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  Genetic deletion of p66shc and/or cyclophilin D results in decreased pulmonary vascular tone

Gierhardt, M., Pak, O., Sydykov, A., Kraut, S., Schaffer, J., Garcia, C., et al. (2022). Genetic deletion of p66shc and/or cyclophilin D results in decreased pulmonary vascular tone. CARDIOVASCULAR RESEARCH, 118(1), 305-315. doi:10.1093/cvr/cvaa310.

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Gierhardt, Mareike1, Author              
Pak, Oleg, Author
Sydykov, Akylbek, Author
Kraut, Simone, Author
Schaffer, Julia, Author
Garcia, Claudia, Author
Veith, Christine, Author
Zeidan, Esraa M., Author
Brosien, Monika, Author
Quanz, Karin, Author
Esfandiary, Azadeh, Author
Saraji, Alireza, Author
Hadzic, Stefan, Author
Kojonazarov, Baktybek, Author
Wilhelm, Jochen1, Author              
Ghofrani, Hossein A., Author
Schermuly, Ralph T., Author
Seeger, Werner1, Author              
Grimminger, Friedrich, Author
Herden, Christiane, Author
Schulz, Rainer, AuthorWeissmann, Norbert, AuthorHeger, Jacqueline, AuthorSommer, Natascha, Author more..
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1Lung Development and Remodeling, Max Planck Institute for Heart and Lung Research, Max Planck Society, ou_2591698              

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 Abstract: Aims The pulmonary vascular tone and hypoxia-induced alterations of the pulmonary vasculature may be regulated by the mitochondrial membrane permeability transition pore (mPTP) that controls mitochondrial calcium load and apoptosis. We thus investigated, if the mitochondrial proteins p66shc and cyclophilin D (CypD) that regulate mPTP opening affect the pulmonary vascular tone. Methods and results Mice deficient for p66shc (p66shc(-/-)), CypD (CypD(-/-)), or both proteins (p66shc/CypD(-/-)) exhibited decreased pulmonary vascular resistance (PVR) compared to wild-type mice determined in isolated lungs and in vivo. In contrast, systemic arterial pressure was only lower in CypD(-/-) mice. As cardiac function and pulmonary vascular remodelling did not differ between genotypes, we determined alterations of vascular contractility in isolated lungs and calcium handling in pulmonary arterial smooth muscle cells (PASMC) as underlying reason for decreased PVR. Potassium chloride (KCl)-induced pulmonary vasoconstriction and KCl-induced cytosolic calcium increase determined by Fura-2 were attenuated in all gene-deficient mice. In contrast, KCl-induced mitochondrial calcium increase determined by the genetically encoded Mito-Car-GECO and calcium retention capacity were increased only in CypD(-/-) and p66shc/CypD(-/-) mitochondria indicating that decreased mPTP opening affected KCl-induced intracellular calcium peaks in these cells. All mouse strains showed a similar pulmonary vascular response to chronic hypoxia, while acute hypoxic pulmonary vasoconstriction was decreased in gene-deficient mice indicating that CypD and p66shc regulate vascular contractility but not remodelling. Conclusions We conclude that p66shc specifically regulates the pulmonary vascular tone, while CypD also affects systemic pressure. However, only CypD acts via regulation of mPTP opening and mitochondrial calcium regulation.

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 Dates: 2020-10-292022-01-07
 Publication Status: Published in print
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 Rev. Type: -
 Identifiers: ISI: 000767569800033
DOI: 10.1093/cvr/cvaa310
PMID: 33119054
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Title: CARDIOVASCULAR RESEARCH
Source Genre: Journal
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Pages: - Volume / Issue: 118 (1) Sequence Number: - Start / End Page: 305 - 315 Identifier: ISSN: 0008-6363