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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:762.)
© 2007 American Heart Association, Inc.

Vascular Biology

Role of the Multidrug Resistance Protein-1 in Hypertension and Vascular Dysfunction Caused by Angiotensin II

Julian D. Widder; Tomasz J. Guzik; Cornelius F.H. Mueller; Roza E. Clempus; Harald H.H.W. Schmidt; Sergey I. Dikalov; Kathy K. Griendling; Dean P. Jones; David G. Harrison

From the Emory University Division of Cardiology, Department of Medicine and the Atlanta Veterans Administration Hospital (J.D.W., T.J.G., C.F.H.M., R.E.C., S.I.D., K.K.G., D.P.J., D.G.H.), Ga; and Monash University, Department of Pharmacology & Centre for Vascular Health (H.H.H.W.S.), Melbourne, Australia.

Correspondence to David G. Harrison, Division of Cardiology, Emory University, 101 Woodruff Circle, WMBR 319, Atlanta, GA 30322. E-mail dharr02{at}emory.edu

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.

This study demonstrates that glutathione loss via the multidrug resistance protein 1 (MRP1) modulates many aspects of vascular function during chronic angiotensin II infusion, including vascular glutathione levels, NO production, and endothelium-dependent vasodilatation, superoxide production, and tetrahydrobiopterin levels. The hypertension caused by angiotensin II was significantly blunted in MRP1^–/– mice, suggesting that MRP1 could be a target for treatment of vascular oxidative stress and hypertension.

Key Words: endothelial function • glutathione • hypertension • MRP1 • oxidative stress

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