title: Aldosterone-induced oxidative stress and inflammation in the brain are mediated by the endothelial cell mineralocorticoid receptor.
abstract: Elevated aldosterone levels, which promote cerebral vascular oxidative stress, inflammation, and endothelial dysfunction, may increase stroke risk, independent of blood pressure and other risk factors. The main target receptor of aldosterone, the mineralocorticoid receptor (MR), is expressed in many cell types, including endothelial cells. Endothelial cell dysfunction is thought to be an initiating step contributing to cardiovascular disease and stroke; however the importance of MR expressed on endothelial cells in the brain is unknown. Here we have examined whether endothelial cell MR mediates cerebral vascular oxidative stress and brain inflammation during aldosterone excess. In male mice, aldosterone (0.72 mg/kg/day, 14 days) caused a small increase (~14 mmHg) in blood pressure. The MR blocker spironolactone (25 mg/kg/d, ip) abolished this increase, whereas endothelial cell MR-deficiency had no effect. Aldosterone increased superoxide production capacity in cerebral arteries, and also mRNA expression of the pro-inflammatory cytokines chemokine (C-C motif) ligand 7 (CCL7), CCL8 and interleukin (IL)-1β in the brain. These increases were prevented by both spironolactone treatment and endothelial cell MR-deficiency; whereas IL-1β expression was blocked by spironolactone only. Endothelial cell MR mediates aldosterone-induced increases in cerebrovascular superoxide levels and chemokine expression in the brain, but not blood pressure or brain IL-1β. Endothelial cell-targeted MR antagonism may represent a novel approach to treat cerebrovascular disease and stroke, particularly during conditions of aldosterone excess.
authors.affiliation: Vascular Biology and Immunopharmacology Group, Department of Pharmacology, Building 13E, Monash University, Wellington Rd, Clayton, Victoria 3800, Australia.
authors.forename: Quynh N
authors.initials: QN
authors.lastname: Dinh
authors.affiliation: Hudson Institute of Medical Research, Clayton, Victoria, Australia.
authors.forename: Morag J
authors.initials: MJ
authors.lastname: Young
authors.affiliation: Vascular Biology and Immunopharmacology Group, Department of Pharmacology, Building 13E, Monash University, Wellington Rd, Clayton, Victoria 3800, Australia.
authors.forename: Megan A
authors.initials: MA
authors.lastname: Evans
authors.affiliation: Vascular Biology and Immunopharmacology Group, Department of Pharmacology, Building 13E, Monash University, Wellington Rd, Clayton, Victoria 3800, Australia.
authors.forename: Grant R
authors.initials: GR
authors.lastname: Drummond
authors.affiliation: Vascular Biology and Immunopharmacology Group, Department of Pharmacology, Building 13E, Monash University, Wellington Rd, Clayton, Victoria 3800, Australia.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Sobey
authors.affiliation: Vascular Biology and Immunopharmacology Group, Department of Pharmacology, Building 13E, Monash University, Wellington Rd, Clayton, Victoria 3800, Australia. Electronic address: s-chrissobolis@onu.edu.
authors.forename: Sophocles
authors.initials: S
authors.lastname: Chrissobolis
mesh_terms: D000450:Aldosterone / Q000097:blood / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001921:Brain / Q000098:blood supply / Q000378:metabolism; D002560:Cerebrovascular Circulation / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D018161:Receptors, Mineralocorticoid / Q000378:metabolism*; D013148:Spironolactone / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism
chemical_list: D016207:Cytokines; D000451:Mineralocorticoid Receptor Antagonists; D018161:Receptors, Mineralocorticoid; C038232:spironolactone receptor; D013481:Superoxides; D013148:Spironolactone; D000450:Aldosterone
keywords: Brain; Cerebral circulation; Endothelium; Inflammation; Mineralocorticoid receptor; Oxidative stress