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Non-anticoagulant Heparin Increases Endothelial Nitric Oxide Synthase Activity: Role of Inhibitory Guanine Nucleotide Proteins

Non-anticoagulant Heparin Increases Endothelial Nitric Oxide Synthase Activity: Role of Inhibitory Guanine Nucleotide Proteins

P C Kouretas, R L Hannan, N K Kapur, R Hendrickson, E M Redmond, A K Myers, Y D Kim, P A Cahill, J V Sitzmann

J Mol Cell Cardiol. 1998 Dec;30(12):2669-82.

PMID: 9990538

Abstract:

Heparin, which is widely used clinically, has recently been shown to have specific properties affecting the vascular endothelium. We hypothesized that heparin stimulates endothelial nitric oxide synthase (eNOS) activity by a mechanism independent of its anticoagulant properties and dependent on an inhibitory guanine nucleotide regulatory protein (Gi). We determined the effect of both heparin and N-acetyl heparin (Non-Hep), a heparin derivative without anticoagulant properties, on eNOS activity in cultured bovine aortic endothelial cells and on endothelium-dependent relaxation in isolated vascular rings. The eNOS activity was determined by measuring both citrulline and nitric oxide (NO) metabolite formation. Heparin and Non-Hep dose-dependently increased basal eNOS activity (ED50 1.0 microgram/ml or 0.15 U/ml), an effect that was significantly inhibited by pertussis toxin (100 ng/ml), a Gi-protein inhibitor. Agonist-stimulated (acetylcholine, 10 microM) eNOS activity was potentiated following pre-treatment with both heparin and Non-Hep and reversed by pertussis toxin. Heparin and Non-Hep induced a dose-dependent relaxation in preconstricted thoracic aortic rings, an effect that was significantly inhibited by pertussis toxin, endothelial inactivation (following treatment with sodium deoxycholate) and NG-nitro-L-arginine-methyl ester (L-NAME). We conclude that heparin and non-anticoagulant heparin induce endothelium-dependent relaxation following activation of eNOS by a mechanism involving a Gi-protein. Administration of heparin derivatives without anticoagulant properties may have therapeutic implications for the preservation of eNOS in conditions characterized by endothelial dysfunction.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
LS741341	N-Acetylheparin sodium salt			Price

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