Role of Mineralocorticoid Receptor on Experimental Cerebral Aneurysms in Rats

Abstract

Abstract-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. (Hypertension. 2009;54:552-557.)Key Words: cerebral Ⅲ aneurysm Ⅲ inflammation Ⅲ mineralocorticoid receptor Ⅲ oxidative stress R upture of cerebral artery aneurysms results in catastrophic subarachnoid hemorrhage and a high risk for morbidity and mortality. 1 On the basis of epidemiological data showing a high incidence of cerebral aneurysms in postmenopausal women, we subjected female rats to increased hemodynamic stress, hypertension, and estrogen deficiency (by oophorectomy); in these animals, the incidence of cerebral aneurysms was high. 2 Treatment with 17␤-estradiol or an angiotensin (Ang) II type 1 receptor blocker reduced this incidence. 2 Elsewhere we suggested that endothelial injury is an initial event in the pathogenesis of cerebral aneurysms and that an increase in Ang II and NADPH oxidase subunits is involved. 2 Also, inflammation and degradation of the extracellular matrix in the vascular wall play a role in the development of cerebral aneurysms. [3][4][5] The renin-Ang-aldosterone system is involved in the pathophysiology of cardiovascular and kidney diseases, activation of the mineralocorticoid receptor (MR) is especially highlighted in recent studies. 6 -10 The identification of a new site of MR expression in nonepithelial tissues, such as the heart, 11 vasculature, 12 and brain, 13 suggested the presence in these tissues of potential new MR target genes with unexpected biological functions. In aortic endothelial cells, aldosterone increased the express...

Statins Promote the Growth of Experimentally Induced Cerebral Aneurysms in Estrogen-Deficient Rats

“…2,3,[5][6][7] The left anterior cerebral artery-olfactory artery (ACA-OA) bifurcation was inspected at 3kV under a scanning electron microscope (SEM; VE8800, Keyence, Osaka, Japan) and changes were recorded as normal (stage 0), endothelial damage (stage 1), moderate protrusion (stage 2), and saccular aneurysm (stage 3). Morphological changes at the bifurcation were evaluated by 3 blinded observers and staged as described elsewhere.…”

“…Morphological changes at the bifurcation were evaluated by 3 blinded observers and staged as described elsewhere. 2,3,[5][6][7] Immunohistochemistry and TUNEL Staining , VC (nϭ6), P-5 (nϭ7), P-50 (nϭ7), and Sim-5 rats (nϭ7) at 12 weeks after OVX (at 23 weeks of age) were used for immunohistochemical study. Primary polyclonal antibodies against cleaved caspase-3 and monoclonal antibody against antismooth muscle ␤-actin (Laboratory Vision, CA) were used.…”

“…2 Using this model, we found that endothelial injury is an initial event in the pathogenesis of cerebral aneurysms, 3 and that infiltration of leukocytes from interendothelial gaps, where tight junction proteins are reduced, is associated with their progression. 4 We also demonstrated that a reduction in endothelial nitric oxide synthase (eNOS) messenger ribonucleic acid (mRNA), an elevation in nicotinamide adenine dinucleotide phosphate oxidase and angiotensin II levels, 5,6 and inflammation mediated by matrix metalloproteinase-9 derived from macrophages in the vascular wall, are associated with the formation of cerebral aneurysms. 3 In contrast, various types of agents including 17␤-estradiol, an angiotensin II type 1 receptor blocker, a phosphodiesterase 4 inhibitor, and the mineralocorticoid receptor antagonist eplerenone, effectively prevented the formation of cerebral aneurysms via their antioxidative and anti-inflammatory effects.…”

“…3 In contrast, various types of agents including 17␤-estradiol, an angiotensin II type 1 receptor blocker, a phosphodiesterase 4 inhibitor, and the mineralocorticoid receptor antagonist eplerenone, effectively prevented the formation of cerebral aneurysms via their antioxidative and anti-inflammatory effects. [5][6][7] As all types of statins exert beneficial antioxidant and anti-inflammatory effects, they may protect against endothelial dysfunction and the development and progression of atherosclerosis. 8 The efficacy of some statins in experimental cerebral aneurysm models has been demonstrated.…”

Eplerenone reduces arterial thrombosis in diabetic rats

“…52 We did not observed changes in the values of the blood pressure, HR and glucose level in STZ-induced diabetic rats after EPL treatment. Similarly, any modifications in hemodynamic parameters in normotensive rats and diabetic mice [53][54][55] as well as glucose level in STZ-induced diabetic rats 9 were not observed after chronic EPL administration. Thus our results suggest that the ability of EPL to inhibit arterial thrombosis is independent of its hypotensive and hypoglycaemic activities.…”