Role of mineralocorticoid receptor on experimental cerebral aneurysms in rats.
Activation of the renin-angiotensin (Ang)-aldosterone system is involved in the pathology of vascular diseases. Although the blockade of the mineralocorticoid receptor protects against vascular diseases, its role in cerebral aneurysms remains to be elucidated. We treated female rats subjected to renal hypertension, increased hemodynamic stress, and estrogen deficiency for 3 months with the mineralocorticoid receptor blocker eplerenone (30 or 100 mg/kg per day) or vehicle (vehicle control). Eplerenone reduced the incidence of cerebral aneurysms and saline intake without lowering of the blood pressure. In the aneurysmal wall, the production of Ang II and nitrotyrosine was increased. The mRNA levels of Ang-converting enzyme 1 and NADPH oxidase subunits NOX4, Rac1, monocyte chemoattractant protein 1, and matrix metalloproteinase 9 were increased. Eplerenone brought about a reduction in these molecules, suggesting that mineralocorticoid receptor blockade suppresses cerebral aneurysm formation by inhibiting oxidative stress, inflammatory factors, local renin-Ang system activation, and saline intake. Other female rats implanted with pellets of the mineralocorticoid receptor agonist deoxycorticosterone acetate manifested a high incidence of cerebral aneurysm formation and the upregulation of molecules related to oxidative stress, inflammatory factors, and the local renin-Ang system; their saline intake was increased. We demonstrate that mineralocorticoid receptor activation at least partly contributes to the pathogenesis of cerebral aneurysms.
Tada
Yoshiteru
Y
Department of Neurosurgery, Institute of Health Biosciences, The University of Tokushima Graduate School, 3-18-15 Kuramoto-cho, Tokushima, Tokushima, Japan. yoshiteru.tada@hotmail.co.jp.
Kitazato
Keiko T
KT
Tamura
Tetsuya
T
Yagi
Kenji
K
Shimada
Kenji
K
Kinouchi
Tomoya
T
Satomi
Junichiro
J
Nagahiro
Shinji
S
D000450:Aldosterone / Q000097:blood; D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002536:Cerebral Arteries / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D000077545:Eplerenone; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006977:Hypertension, Renal / Q000188:drug therapy / Q000503:physiopathology; D007150:Immunohistochemistry; D002532:Intracranial Aneurysm / Q000097:blood / Q000503:physiopathology / Q000517:prevention & control*; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism; D010052:Ovariectomy; D018384:Oxidative Stress / Q000187:drug effects; D007703:Peptidyl-Dipeptidase A / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018161:Receptors, Mineralocorticoid / Q000502:physiology; D012084:Renin-Angiotensin System / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013148:Spironolactone / Q000031:analogs & derivatives* / Q000494:pharmacology; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D000451:Mineralocorticoid Receptor Antagonists; D012333:RNA, Messenger; D018161:Receptors, Mineralocorticoid; D000804:Angiotensin II; D013148:Spironolactone; C002744:3-nitrotyrosine; D014443:Tyrosine; D000450:Aldosterone; D000077545:Eplerenone; D019255:NADPH Oxidases; D007703:Peptidyl-Dipeptidase A