Source Paper
Role of the T cell in the genesis of angiotensin II–induced hypertension and vascular dysfunction
Tomasz J. Guzik, Nyssa E. Hoch, Kathryn A. Brown, Louise A. McCann, Ayaz Rahman et al.
The Journal of Experimental Medicine • 2007
Source Paper
Tomasz J. Guzik, Nyssa E. Hoch, Kathryn A. Brown, Louise A. McCann, Ayaz Rahman et al.
The Journal of Experimental Medicine • 2007
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) α, and treatment with the TNFα 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.
Objective: Induction of hypertension using DOCA-salt treatment and assessment of hypertension-related outcomes 40 days after induction
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eBioscience • Clone R4-6A2 • Not specified • Not specified
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Obtain C57BL/6, RAG-1 -/-, and AT1a -/- mice from Jackson ImmunoResearch Laboratories and p47 phox -/- mice from Taconic. Maintain all mice in sterile environment and regularly screen for infections.
Note: All mice on C57BL/6 background. Protocols approved by institutional Animal Care and Use Committee at Emory University.
“C57BL/6, RAG-1 -/-, and AT1a -/- mice were obtained from Jackson ImmunoResearch Laboratories. The p47 phox -/- mice and their appropriate controls were obtained from Taconic. Animals were maintained in a sterile environment and were regularly screened for infections.”
Anesthetize mice with xylazine/ketamine and inject cells via tail vein for adoptive transfer experiments.
Note: This step is only for experiments involving adoptive transfer
“For adoptive transfer, mice were anesthetized with xylazine/ketamine and cells were injected via tail vein.”
Allow 3 weeks to elapse after adoptive cell transfer before beginning angiotensin II infusion and blood pressure monitoring.
Note: This step only applies to adoptive transfer experiments
“Angiotensin II infusion and blood pressure monitoring was begun 3 wk after adoptive transfer.”
Administer etanercept (8 mg/kg) or neutralizing IFN-gamma antibody (0.5 mg per injection per 30g mouse) intraperitoneally 3 days before angiotensin II infusion begins.
Note: This step is only for experiments testing TNF-alpha or IFN-gamma inhibition
“8 mg/kg etanercept (AmGen) or a neutralizing IFN-gamma antibody (eBioscience; clone R4-6A2; 0.5 mg per injection per 30 g mouse) was administered i.p. 3 d before and every 3 d during angiotensin II infusion.”
Start continuous infusion of angiotensin II at 490 ng/min/kg. Measure blood pressure both invasively and noninvasively throughout infusion period.
Note: Blood pressure measured by both invasive and noninvasive methods
“490 ng/min/kg angiotensin II was infused and blood pressure was measured both invasively and noninvasively”
Continue administering etanercept or neutralizing IFN-gamma antibody intraperitoneally every 3 days during the angiotensin II infusion period.
Note: This step is only for experiments testing TNF-alpha or IFN-gamma inhibition
“8 mg/kg etanercept (AmGen) or a neutralizing IFN-gamma antibody (eBioscience; clone R4-6A2; 0.5 mg per injection per 30 g mouse) was administered i.p. 3 d before and every 3 d during angiotensin II infusion.”
Create DOCA-salt hypertension in mice using previously described methods.
Note: Specific protocol details referenced as previously described
“DOCA-salt hypertension was created as previously described”
Allow 40 days to elapse after DOCA-salt hypertension induction before performing experimental studies.
Note: This is the critical timepoint for this specific experiment
“studies were performed after 40 d from the induction of hypertension”
C57BL/6 background for all strains. Some mice obtained from Jackson ImmunoResearch Laboratories, p47 phox -/- and controls from Taconic. Animals maintained in sterile environment and regularly screened for infections.
Evidence-Based
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