Role of multidrug resistance protein-1 in hypertension and vascular dysfunction caused by angiotensin II

Julian D Widder, Tomasz J Guzik, Cornelius FH Mueller, Roza E Clempus, Harald Schmidt, Sergey I Dikalov, Kathy K Griendling, Dean P Jones, David G Harrison

Research output: Contribution to journalArticleResearchpeer-review

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). CONCLUSIONS: 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.
Original languageEnglish
Pages (from-to)762 - 768
Number of pages7
JournalArteriosclerosis, Thrombosis and Vascular Biology
Volume27
Issue number4
Publication statusPublished - 2007

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