Heparin regulates endothelin production through endothelium-derived nitric oxide in human endothelial cells.

Yokokawa, Koji; Tahara, Hideki; Kohno, Masakazu; Mandal, Anil K.; Yanagisawa, Isao; Takeda, Tadanao

doi:10.1172/jci116805

Cited by 95 publications

(40 citation statements)

References 32 publications

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“…Stimulation of HUVECs with ACh in the present study significantly increased cGMP to levels consistent with previous reports. 46 Reoxygenation of hypoxic HUVECs in human sera significantly decreased ACh-induced increases in cGMP. Inhibition of C5b-9 formation with h5G1.1-scFv significantly attenuated cGMP loss.…”

Section: Discussionmentioning

confidence: 99%

Endothelial Nuclear Factor-κB Translocation and Vascular Cell Adhesion Molecule-1 Induction by Complement

Collard¹,

Agah²,

Reenstra³

et al. 1999

ATVB

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Abstract-We have previously shown that reoxygenation of hypoxic human umbilical vein endothelial cells (HUVECs) leads to the activation and deposition of complement. In the present study, we investigated whether the terminal complement complex (C5b-9) influences HUVEC nuclear factor-B (NF-B) translocation and vascular cell adhesion molecule-1 (VCAM-1) protein expression after hypoxia/reoxygenation by decreasing endothelial cGMP. Additionally, we investigated the action of anti-human C5 therapy on endothelial cGMP, NF-B translocation, and VCAM-1 protein expression. Reoxygenation (0.5 to 3 hours, 21% O 2 ) of hypoxic (12 hours, 1% O 2 ) HUVECs in human serum (HS) significantly increased C5b-9 deposition, VCAM-1 expression, and NF-B translocation compared with hypoxic/reoxygenated HUVECs treated with the recombinant human C5 inhibitor h5G1.1-scFv. Acetylcholine (ACh)-induced cGMP synthesis was significantly higher in normoxic HUVECs compared with hypoxic HUVECs reoxygenated in HS but did not differ from hypoxic HUVECs reoxygenated in buffer or HS treated with h5G1.1-scFv. Treatment of hypoxic/reoxygenated HUVECs with h5G1.1-scFv or cGMP analogues significantly attenuated NF-B translocation and VCAM-1 protein expression. Treatment with NO analogues, but not a cAMP analogue, cGMP antagonists, or an NO antagonist, also significantly attenuated VCAM-1 expression. We conclude that (1) C5b-9 deposition, NF-B translocation, and VCAM-1 protein expression are increased in hypoxic HUVECs reoxygenated in HS; (2) reoxygenation of hypoxic HUVECs in HS, but not buffer alone, attenuates ACh-induced cGMP synthesis; and (3) Key Words: adhesion molecules Ⅲ hypoxia Ⅲ inflammation Ⅲ nitric oxide Ⅲ immunotherapy I ncreasing evidence suggests that the terminal complement complex (C5b-9) plays an integral role in the pathogenesis of atherosclerosis 1-5 and vascular injury after ischemiareperfusion, cardiopulmonary bypass, and acute myocardial infarction. 6 -11 In addition to amplifying the local inflammatory response by inducing endothelial interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1) secretion, 12 C5b-9 also influences endothelial vascular tone [13][14][15] 16 ). Yet the mechanisms by which C5b-9 influences endothelium-dependent relaxation and leukocyte adhesion molecule expression have not been fully elucidated.Vascular tone and leukocyte adhesion molecule expression can be regulated by NO. 18,19 NO synthesized by the vascular endothelium induces vasodilation by activation of soluble guanylate cyclase and the subsequent increase of cGMP. 20 In addition to being a potent smooth muscle relaxant, NO inhibits platelet aggregation 21 and suppresses endothelial neutrophil adhesion molecule expression. 19 Adhesion molecules regulated by NO include P-selectin, 22 VCAM-1, 23 and ICAM-1. 24 Specifically, increased levels of NO are associated with decreased leukocyte adhesion molecule expression. [23][24][25][26] The mechanisms by which NO modulates expression of these adherence molecules is unclear but have been specul...

