5 research outputs found
Cigarette smoke induces pulmonary arterial dysfunction through an imbalance in the redox status of the soluble guanylyl cyclase
Chronic obstructive pulmonary disease (COPD), whose main risk factor is cigarette smoking (CS), is one of the most common diseases globally. Some COPD patients also develop pulmonary hypertension (PH), a severe complication that leads to premature death. Evidence suggests reactive oxygen species (ROS) involvement in COPD and PH, especially regarding pulmonary artery smooth muscle cells (PASMC) dysfunction. However, the effects of CS-driven oxidative stress on the pulmonary vasculature are not completely understood. Herein we provide evidence on the effects of CS extract (CSE) exposure on PASMC regarding ROS production, antioxidant response and its consequences on vascular tone dysregulation. Our results indicate that CSE exposure promotes mitochondrial fission, mitochondrial membrane depolarization and increased mitochondrial superoxide levels. However, this superoxide increase did not parallel a counterbalancing antioxidant response in human pulmonary artery (PA) cells. Interestingly, the mitochondrial superoxide scavenger mitoTEMPO reduced mitochondrial fission and membrane potential depolarization caused by CSE. As we have previously shown, CSE reduces PA vasoconstriction and vasodilation. In this respect, mitoTEMPO prevented the impaired nitric oxide-mediated vasodilation, while vasoconstriction remained reduced. Finally, we observed a CSE-driven downregulation of the Cyb5R3 enzyme, which prevents soluble guanylyl cyclase oxidation in PASMC. This might explain the CSE-mediated decrease in PA vasodilation. These results provide evidence that there might be a connection between mitochondrial ROS and altered vasodilation responses in PH secondary to COPD, and strongly support the potential of antioxidant strategies specifically targeting mitochondria as a new therapy for these diseasesThe Spanish Ministerio de Ciencia e Innovacion, ´ Programa Retos en
Investigacion ´ (grant number PID2019-104406RB-100) to MJC provided
the financial support for the conduct of the research included in this
manuscript. Garantia Juvenil program from Comunidad de Madrid
contributed with the research assistant contract to M-R,
Corrigendum to “Downregulation of Thioredoxin-1-dependent CD95 S-nitrosation by Sorafenib reduces liver cancer” [Redox Biol. 34 (2020) 101528]
Downregulation of thioredoxin-1-dependent CD95 S-nitrosation by Sorafenib reduces liver cancer
Hepatocellular carcinoma (HCC) represents 80% of the primary hepatic neoplasms. It is the sixth most frequent neoplasm, the fourth cause of cancer-related death, and 7% of registered malignancies. Sorafenib is the first line molecular targeted therapy for patients in advanced stage of HCC. The present study shows that Sorafenib exerts free radical scavenging properties associated with the downregulation of nuclear factor E2-related factor 2 (Nrf2)-regulated thioredoxin 1 (Trx1) expression in liver cancer cells. The experimental downregulation and/or overexpression strategies showed that Trx1 induced activation of nitric oxide synthase (NOS) type 3 (NOS3) and S-nitrosation (SNO) of CD95 receptor leading to an increase of caspase-8 activity and cell proliferation, as well as reduction of caspase-3 activity in liver cancer cells. In addition, Sorafenib transiently increased mRNA expression and activity of S-nitrosoglutathione reductase (GSNOR) in HepG2 cells. Different experimental models of hepatocarcinogenesis based on the subcutaneous implantation of HepG2 cells in nude mice, as well as the induction of HCC by diethylnitrosamine (DEN) confirmed the relevance of Trx1 downregulation during the proapoptotic and antiproliferative properties induced by Sorafenib. In conclusion, the induction of apoptosis and antiproliferative properties by Sorafenib were related to Trx1 downregulation that appeared to play a relevant role on SNO of NOS3 and CD95 in HepG2 cells. The transient increase of GSNOR might also participate in the deactivation of CD95-dependent proliferative signaling in liver cancer cells.This study was funded by Institute of Health Carlos III (ISCIII) (PI13/00021, PI15/00107, PI16/00090 and PI19/01266), Spanish Ministry of Economy and Competitiveness (SAF2015-71208-R, BFU2016-8006-P, PGC2018-094276-B-I00 and RED2018-102576-T), Andalusian Ministry of Economy, Innovation, Science and Employment (BIO-216 and CTS-6264) and Andalusian Ministry of Equality, Health and Social Policies (PI-00025-2013 and PI-0198-2016). P de la C–O was supported by FPU predoctoral fellowship (FPU17/00026) from Ministry of Education, Culture and Sports. We thank the Biomedical Research Network Center for Cardiovascular Diseases (CIBERCV), and the Biomedical Research Network Center for Liver and Digestive Diseases (CIBERehd) founded by the ISCIII and co-financed by European Development Regional Fund “A way to achieve Europe” ERDF for their financial support.Ye
