FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2912862221> ?p ?o ?g. }

• W2912862221 endingPage "2255" @default.
• W2912862221 startingPage "2238" @default.
• W2912862221 abstract "Background: Deficiencies of iron-sulfur (Fe-S) clusters, metal complexes that control redox state and mitochondrial metabolism, have been linked to pulmonary hypertension (PH), a deadly vascular disease with poorly defined molecular origins. BOLA3 (BolA Family Member 3) regulates Fe-S biogenesis, and mutations in BOLA3 result in multiple mitochondrial dysfunction syndrome, a fatal disorder associated with PH. The mechanistic role of BOLA3 in PH remains undefined. Methods: In vitro assessment of BOLA3 regulation and gain- and loss-of-function assays were performed in human pulmonary artery endothelial cells using siRNA and lentiviral vectors expressing the mitochondrial isoform of BOLA3. Polymeric nanoparticle 7C1 was used for lung endothelium-specific delivery of BOLA3 siRNA oligonucleotides in mice. Overexpression of pulmonary vascular BOLA3 was performed by orotracheal transgene delivery of adeno-associated virus in mouse models of PH. Results: In cultured hypoxic pulmonary artery endothelial cells, lung from human patients with Group 1 and 3 PH, and multiple rodent models of PH, endothelial BOLA3 expression was downregulated, which involved hypoxia inducible factor-2α–dependent transcriptional repression via histone deacetylase 1–mediated histone deacetylation. In vitro gain- and loss-of-function studies demonstrated that BOLA3 regulated Fe-S integrity, thus modulating lipoate-containing 2-oxoacid dehydrogenases with consequent control over glycolysis and mitochondrial respiration. In contexts of siRNA knockdown and naturally occurring human genetic mutation, cellular BOLA3 deficiency downregulated the glycine cleavage system protein H, thus bolstering intracellular glycine content. In the setting of these alterations of oxidative metabolism and glycine levels, BOLA3 deficiency increased endothelial proliferation, survival, and vasoconstriction while decreasing angiogenic potential. In vivo, pharmacological knockdown of endothelial BOLA3 and targeted overexpression of BOLA3 in mice demonstrated that BOLA3 deficiency promotes histological and hemodynamic manifestations of PH. Notably, the therapeutic effects of BOLA3 expression were reversed by exogenous glycine supplementation. Conclusions: BOLA3 acts as a crucial lynchpin connecting Fe-S–dependent oxidative respiration and glycine homeostasis with endothelial metabolic reprogramming critical to PH pathogenesis. These results provide a molecular explanation for the clinical associations linking PH with hyperglycinemic syndromes and mitochondrial disorders. These findings also identify novel metabolic targets, including those involved in epigenetics, Fe-S biogenesis, and glycine biology, for diagnostic and therapeutic development." @default.
• W2912862221 created "2019-02-21" @default.
• W2912862221 creator A5000069942 @default.
• W2912862221 creator A5001684279 @default.
• W2912862221 creator A5003414642 @default.
• W2912862221 creator A5003686337 @default.
• W2912862221 creator A5007489671 @default.
• W2912862221 creator A5007566392 @default.
• W2912862221 creator A5007850965 @default.
• W2912862221 creator A5011465271 @default.
• W2912862221 creator A5012173616 @default.
• W2912862221 creator A5012587136 @default.
• W2912862221 creator A5021150751 @default.
• W2912862221 creator A5024026360 @default.
• W2912862221 creator A5030865403 @default.
• W2912862221 creator A5031246678 @default.
• W2912862221 creator A5031499770 @default.
• W2912862221 creator A5035123411 @default.
• W2912862221 creator A5036096394 @default.
• W2912862221 creator A5036723734 @default.
• W2912862221 creator A5039783745 @default.
• W2912862221 creator A5040040696 @default.
• W2912862221 creator A5042527382 @default.
• W2912862221 creator A5042597057 @default.
• W2912862221 creator A5045151213 @default.
• W2912862221 creator A5048707762 @default.
• W2912862221 creator A5051374236 @default.
• W2912862221 creator A5053397530 @default.
• W2912862221 creator A5059572789 @default.
• W2912862221 creator A5060836626 @default.
• W2912862221 creator A5067493084 @default.
• W2912862221 creator A5069063294 @default.
• W2912862221 creator A5071151211 @default.
• W2912862221 creator A5074097272 @default.
• W2912862221 creator A5077886342 @default.
• W2912862221 creator A5079704367 @default.
• W2912862221 creator A5081908185 @default.
• W2912862221 creator A5090015054 @default.
• W2912862221 creator A5090056922 @default.
• W2912862221 date "2019-05-07" @default.
• W2912862221 modified "2023-10-17" @default.
• W2912862221 title "BOLA (BolA Family Member 3) Deficiency Controls Endothelial Metabolism and Glycine Homeostasis in Pulmonary Hypertension" @default.
• W2912862221 cites W103353483 @default.
• W2912862221 cites W1497017942 @default.
• W2912862221 cites W1900467627 @default.
• W2912862221 cites W1967185435 @default.
• W2912862221 cites W1970878086 @default.
• W2912862221 cites W1973041701 @default.
• W2912862221 cites W1985886743 @default.
• W2912862221 cites W1991852898 @default.
• W2912862221 cites W1993238514 @default.
• W2912862221 cites W1995630908 @default.
• W2912862221 cites W2001986473 @default.
• W2912862221 cites W2002050544 @default.
• W2912862221 cites W2007535250 @default.
• W2912862221 cites W2012141674 @default.
• W2912862221 cites W2020646157 @default.
• W2912862221 cites W2021295284 @default.
• W2912862221 cites W2029446405 @default.
• W2912862221 cites W2035104998 @default.
• W2912862221 cites W2040995700 @default.
• W2912862221 cites W2045371106 @default.
• W2912862221 cites W2045958608 @default.
• W2912862221 cites W2049276231 @default.
• W2912862221 cites W2062700139 @default.
• W2912862221 cites W2068547911 @default.
• W2912862221 cites W2075209047 @default.
• W2912862221 cites W2076570515 @default.
• W2912862221 cites W2077065151 @default.
• W2912862221 cites W2087408461 @default.
• W2912862221 cites W2099880703 @default.
• W2912862221 cites W2108195113 @default.
• W2912862221 cites W2112808685 @default.
• W2912862221 cites W2113439382 @default.
• W2912862221 cites W2114552998 @default.
• W2912862221 cites W2120339601 @default.
• W2912862221 cites W2123818367 @default.
• W2912862221 cites W2139036888 @default.
• W2912862221 cites W2140959728 @default.
• W2912862221 cites W2145237733 @default.
• W2912862221 cites W2149343354 @default.
• W2912862221 cites W2166566843 @default.
• W2912862221 cites W2171937707 @default.
• W2912862221 cites W2237013884 @default.
• W2912862221 cites W2518509726 @default.
• W2912862221 cites W2567210166 @default.
• W2912862221 cites W2606625532 @default.
• W2912862221 cites W2732380803 @default.
• W2912862221 cites W2766012717 @default.
• W2912862221 cites W2776101627 @default.
• W2912862221 cites W2791551952 @default.
• W2912862221 cites W2886140570 @default.
• W2912862221 doi "https://doi.org/10.1161/circulationaha.118.035889" @default.
• W2912862221 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/6519484" @default.
• W2912862221 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/30759996" @default.
• W2912862221 hasPublicationYear "2019" @default.
• W2912862221 type Work @default.
• W2912862221 sameAs 2912862221 @default.

• next