Browsing by Author "Knowlton, Anne A"

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Effects of Dietary Decosahexaenoic Acid (DHA) on eNOS in Human Coronary Artery Endothelial Cells
(2008) Stebbins, Charles L; Stice, James P; Hart, Michael; Mbai, Fiona N; Knowlton, Anne A
Endothelial dysfunction occurs in heart disease and may reduce functional capacity via attenuations in peripheral blood flow. Dietary decosahexaenoic acid (DHA) may improve this dysfunction, but the mechanism is unknown. This study determined if DHA enhances expression and activity of eNOS in cultured human coronary artery endothelial cells (HCAEC). HCAEC from 4 donors were treated with 5 nM, 50 nM, or 1 μM DHA for 7 days to model chronic DHA exposure. A trend for increased expression of endothelial nitric oxide synthase (eNOS) and phospho-eNOS was observed with 5 and 50 nM DHA. DHA also enhanced expression of 2 proteins instrumental in activation of eNOS: phospho-Akt (5 and 50 nM) and HSP90 (50 nM and 1 μM). Vascular endothelial growth factor–induced activation of Akt increased NOx in treated (50 nM DHA) versus untreated HCAEC (9.2 ± 1.0 vs 3.3 ± 1.1 μmol/μg protein/μL). Findings suggest that DHA enhances eNOS and Akt activity, augments HSP90 expression, and increases NO bioavailability in response to Akt kinase activation
Gender differences in cardiovascular disease: The effects of estrogen
(2005) Mbai, Fiona N; Hamilton, Karyn L; Knowlton, Anne A
Estrogen and its therapeutic application in cardiovascular disease are highly controversial. There has been a paucity of basic research on estrogen and its molecular effects, which has weakened the underpinnings of clinical trials of estrogen treatment. In the past 10 years, much has been discovered about both the genomic and nongenomic effects of estrogen. The identification of at least three distinct receptors for estrogen, as well as the development of drugs with varying binding affinities for different receptors, has created exciting therapeutic possibilities.
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