Browsing by Author "Chen, Le"

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Rapid Activation of Nuclear Factor-κB by 17β-Estradiol and Selective Estrogen Receptor Modulators: Pathways Mediating Cellular Protection
(2012) Stice, James P; Mbai, Fiona N; Chen, Le; Knowlton, Anne A
17 β -estradiol (E2) treatment activates a set of protective response that have been found to protect cells from injury and more importantly to significantly abate the injuries associated with trauma- hemorrhage in vivo . Rapid NF κ B activation has been found to be an important signaling step in E2 mediated protection in cell culture, in vivo ischemia and trauma-hemorrhage. In the current study, we investigated the signaling cascades linking E2 signaling with NF κ B activation and the protective response, and compared them with the effects of two selective estrogen receptor modulators (SERMs), raloxifene and tamoxifen. Two candidate pathways, mitogen activated protein kinases (MAPK), and phosphatidylinositol-3-kinase (PI3-K) were studied. Selective inhibitors were used to identify each pathway's contribution to NF κ B activation. Treatment of HCAECs with E2 activated PI3-K/Akt, p38, and JNK, all of which activated ERK 1/2 followed by NF κ B activation. The combined activation of Akt, p38 and JNK was essential to activate NF κ B. The two SERMs activated PI3-K and p38, which then phosphorylated ERK 1/2 and activated NF κ B independent of the JNK pathway. NFkB activation by these compounds protected cells from hypoxia/reoxygenation injury. However, E2, unlike either SERM, led to modest increases in apoptosis through the JNK pathway. SERM treatment led to increased expression of the protective proteins, Mn-superoxide dismutase and endothelial nitric oxide synthase, that was not seen with E2. These results provide new insight into the pathways activating NFkB by E2 and SERMS and demonstrate that SERMs may have greater protective benefits than E2 in adult endothelial cells and potentially in vivo , as well