The goal of this study was to elucidate the mechanisms of 17-estradiol (E 2 ) antioxidant and neuroprotective actions in stroke. The results reveal a novel extranuclear receptor-mediated antioxidant mechanism for E 2 during stroke, as well as a hypersensitivity of the CA3/CA4 region to ischemic injury after prolonged hypoestrogenicity. E 2 neuroprotection was shown to involve a profound attenuation of NADPH oxidase activation and superoxide production in hippocampal CA1 pyramidal neurons after stroke, an effect mediated by extranuclear estrogen receptor ␣ (ER␣)-mediated nongenomic signaling, involving Akt activation and subsequent phosphorylation/ inactivation of Rac1, a factor critical for activation of NOX2 NADPH oxidase. Intriguingly, E 2 nongenomic signaling, antioxidant action, and neuroprotection in the CA1 region were lost after long-term E 2 deprivation, and this loss was tissue specific because the uterus remained responsive to E 2 . Correspondingly, a remarkable loss of ER␣, but not ER, was observed in the CA1 after long-term E 2 deprivation, with no change observed in the uterus. As a whole, the study reveals a novel, membrane-mediated antioxidant mechanism in neurons by E 2 provides support and mechanistic insights for a "critical period" of E 2 replacement in the hippocampus and demonstrates a heretofore unknown hypersensitivity of the CA3/CA4 to ischemic injury after prolonged hypoestrogenicity.
We established a mouse model of cardiac dysfunction due to myocardial infarction (MI). For this we ligated the left anterior descending coronary artery in male C57BL/6J mice and assessed healing and left ventricular (LV) remodelling at 1, 2 and 4 days and 1, 2 and 4 weeks after MI. Echocardiography was performed at 1 and 2 weeks and 1, 2, 4 and 6 months after MI. We found that neutrophil infiltration of the infarct border was noticeable at 1-2 days. Marked macrophage infiltration occurred at day 4, while lymphocyte infiltration was apparent at 7-14 days. Massive proliferation of fibroblasts and collagen accumulation began by day 7-14, and scar formation was completed by day 21. LV diastolic dimension increased markedly at 2 weeks and remained at the same level thereafter. LV shortening fraction decreased significantly at 2 weeks and then slowly decreased. In non-infarcted areas of the LV, myocyte cross-sectional area and interstitial collagen fraction increased progressively, reaching a maximum at 4 months. This study provides important qualitative and quantitative information about the natural history of cardiac remodelling after MI in mice. Experimental Physiology (2002) 87.5, 547-555. 2385
Objective-Our preliminary data suggested that angiotensin II (Ang II)-induced reactive oxygen species are involved in intercellular adhesion molecule-1 (ICAM-1) expression and leukocyte infiltration in the rat thoracic aorta. Other reports demonstrating reactive oxygen species-induced cell growth suggested a potential role of NAD(P)H oxidase in vascular hypertrophy. In the present study, we postulate that NAD(P)H oxidase is functionally involved in Ang II-induced ICAM-1 expression, macrophage infiltration, and vascular growth, and that oxidase inhibition attenuates these processes independently of a reduction in blood pressure. Methods and Results-Rats were infused subcutaneously with vehicle or Ang II (750 g/kg per day) for 1 week in the presence or absence of gp91 docking sequence (gp91ds)-tat peptide (1 mg/kg per day), a cell-permeant inhibitor of NAD(P)H oxidase. Immunohistochemical staining for ICAM-1 and ED1, a marker of monocytes and macrophages, showed that both were markedly increased with Ang II compared with vehicle and were reduced in rats receiving Ang II plus gp91ds-tat. This effect was accompanied by an Ang II-induced increase in medial hypertrophy that was attenuated by coinfusion of gp91ds-tat; however, gp91ds-tat had no effect on blood pressure. Key Words: NADPH oxidoreductase Ⅲ NAD(P)H oxidase Ⅲ hypertrophy Ⅲ inflammation Ⅲ angiotensin II A ngiotensin II (Ang II) has been shown to increase vascular adhesion molecule expression by stimulating the production of reactive oxygen species (ROS). 1,2 Mediators of increased adhesion molecule expression include activation of nuclear factor-B (NF-B) and activator protein-1 transcription factors. 3 Ang II has been implicated in vascular dysfunction, acting via a variety of mechanisms, including (1) stimulation of superoxide anion (O 2 ·Ϫ ) production by large and small blood vessels 4 through activation of vascular NAD(P)H oxidases, 5,6 leading to impairment of endothelial function 7,8 ; (2) induction of adhesion molecules, such as vascular cell adhesion molecule-1, via activation of NF-Bdependent gene expression 9 ; and (3) hypertrophy and remodeling. 10,11 Conclusions-Ang See page 707There is substantial evidence indicating that the cellular actions of Ang II are proinflammatory and potentially injurious to the blood vessel. In hypertension, medial hypertrophy is a normal response, 12,13 yet the mechanisms mediating this hypertrophy are still not clear. Reports have demonstrated that Ang II can induce medial thickening and increase the vascular cross-sectional area independently of blood pressure elevation. 14 -16 In smooth muscle cell cultures, Ang II has been shown to induce hypertrophy, 17 which appears to be mediated by the stimulation of NAD(P)H oxidase-derived H 2 O 2 , which in turn activates proto-oncogenes, mitogenactivated protein kinases, and transcription factors, leading to the growth response. 5,18,19 A recent study by Wang et al 16 also posited an in vivo role for NAD(P)H oxidase in medial hypertrophy in response to Ang II, but this int...
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