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. 2011 Jan;178(1):434-41.
doi: 10.1016/j.ajpath.2010.11.034. Epub 2010 Dec 23.

Natural regulatory T cells control coronary arteriolar endothelial dysfunction in hypertensive mice

Khalid Matrougui  1 , Zakaria Abd Elmageed, Modar Kassan, Sookyoung Choi, Devika Nair, Romer A Gonzalez-Villalobos, Aziz A Chentoufi, Philip Kadowitz, Souad Belmadani, Megan Partyka
Affiliations

Natural regulatory T cells control coronary arteriolar endothelial dysfunction in hypertensive mice

Khalid Matrougui et al. Am J Pathol. 2011 Jan.

Erratum in

  • Am J Pathol. 2011 Mar;178(3):1406. Zakaria, Abd Elmageed [corrected to Abd Elmageed, Zakaria]

Abstract

Coronary artery disease in patients with hypertension is increasing worldwide and leads to severe cardiovascular complications. The cellular and molecular mechanisms that underlie this pathologic condition are not well understood. Experimental and clinical research indicates that immune cells and inflammation play a central role in the pathogenesis of cardiovascular diseases. Recently, it has been reported that CD4(+)CD25(+) regulatory T cells (Tregs) regulate heart fibrosis in hypertension. In this study, we determined the role of Tregs in coronary arteriolar endothelial dysfunction in angiotensin II-dependent hypertensive mice. Mice infused with angiotensin II had significantly increased blood pressure, as determined using telemetry, and apoptotic Treg numbers, as measured using flow cytometry. The mice displayed inflammation, assessed by macrophage activation/infiltration into coronary arterioles and the heart, and increased local tumor necrosis factor-α release, which participates in reduced coronary arteriolar endothelial-dependent relaxation in response to acetylcholine using an arteriograph. Hypertensive mice injected with Tregs isolated from control mice had significantly reduced macrophage activation and infiltration, reduced tumor necrosis factor-α release, and improved coronary arteriolar endothelium-dependent relaxation. Our novel data indicate that Tregs are important in the development of coronary arteriolar endothelial dysfunction in hypertension. These results suggest a new direction in the investigation of vascular disease in hypertension and could lead to a therapeutic strategy that involves immune system modulation using Tregs.