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Section: Discussionmentioning

confidence: 99%

Endothelial Nuclear Factor-κB Translocation and Vascular Cell Adhesion Molecule-1 Induction by Complement

Collard¹,

Agah²,

Reenstra³

et al. 1999

ATVB

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“…We gave heparin to our patients before beginning coronary catheterization; this drug can interact with mediators of the vascular endothelium, ie, ET, and decreases plasma ET-1 levels, 30 possibly by a nitric oxide-mediated mechanism. 31 However, because of the experimental protocol, it was not possible to do the study without heparinization of the patients. Because the study was placebo-controlled and all patients received the same amount of heparin, this effect is not likely to influence the results.…”

Section: Discussionmentioning

confidence: 99%

Hemodynamic and Coronary Effects of the Endothelin Antagonist Bosentan in Patients With Coronary Artery Disease

et al. 1998

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Background-Endothelin is a potent endothelium-derived vasoconstrictor peptide with proliferative properties. Elevated levels of the peptide occur in coronary artery disease; however, its pathophysiological role as a regulator of coronary tone and structure is uncertain. Endothelin-receptor antagonists are specific tools to clarify this issue and might be useful in the treatment of coronary artery disease. Methods and Results-In a double-blind, placebo-controlled randomized study, we investigated the effects of the ET A /ET B endothelin-receptor antagonist bosentan or placebo on systemic and coronary hemodynamics in 28 patients with angiographically documented stable coronary artery disease by quantitative coronary angiography and an intracoronary Doppler guidewire. Bosentan 200 mg IV decreased systolic blood pressure (PϽ0.05), whereas heart rate increased slightly (PϽ0.05). Coronary diameter increased, particularly in vessels with no or mild angiographic changes (PϽ0.01). Glycerol trinitrate did not further dilate these segments, whereas coronary diameter increased significantly after nitrate in the placebo group. The increase in coronary diameter after bosentan correlated inversely with plasma LDL-cholesterol levels (PϽ0.01) in both stenotic and angiographically normal coronary segments. Coronary flow velocity did not change. Bosentan was well tolerated. Conclusions-Endogenous endothelin exerts a vasoconstrictor tone in epicardial coronary arteries of patients with coronary artery disease, as evidenced by the vasodilation exerted by the combined ET A /ET B endothelin-receptor antagonist bosentan under acute conditions. Bosentan can safely be given to these patients. Hence, further long-term studies are necessary to determine the therapeutic potential of endothelin-receptor antagonists in patients with coronary artery disease. (Circulation. 1998;98:2235-2240.)

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“…62 The actions of LMWH improve endothelial function through mechanisms that are independent of its anticoagulant activity. 63 Heparin has also been shown to suppress endothelin-1 mRNA expression from human endothelial cells, while concurrently enhancing the production of NO 64 . Glomerular endothelial cells exposed to serum from women with PE demonstrate an increase in permeability and endothelin-1 mRNA expression; both the permeability of these cells and endothelin-1 expression were decreased in the presence of LMWH.…”

Section: Does Lmwh Improve Vascular Function?mentioning

confidence: 99%

Current Theories on the Prevention of Severe Preeclampsia With Low-Molecular Weight Heparin

et al. 2015

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Heparin regulates endothelin production through endothelium-derived nitric oxide in human endothelial cells.

Cited by 95 publications

References 32 publications

Endothelial Nuclear Factor-κB Translocation and Vascular Cell Adhesion Molecule-1 Induction by Complement

Endothelial Nuclear Factor-κB Translocation and Vascular Cell Adhesion Molecule-1 Induction by Complement

Hemodynamic and Coronary Effects of the Endothelin Antagonist Bosentan in Patients With Coronary Artery Disease

Current Theories on the Prevention of Severe Preeclampsia With Low-Molecular Weight Heparin

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