Genetic deletion of p66shc and/or cyclophilin D results in decreased pulmonary vascular tone.
Animals
Arterial Pressure
Calcium
/ metabolism
Calcium Signaling
Cell Proliferation
Cells, Cultured
Peptidyl-Prolyl Isomerase F
/ deficiency
Disease Models, Animal
Gene Deletion
Hypertension, Pulmonary
/ enzymology
Hypoxia
/ complications
Mice, Inbred C57BL
Mice, Knockout
Mitochondria
/ enzymology
Mitochondrial Permeability Transition Pore
/ metabolism
Pulmonary Artery
/ enzymology
Src Homology 2 Domain-Containing, Transforming Protein 1
/ deficiency
Vascular Remodeling
Vascular Resistance
Vasoconstriction
Calcium
CypD
Pulmonary hypertension
mitochondria
p66shc
Journal
Cardiovascular research
ISSN: 1755-3245
Titre abrégé: Cardiovasc Res
Pays: England
ID NLM: 0077427
Informations de publication
Date de publication:
07 01 2022
07 01 2022
Historique:
received:
28
04
2019
accepted:
15
10
2020
pubmed:
30
10
2020
medline:
8
3
2022
entrez:
29
10
2020
Statut:
ppublish
Résumé
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. 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. 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.
Identifiants
pubmed: 33119054
pii: 5942975
doi: 10.1093/cvr/cvaa310
pmc: PMC8752355
doi:
Substances chimiques
Peptidyl-Prolyl Isomerase F
0
Mitochondrial Permeability Transition Pore
0
Shc1 protein, mouse
0
Src Homology 2 Domain-Containing, Transforming Protein 1
0
Calcium
SY7Q814VUP
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
305-315Commentaires et corrections
Type : CommentIn
Informations de copyright
© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.
Références
Am J Physiol Lung Cell Mol Physiol. 2000 Nov;279(5):L884-94
pubmed: 11053024
Am J Respir Cell Mol Biol. 2013 Sep;49(3):358-67
pubmed: 23590303
Circ Res. 2012 Oct 12;111(9):1237-47
pubmed: 23065346
Cardiovasc Res. 2001 Apr;50(1):145-50
pubmed: 11282087
Br J Pharmacol. 2000 Sep;131(1):5-9
pubmed: 10960061
Am J Respir Crit Care Med. 2012 Feb 15;185(4):409-19
pubmed: 22161164
Am J Physiol. 1993 Mar;264(3 Pt 1):L323-8
pubmed: 8384800
Int J Cardiol. 2013 Sep 10;167(6):2630-7
pubmed: 22854298
Br J Pharmacol. 2017 Jun;174(12):1690-1703
pubmed: 26990284
Antioxid Redox Signal. 2015 Feb 20;22(6):537-52
pubmed: 25545236
J Clin Invest. 2010 Oct;120(10):3680-7
pubmed: 20890047
Am J Physiol. 1992 Jun;262(6 Pt 2):H1699-704
pubmed: 1377876
PLoS One. 2013 Nov 07;8(11):e80574
pubmed: 24348912
Proc Natl Acad Sci U S A. 1998 Sep 29;95(20):11715-20
pubmed: 9751731
Compr Physiol. 2016 Mar 15;6(2):897-943
pubmed: 27065170
Circ Res. 2001 Jun 22;88(12):1259-66
pubmed: 11420302
Chest. 2009 Mar;135(3):794-804
pubmed: 19265089
Endocrinology. 2001 Aug;142(8):3317-23
pubmed: 11459773
J Biol Chem. 2013 Oct 18;288(42):30672-30681
pubmed: 24014035
Thromb Haemost. 2005 Sep;94(3):630-8
pubmed: 16268482
Biochim Biophys Acta. 2011 Jul;1813(7):1316-22
pubmed: 21295622
Science. 2007 Feb 2;315(5812):659-63
pubmed: 17272725
Histochem Cell Biol. 2016 Jul;146(1):71-84
pubmed: 27010815
Arch Biochem Biophys. 2009 Jun 1;486(1):73-80
pubmed: 19327338
Nature. 1999 Nov 18;402(6759):309-13
pubmed: 10580504
Nat Rev Mol Cell Biol. 2012 Sep;13(9):566-78
pubmed: 22850819
Basic Res Cardiol. 2011 Nov;106(6):1123-34
pubmed: 21744279
Eur Respir J. 2016 Jan;47(1):288-303
pubmed: 26493804
Proc Natl Acad Sci U S A. 2006 Dec 12;103(50):19093-8
pubmed: 17142322
Basic Res Cardiol. 2009 Mar;104(2):131-9
pubmed: 19242637
Circulation. 2015 Feb 10;131(6):582-90
pubmed: 25666980
Circ Res. 2004 Aug 6;95(3):261-8
pubmed: 15217909
Biosci Rep. 2019 Apr 30;39(4):
pubmed: 30918103
Cell. 2005 Jul 29;122(2):221-33
pubmed: 16051147
Free Radic Biol Med. 2014 Mar;68:268-77
pubmed: 24378437
Circulation. 2006 Jan 17;113(2):286-95
pubmed: 16391154
Circ Res. 1977 Jul;41(1):19-26
pubmed: 862138
Int J Clin Exp Pathol. 2015 Feb 01;8(2):1081-92
pubmed: 25972995
Mitochondrion. 2015 Jul;23:7-16
pubmed: 25922169
Biochem J. 1992 Jun 1;284 ( Pt 2):381-5
pubmed: 1599421
J Biol Chem. 2005 May 13;280(19):18558-61
pubmed: 15792954
J Res Natl Inst Stand Technol. 2008 Aug 01;113(4):239-49
pubmed: 27096124
Hypertension. 2005 Aug;46(2):433-40
pubmed: 15998704
Oxid Med Cell Longev. 2013;2013:719407
pubmed: 23766859
J Biol Chem. 2013 Feb 22;288(8):5553-61
pubmed: 23303179
Circ Res. 1976 Feb;38(2):99-104
pubmed: 1245025
J Vis Exp. 2013 Nov 27;(81):
pubmed: 24326586
Mol Cancer. 2015 Apr 08;14:76
pubmed: 25890053
Pulm Circ. 2016 Mar;6(1):93-102
pubmed: 27076907