Browsing by Author "Sanhueza, Carlos"
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Item Caveolin-1-Mediated Tumor Suppression Is Linked to Reduced HIF1α S-Nitrosylation and Transcriptional Activity in Hypoxia(2020) Sanhueza, Carlos; Castillo Bennett, Jimena; Valenzuela-Valderrama, Manuel; Contreras, Pamela; Lobos-González, Lorena; Campos, América; Wehinger, Sergio; Lladser, Álvaro; Kiessling, Rolf; Leyton, Lisette; Quest, Andrew F. G.Caveolin-1 (CAV1) is a well-established nitric oxide synthase inhibitor, whose function as a tumor suppressor is favored by, but not entirely dependent on, the presence of E-cadherin. Tumors are frequently hypoxic and the activation of the hypoxia-inducible factor-1α (HIF1α) promotes tumor growth. HIF1α is regulated by several post-translational modifications, including S-nitrosylation. Here, we evaluate the mechanisms underlying tumor suppression by CAV1 in cancer cells lacking E-cadherin in hypoxia. Our main findings are that CAV1 reduced HIF activity and Vascular Endothelial Growth Factor expression in vitro and in vivo. This effect was neither due to reduced HIF1α protein stability or reduced nuclear translocation. Instead, HIF1α S-nitrosylation observed in hypoxia was diminished by the presence of CAV1, and nitric oxide synthase (NOS) inhibition by Nω-Nitro-L-arginine methyl ester hydrochloride (L-NAME) reduced HIF1α transcriptional activity in cells to the same extent as observed upon CAV1 expression. Additionally, arginase inhibition by (S)-(2-Boronoethyl)-L-cysteine (BEC) partially rescued cells from the CAV1-mediated suppression of HIF1α transcriptional activity. In vivo, CAV1-mediated tumor suppression was dependent on NOS activity. In summary, CAV1-dependent tumor suppression in the absence of E-cadherin is linked to reduced HIF1α transcriptional activity via diminished NOS-mediated HIF1α S-nitrosylation.Item Maternal supraphysiological hypercolesterolemia leads to endothelial dysfunction of the human fetoplacental macro and microvasculature(2015) Leiva, Andrea; Salsoso, Rocío; Sáez, Tamara; Silva, Luis; Sanhueza, Carlos; Pardo, Fabian; Sobrevía, LuisMaternal physiological hypercholesterolemia (MPH) occurs in pregnancy assuring fetal growth and development. However, maternal supraphysiological hypercholesterolemia (MSPH) leads to increased atherosclerosis in the fetal vasculature. In this study the maternal and neonatal total cholesterol (TCh) and lipoprotein levels were determined in a group of pregnant women and her newborns. A cut-off value for MSPH was established as maternal TCh levels at term of pregnancy >280 mg/dl. Pregnancies with values over this cut-off point were associated with fetoplacental endothelial dysfunction evaluated as reduced endothelial-dependent vascular dilation in the macro- (umbilical vein; 41 ± 7% and 10± 2% for MPH and MSPH, respectively) and microvasculature (veins in placental stem villi; 52 ± 6% and 1± 0.2% for MPH and MSPH, respectively). The mechanisms involved in this phenomenon include reduced nitric oxide synthase (NOS) activity and therefore reduced nitric oxide (NO) availability in human umbilical vein endothelial cells (HUVEC; reduction of 51 ± 2% compared with MPH) and human placental microvascular endothelial cells (HPMEC; reduction of 83 ± 4% compared with MPH). MSPH was also associated with reduced synthesis of the eNOS cofactor tetrahydrobiopterin (BH4; reduction of 87.5 ± 5% compared with MPH) as well as increased activity of arginases, a group of enzymes that compete with NOS for the substrate L-arginine (1.5 times compared with MPH). Interestingly, the restoration of the BH4 levels and the inhibition of arginases improved the endothelial function impaired by the MSPH condition. Therefore MSPH is a maternal condition likely involved in the endothelial dysfunction and the later development of atherosclerosis described for MSPH offspring. However, the mechanism(s) leading to the development MSPH as well as whether this maternal condition modifies the placental transport of cholesterol and therefore the fetal lipid function are actually unknown.Item Maternal supraphysiological hypercolesterolemia leads to endothelial dysfunction of the human fetoplacental macro and microvasculature(2015) Leiva, Andrea; Salsoso, Rocío; Sáez, Tamara; Silva, Luis; Sanhueza, Carlos; Pardo, Fabian; Sobrevía, LuisMaternal physiological hypercholesterolemia (MPH) occurs in pregnancy assuring fetal growth and development. However, maternal supraphysiological hypercholesterolemia (MSPH) leads to increased atherosclerosis in the fetal vasculature. In this study the maternal and neonatal total cholesterol (TCh) and lipoprotein levels were determined in a group of pregnant women and her newborns. A cut-off value for MSPH was established as maternal TCh levels at term of pregnancy >280 mg/dl. Pregnancies with values over this cut-off point were associated with fetoplacental endothelial dysfunction evaluated as reduced endothelial-dependent vascular dilation in the macro- (umbilical vein; 41 ± 7% and 10± 2% for MPH and MSPH, respectively) and microvasculature (veins in placental stem villi; 52 ± 6% and 1± 0.2% for MPH and MSPH, respectively). The mechanisms involved in this phenomenon include reduced nitric oxide synthase (NOS) activity and therefore reduced nitric oxide (NO) availability in human umbilical vein endothelial cells (HUVEC; reduction of 51 ± 2% compared with MPH) and human placental microvascular endothelial cells (HPMEC; reduction of 83 ± 4% compared with MPH). MSPH was also associated with reduced synthesis of the eNOS cofactor tetrahydrobiopterin (BH4; reduction of 87.5 ± 5% compared with MPH) as well as increased activity of arginases, a group of enzymes that compete with NOS for the substrate L-arginine (1.5 times compared with MPH). Interestingly, the restoration of the BH4 levels and the inhibition of arginases improved the endothelial function impaired by the MSPH condition. Therefore MSPH is a maternal condition likely involved in the endothelial dysfunction and the later development of atherosclerosis described for MSPH offspring. However, the mechanism(s) leading to the development MSPH as well as whether this maternal condition modifies the placental transport of cholesterol and therefore the fetal lipid function are actually unknown.