Downregulation of thioredoxin-1-dependent CD95 S-nitrosation by Sorafenib reduces liver cancer
Hepatocellular carcinoma (HCC) represents 80% of the primary hepatic neoplasms. It is the sixth most frequent neoplasm, the fourth cause of cancer-related death, and 7% of registered malignancies. Sorafenib is the first line molecular targeted therapy for patients in advanced stage of HCC. The present study shows that Sorafenib exerts free radical scavenging properties associated with the downregulation of nuclear factor E2-related factor 2 (Nrf2)-regulated thioredoxin 1 (Trx1) expression in liver cancer cells. The experimental downregulation and/or overexpression strategies showed that Trx1 induced activation of nitric oxide synthase (NOS) type 3 (NOS3) and S-nitrosation (SNO) of CD95 receptor leading to an increase of caspase-8 activity and cell proliferation, as well as reduction of caspase-3 activity in liver cancer cells. In addition, Sorafenib transiently increased mRNA expression and activity of S-nitrosoglutathione reductase (GSNOR) in HepG2 cells. Different experimental models of hepatocarcinogenesis based on the subcutaneous implantation of HepG2 cells in nude mice, as well as the induction of HCC by diethylnitrosamine (DEN) confirmed the relevance of Trx1 downregulation during the proapoptotic and antiproliferative properties induced by Sorafenib. In conclusion, the induction of apoptosis and antiproliferative properties by Sorafenib were related to Trx1 downregulation that appeared to play a relevant role on SNO of NOS3 and CD95 in HepG2 cells. The transient increase of GSNOR might also participate in the deactivation of CD95-dependent proliferative signaling in liver cancer cells.This study was funded by Institute of Health Carlos III (ISCIII) (PI13/00021, PI15/00107, PI16/00090 and PI19/01266), Spanish Ministry of Economy and Competitiveness (SAF2015-71208-R, BFU2016-8006-P, PGC2018-094276-B-I00 and RED2018-102576-T), Andalusian Ministry of Economy, Innovation, Science and Employment (BIO-216 and CTS-6264) and Andalusian Ministry of Equality, Health and Social Policies (PI-00025-2013 and PI-0198-2016). P de la C–O was supported by FPU predoctoral fellowship (FPU17/00026) from Ministry of Education, Culture and Sports. We thank the Biomedical Research Network Center for Cardiovascular Diseases (CIBERCV), and the Biomedical Research Network Center for Liver and Digestive Diseases (CIBERehd) founded by the ISCIII and co-financed by European Development Regional Fund “A way to achieve Europe” ERDF for their financial support
Na+ controls hypoxic signalling by the mitochondrial respiratory chain
All metazoans depend on O2 delivery and consumption by the mitochondrial oxidative phosphorylation (OXPHOS) system to produce energy. A decrease in O2 availability (hypoxia) leads to profound metabolic rewiring. In addition, OXPHOS uses O2 to produce reactive oxygen species (ROS) that can drive cell adaptations through redox signalling, but also trigger cell damage1–4, and both phenomena occur in hypoxia4–8. However, the precise mechanism by which acute hypoxia triggers mitochondrial ROS production is still unknown. Ca2+ is one of the best known examples of an ion acting as a second messenger9, yet the role ascribed to Na+ is to serve as a mere mediator of membrane potential and collaborating in ion transport10. Here we show that Na+ acts as a second messenger regulating OXPHOS function and ROS production by modulating fluidity of the inner mitochondrial membrane (IMM). We found that a conformational shift in mitochondrial complex I during acute hypoxia11 drives the acidification of the matrix and solubilization of calcium phosphate precipitates. The concomitant increase in matrix free-Ca2+ activates the mitochondrial Na+/Ca2+ exchanger (NCLX), which imports Na+ into the matrix. Na+ interacts with phospholipids reducing IMM fluidity and mobility of free ubiquinone between complex II and complex III, but not inside supercomplexes. As a consequence, superoxide is produced at complex III, generating a redox signal. Inhibition of mitochondrial Na+ import through NCLX is sufficient to block this pathway, preventing adaptation to hypoxia. These results reveal that Na+ import into the mitochondrial matrix controls OXPHOS function and redox signalling through an unexpected interaction with phospholipids, with profound consequences in cellular metabolism