title: T regulatory lymphocytes prevent aldosterone-induced vascular injury.
abstract: Aldosterone mediates actions of the renin-angiotensin-aldosterone system inducing hypertension, oxidative stress, and vascular inflammation. Recently, we showed that angiotensin II-induced hypertension and vascular damage are mediated at least in part by macrophages and T-helper effector lymphocytes. Adoptive transfer of suppressor T-regulatory lymphocytes (Tregs) prevented angiotensin II action. We hypothesized that Treg adoptive transfer would blunt aldosterone-induced hypertension and vascular damage. Thirteen to 15-week-old male C57BL/6 mice were injected intravenously at 1-week intervals with 3×10(5) CD4(+)CD25(+) cells (representing Treg) or control CD4(+)CD25(-) cells and then infused or not for 14 days with aldosterone (600 μg/kg per day, SC) while receiving 1% saline to drink. Aldosterone induced a small but sustained increase in blood pressure (P<0.001), decreased vasodilatory responses to acetylcholine by 66% (P<0.001), increased both media:lumen ratio (P<0.001) and media cross-sectional area of resistance arteries by 60% (P<0.05), and increased NADPH oxidase activity 2-fold in aorta (P<0.001), kidney and heart (P<0.05), and aortic superoxide production. As well, aldosterone enhanced aortic and renal cortex macrophage infiltration and aortic T-cell infiltration (all P<0.05), and tended to decrease Treg in the renal cortex. Treg adoptive transfer prevented all of the vascular and renal effects induced by aldosterone. Adoptive transfer of CD4(+)CD25(-) cells exacerbated aldosterone effects except endothelial dysfunction and increases in media:lumen ratio of resistance arteries. Thus, Tregs suppress aldosterone-mediated vascular injury, in part through effects on innate and adaptive immunity, suggesting that aldosterone-induced vascular damage could be prevented by an immunomodulatory approach.
authors.affiliation: Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, Montreal, Quebec, Canada.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Kasal
authors.forename: Tlili
authors.initials: T
authors.lastname: Barhoumi
authors.forename: Melissa W
authors.initials: MW
authors.lastname: Li
authors.forename: Naoki
authors.initials: N
authors.lastname: Yamamoto
authors.forename: Evguenia
authors.initials: E
authors.lastname: Zdanovich
authors.forename: Asia
authors.initials: A
authors.lastname: Rehman
authors.forename: Mario F
authors.initials: MF
authors.lastname: Neves
authors.forename: Pascal
authors.initials: P
authors.lastname: Laurant
authors.forename: Pierre
authors.initials: P
authors.lastname: Paradis
authors.forename: Ernesto L
authors.initials: EL
authors.lastname: Schiffrin
mesh_terms: D056704:Adaptive Immunity; D019264:Adoptive Transfer; D000450:Aldosterone / Q000009:adverse effects* / Q000494:pharmacology; D000818:Animals; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D006973:Hypertension / Q000139:chemically induced* / Q000517:prevention & control*; D007113:Immunity, Innate; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D019255:NADPH Oxidases / Q000378:metabolism; D012077:Renal Artery / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D013481:Superoxides / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000502:physiology*; D014657:Vasculitis / Q000139:chemically induced* / Q000517:prevention & control*
chemical_list: D013481:Superoxides; D000450:Aldosterone; D019255:NADPH Oxidases