper M, Augstein A, Knels L, Bleyl JU, Koch T. Localization of endothelin receptors in bleomycin-induced pulmonary fibrosis in the rat. Histochem Cell Biol 122:507–517, 2004.[Medline]
  18. Cramer H, Muller-Esterl W, Schroeder C. Subtype-specific desensitization of human endothelin ETA and ETB receptors reflects differential receptor phosphorylation. Biochemistry 36:13325–13332, 1997.[Medline]
  19. Niemann B, Rohrbach S, Catar RA, Muller G, Barton M, Morawietz H. Native and oxidized low-density lipoproteins stimulate endothelin-converting enzyme-1 expression in human endothelial cells. Biochem Biophys Res Commun 334:747–753, 2005.[Medline]
  20. Nickenig G, Sachinidis A, Michaelsen F, Bohm M, Seewald S, Vetter H. Upregulation of vascular angiotensin II receptor gene expression by low-density lipoprotein in vascular smooth muscle cells. Circulation 95: 473–478, 1997.[Abstract/Free Full Text]
  21. Nickenig G, Sachinidis A, Seewald S, Bohm M, Vetter H. Influence of oxidized low-density lipoprotein on vascular angiotensin II receptor expression. J Hypertens (Suppl) 15:S27–S30, 1997.[Medline]
  22. Han J, Nicholson AC. Lipoproteins modulate expression of the macrophage scavenger receptor. Am J Pathol 152:1647–1654, 1998.[Abstract]
  23. Stengel D, Antonucci M, Gaoua W, Dachet C, Lesnik P, Hourton D, Ninio E, Chapman MJ, Griglio S. Inhibition of LPL expression in human monocyte-derived macrophages is dependent on LDL oxidation state: a key role for lysophosphatidylcholine. Arterioscler Thromb Vasc Biol 18:1172–1180, 1998.[Abstract/Free Full Text]
  24. Abidi P, Zhou Y, Jiang JD, Liu J. Extracellular signal-regulated kinase-dependent stabilization of hepatic low-density lipoprotein receptor mRNA by herbal medicine berberine. Arterioscler Thromb Vasc Biol 25:2170–2176, 2005.[Abstract/Free Full Text]
  25. Hansen-Schwartz J, Svensson CL, Xu CB, Edvinsson L. Protein kinase mediated upregulation of endothelin A, endothelin B and 5-hydroxy-tryptamine 1B/1D receptors during organ culture in rat basilar artery. Br J Pharmacol 137:118–126, 2002.[Medline]
  26. Xie H, Bevan JA. Oxidized low-density lipoprotein enhances myogenic tone in the rabbit posterior cerebral artery through the release of endothelin-1. Stroke 30:2423–2429, 1999.[Abstract/Free Full Text]
  27. Rask-Madsen C, King GL. Proatherosclerotic mechanisms involving protein kinase C in diabetes and insulin resistance. Arterioscler Thromb Vasc Biol 25:487–496, 2005.[Abstract/Free Full Text]
  28. Pernow J, Bohm F, Johansson BL, Hedin U, Ryden L. Enhanced vasoconstrictor response to endothelin-B-receptor stimulation in patients with atherosclerosis. J Cardiovasc Pharmacol 36:S418–S420, 2000.[Medline]
  29. Iwasa S, Fan J, Shimokama T, Nagata M, Watanabe T. Increased immunoreactivity of endothelin-1 and endothelin B receptor in human atherosclerotic lesions. A possible role in atherogenesis. Atherosclerosis 146:93–100, 1999.[Medline]
  30. Dagassan PH, Breu V, Clozel M, Kunzli A, Vogt P, Turina M, Kiowski W, Clozel JP. Up-regulation of endothelin-B receptors in atherosclerotic human coronary arteries. J Cardiovasc Pharmacol 27:147–153, 1996.[Medline]
  31. Cardillo C, Campia U, Bryant MB, Panza JA. Increased activity of endogenous endothelin in patients with type II diabetes mellitus. Circulation 106:1783–1787, 2002.[Abstract/Free Full Text]
  32. Bohm F, Beltran E, Pernow J. Endothelin receptor blockade improves endothelial function in atherosclerotic patients on angiotensin converting enzyme inhibition. J Intern Med 257:263–271, 2005.[Medline]
  33. Boulanger C, Luscher TF. Release of endothelin from the porcine aorta. Inhibition by endothelium-derived nitric oxide. J Clin Invest 85:587–590, 1990.[Medline]
  34. Shichiri M, Kato H, Marumo F, Hirata Y. Endothelin-1 as an autocrine/paracrine apoptosis survival factor for endothelial cells. Hypertension 30:1198–1203, 1997.[Abstract/Free Full Text]
  35. Lerman A, Edwards BS, Hallett JW, Heublein DM, Sandberg SM, Burnett JC, Jr. Circulating and tissue endothelin immunoreactivity in advanced atherosclerosis. N Engl J Med 325:997–1001, 1991.[Abstract]
  36. Lerman A, Holmes DR, Jr., Bell MR, Garratt KN, Nishimura RA, Burnett JC, Jr. Endothelin in coronary endothelial dysfunction and early atherosclerosis in humans. Circulation 92:2426–2431, 1995.[Abstract/Free Full Text]
  37. Barton M, Haudenschild CC, d’Uscio LV, Shaw S, Munter K, Luscher TF. Endothelin ETA receptor blockade restores NO-mediated endothelial function and inhibits atherosclerosis in apolipoprotein E-deficient mice. Proc Natl Acad Sci U S A 95:14367–14372, 1998.[Abstract/Free Full Text]
  38. Best PJ, Lerman LO, Romero JC, Richardson D, Holmes DR, Jr., Lerman A. Coronary endothelial function is preserved with chronic endothelin receptor antagonism in experimental hypercholesterolemia in vitro. Arterioscler Thromb Vasc Biol 19:2769–2775, 1999.[Abstract/Free Full Text]




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