The Journal of Experimental Medicine
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Published online September 17, 2007
doi:10.1084/jem.20070657
The Journal of Experimental Medicine, Vol. 204, No. 10, 2449-2460
The Rockefeller University Press, 0022-1007 $30.00
© 2007 Guzik et al.
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ARTICLE

 Role of the T cell in the genesis of angiotensin II–induced hypertension and vascular dysfunction

Tomasz J. Guzik1,2, Nyssa E. Hoch1,2, Kathryn A. Brown1,2, Louise A. McCann1,2, Ayaz Rahman1,2, Sergey Dikalov1,2, Jorg Goronzy1,2, Cornelia Weyand1,2, and David G. Harrison1,2,3

1 Division of Cardiology and 2 Lowance Center for Human Immunology, Department of Medicine, Emory University School of Medicine, Atlanta, GA 30033
3 Atlanta Veteran Administration Hospital, Atlanta, GA 30033

CORRESPONDENCE David G Harrison: dharr02{at}emory.edu

Hypertension promotes atherosclerosis and is a major source of morbidity and mortality. We show that mice lacking T and B cells (RAG-1–/– mice) have blunted hypertension and do not develop abnormalities of vascular function during angiotensin II infusion or desoxycorticosterone acetate (DOCA)–salt. Adoptive transfer of T, but not B, cells restored these abnormalities. Angiotensin II is known to stimulate reactive oxygen species production via the nicotinamide adenosine dinucleotide phosphate (NADPH) oxidase in several cells, including some immune cells. Accordingly, adoptive transfer of T cells lacking the angiotensin type I receptor or a functional NADPH oxidase resulted in blunted angiotensin II–dependent hypertension and decreased aortic superoxide production. Angiotensin II increased T cell markers of activation and tissue homing in wild-type, but not NADPH oxidase–deficient, mice. Angiotensin II markedly increased T cells in the perivascular adipose tissue (periadventitial fat) and, to a lesser extent the adventitia. These cells expressed high levels of CC chemokine receptor 5 and were commonly double negative (CD3+CD4–CD8–). This infiltration was associated with an increase in intercellular adhesion molecule-1 and RANTES in the aorta. Hypertension also increased T lymphocyte production of tumor necrosis factor (TNF) {alpha}, and treatment with the TNF{alpha} antagonist etanercept prevented the hypertension and increase in vascular superoxide caused by angiotensin II. These studies identify a previously undefined role for T cells in the genesis of hypertension and support a role of inflammation in the basis of this prevalent disease. T cells might represent a novel therapeutic target for the treatment of high blood pressure.

Abbreviations used: CCR, CC chemokine receptor; DN, double-negative; DOCA, desoxycorticosterone acetate; ICAM, intercellular adhesion molecule; NADPH, nicotinamide adenosine dinucleotide phosphate; NO, nitric oxide; RAG, recombinase-activating gene; ROS, reactive oxygen species.


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