Widder, J. D., Guzik, T. J., Mueller, C. F.H., Clempus, R. E., Schmidt, H. H.H.W., Dikalov, S. I., Griendling, K. K., Jones, D. P. and Harrison, D. G. (2007) Role of the multidrug resistance protein-1 in hypertension and vascular dysfunction caused by angiotensin II. Arteriosclerosis, Thrombosis, and Vascular Biology, 27(4), pp. 762-768. (doi: 10.1161/01.ATV.0000259298.11129.a2) (PMID:17272743)
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Abstract
Objective— Human endothelial cells use the multidrug resistance protein-1 (MRP1) to export glutathione disulfide (GSSG). This can promotes thiol loss during states of increased glutathione oxidation. We investigated how MRP1 modulates blood pressure and vascular function during angiotensin II-induced hypertension. Methods and Results— Angiotensin II–induced hypertension altered vascular glutathione flux by increasing GSSG export and decreasing vascular levels of glutathione in wild-type (FVB) but not in MRP1−/− mice. Aortic endothelium-dependent vasodilatation was reduced in FVB after angiotensin II infusion, but unchanged in MRP1−/− mice. Aortic superoxide (O2·−) production and expression of several NADPH oxidase subunits were increased by angiotensin II in FVB. These effects were markedly blunted in MRP1−/− vessels. The increase in O2·− production in FVB vessels caused by angiotensin II was largely inhibited by L-NAME, suggesting eNOS uncoupling. Accordingly, aortic tetrahydrobiopterin and levels of NO were decreased by angiotensin II in FVB but were unchanged in MRP1−/−. Finally, the hypertension caused by angiotensin II was markedly blunted in MRP1−/− mice (137±4 versus 158±6 mm Hg). Conclusion— MRP1 plays a crucial role in the genesis of multiple vascular abnormalities that accompany hypertension and its presence is essential for the hypertensive response to angiotensin II.
Item Type: | Articles |
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Status: | Published |
Refereed: | Yes |
Glasgow Author(s) Enlighten ID: | Harrison, Professor David and Guzik, Professor Tomasz |
Authors: | Widder, J. D., Guzik, T. J., Mueller, C. F.H., Clempus, R. E., Schmidt, H. H.H.W., Dikalov, S. I., Griendling, K. K., Jones, D. P., and Harrison, D. G. |
College/School: | College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health |
Journal Name: | Arteriosclerosis, Thrombosis, and Vascular Biology |
Publisher: | American Heart Association |
ISSN: | 1079-5642 |
ISSN (Online): | 1524-4636 |
Published Online: | 01 February 2007 |
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