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Figures

Figure 1
Figure 1
Effect of long-term Ang II (400 ng/kg/min) infusion with or without Tregs (200,000 cells) on mean arterial blood pressure as determined by means of telemetry. *P < 0.05, sham versus HT mice; †P < 0.05, sham versus HT + Tregs mice.
Figure 2
Figure 2
A:In vivo number of Tregs in sham, HT, and HT + Tregs mice as determined using FACS analysis (n = 5). *P < 0.05, sham versus HT or HT + Tregs mice. B:In vitro apoptotic Tregs as determined by means of FACS analysis. Isolated, purified, and cultured Tregs from sham mice were then stimulated with Ang II for 24 hours with or without candesartan (Cand; 10 μmol/L) (n = 6). *P < 0.05, Ang II versus CTR or Ang II + Cand. C:In vitro terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay and cumulative data indicating apoptotic Tregs under CTR, Ang II, or Cand (10 μmol/L) conditions. *P < 0.05, Ang II versus CTR or Ang II + Cand. D, E: Illustrates in vivo Foxp3 staining, and cumulative data, in green with DAPI nuclear counterstaining in blue of the spleen from sham, HT, and HT + Tregs mice (n = 5); negative control represents staining using only secondary antibody (n = 3). CTR, control.
Figure 3
Figure 3
A: Western blot analysis and cumulative data of the ratio of Foxp3 to active caspase-3 expression in spleens from sham, HT, and HT + Tregs mice. β-Actin indicates the equal loading between samples (n = 6). *P < 0.05, HT versus sham or HT + Tregs mice. B: IL-10 measurement in the plasma from sham, HT, and HT + Tregs mice (n = 6). *P < 0.05, HT versus sham or HT + Tregs mice. C, D: Western blot analysis and quantitative data of ICAM-1 and VCAM-1 in coronary arterioles from sham, HT, and HT + Tregs mice. β-Actin indicates the equal loading between samples (n = 6). *P < 0.05, HT versus sham or HT + Tregs mice.
Figure 4
Figure 4
A: Western blot analysis and cumulative data of ICAM-1 in macrophages from sham, HT, and HT + Tregs mice. β-Actin indicates the equal loading between samples (n = 6). *P < 0.05, HT versus sham or HT + Tregs mice. B: Western blot analysis and quantitative data of VCAM-1 in macrophages from sham, HT, and HT + Tregs mice. β-Actin indicates the equal loading between samples (n = 5). *P < 0.05, HT versus sham or HT + Tregs mice. C: Staining showing macrophage (using CD68 antibody) infiltration into coronary arterioles and the heart in sham, HT, and HT + Tregs mice. All red points are macrophage infiltration. D: Western blot analysis and cumulative data of TNF-α in the heart from sham, HT, and HT + Tregs mice. β-Actin indicates the equal loading between samples (n = 6). *P < 0.05, HT versus sham or HT + Tregs mice. E: Western blot analysis and cumulative data indicating the expression of the chemokine receptor CCR5 in coronary arterioles from sham, HT, and HT + Tregs mice. β-Actin indicates the equal loading between samples (n = 4). *P < 0.05, HT versus sham or HT + Tregs mice.
Figure 5
Figure 5
A: Changes in diameter in response to dose response (10−10 to 10−5 mol/L) of acetylcholine in coronary arterioles from sham mice with or without L-NAME (100 μmol/L) (n = 6). *P < 0.05, sham versus sham + L-NAME mice. B: Changes in diameter in response to dose response (10−10 to 10−5 mol/L) of acetylcholine in coronary arterioles from sham, HT, and HT + L-NAME mice (n = 6). *P < 0.05, sham versus HT mice. C: Changes in diameter in response to dose response (10−10 to 10−5 mol/L) of acetylcholine in coronary arterioles from sham, HT, and HT + Tregs mice (n = 6). *P < 0.05, sham versus HT + Tregs mice; *P < 0.05, HT + Tregs versus HT mice. D: Endothelium-dependent relaxation of coronary arterioles from sham mice with or without L-NAME injected with Tregs (n = 6). *P < 0.05, sham/sham + Tregs versus sham + L-NAME or sham + Tregs + L-NAME mice. E: Endothelium-dependent relaxation of coronary arterioles from HT mice with or without L-NAME injected with CD4− T cells (n = 7). F: Western blot analysis and cumulative data of phosphorylated and total eNOS in coronary arterioles from sham, HT, and HT + Tregs mice. β-Actin indicates the equal loading between samples (n = 5). *P < 0.05, HT mice versus sham or HT + Tregs mice.
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References

    1. Matrougui K., Maclouf J., Levy B.I., Henrion D. Impaired nitric oxide- and prostaglandin-mediated responses to flow in resistance arteries of hypertensive rats. Hypertension. 1997;30:942–947. - PubMed
    1. Matrougui K., Loufrani L., Levy B.I., Henrion D. High NaCl intake decreases both flow-induced dilation and pressure-induced myogenic tone in resistance arteries from normotensive rats: involvement of cyclooxygenase-2. Pharmacol Toxicol. 2001;89:183–187. - PubMed
    1. Matrougui K., Levy B.I., Schiavi P., Guez D., Henrion D. Indapamide improves flow-induced dilation in hypertensive rats with a high salt intake. J Hypertens. 1998;16:1485–1490. - PubMed
    1. Suzuki H., DeLano F.A., Parks D.A., Jamshidi N., Granger D.N., Ishii H., Suematsu M., Zweifach B.W., Schmid-Schonbein G.W. Xanthine oxidase activity associated with arterial blood pressure in spontaneously hypertensive rats. Proc Natl Acad Sci U S A. 1998;95:4754–4759. - PMC - PubMed
    1. Lominadze D., Joshua I.G., Schuschke D.A. Blood flow shear rates in arterioles of spontaneously hypertensive rats at early and established stages of hypertension. Clin Exp Hypertens. 2001;23:317–328. - PubMed

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