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dc.contributor.advisorSommer, Natascha
dc.contributor.advisorMazurek, Sybille
dc.contributor.authorAlebrahimdehkordi, Nasim
dc.date.accessioned2021-06-28T09:40:37Z
dc.date.available2021-06-28T09:40:37Z
dc.date.issued2021
dc.identifier.urihttps://jlupub.ub.uni-giessen.de//handle/jlupub/81
dc.identifier.urihttp://dx.doi.org/10.22029/jlupub-29
dc.description.abstractHypoxic pulmonary vasoconstriction (HPV) is essential to match local blood perfusion to ventilation, and thus to prevent life-threatening hypoxemia under conditions of acute alveolar hypoxia (HOX). Chronic hypoxic exposure can cause thickening of the pulmonary vascular lumen which leads to pulmonary hypertension (PH). An increase or decrease of reactive oxygen species release (ROS) from complex I (CI) and/or complex III (CIII) of the mitochondrial electron transport chain (METC) have been suggested as important mediators for the oxygen (O2) sensing mechanism underlying both responses. This study thus used novel ROS inhibitors and genetically modified mice to investigate the effect of ROS inhibition on HPV and hypoxia-induced PH. Mitochondrial ROS inhibitors, including MitoTempo, a mitochondria-targeted mimetic of the superoxide dismutase, SkQ1, a mitochondria-targeted antioxidant, and S3QEL, an inhibitor of superoxide release from mitochondrial CIII, inhibited HPV but only partially attenuated hypoxia-independent vasoconstriction. Moreover, HPV was absent in mice overexpressing the alternative oxidase (Aoxtg) which is activated during inhibition of CIII or CIV of the METC and bypasses CIII thereby decreasing superoxide release. Aox expression in the mouse pulmonary arterial smooth muscle cell (PASMC) prevented acute HOX-induced mitochondrial hyperpolarization and superoxide release and attenuated HOX-induced cellular membrane depolarization. In contrast, chronic HOX exposure of Aoxtg and wild-type (WT) mice induced PH to a similar degree in both strains as well as stabilization of hypoxia-inducible factor-1α (HIF-1α). Furthermore, in response to acute HOX, isolated lungs of mice with global knockout of cytochrome c oxidase complex 4 isoform 2 (Cox4i2), which is specifically expressed in oxygen sensing cell types and may regulate mitochondrial superoxide release, lacked HPV. Cox4i2 deficient PASMC showed absence of the HOX-induced mitochondrial hyperpolarization and superoxide release and attenuated HOX-induced cellular membrane depolarization. To further investigate the role of ROS for non-hypoxia induced PH development mice with SMC-specific inducible knockout of the uncoupling protein 2 (UCP2), a protein that is shown to attenuate mitochondrial ROS release, were investigated. These investigations showed that SMC-specific Ucp2 knockout mice exhibited signs of PH in normoxic conditions, but no difference in pulmonary vascular remodeling. Interestingly, SMC-specific Ucp2 knockout showed lower HOX-induced increase in right ventricular internal diameter (RVID) and decrease in tricuspid annular plane systolic excursion (TAPSE), although parameters characterizing HOX-induced PH were not different. Taken together, the data presented in this work suggest that ROS release (most probably from mitochondrial complex III) is an upstream event in HPV signaling and COX4i2 is essential for acute hypoxic signaling in the pulmonary vasculature. The role of mitochondrial hyperpolarization needs to be further investigated. Most importantly, acute hypoxic signaling may depend on different mechanisms than chronic hypoxic signaling. Furthermore, Ucp2 knockout specifically in smooth muscle α-actin expressing cells is sufficient to trigger pulmonary vascular alterations under normoxic conditions.de_DE
dc.description.sponsorshipDFGde_DE
dc.language.isoende_DE
dc.subject.ddcddc:570de_DE
dc.titleThe role of mitochondrial reactive oxygen species in oxygen sensing in the pulmonary vasculature – use of novel genetic toolsde_DE
dc.typedoctoralThesisde_DE
dcterms.dateAccepted2021-05-31
local.affiliationMedizinde_DE
local.projectProject number 268555672, SFB 1213, Project A06de_DE
thesis.levelthesis.doctoralde_DE


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