PKG1α Cysteine-42 Redox State Controls mTORC1 Activation in Pathological Cardiac Hypertrophy.
Animals
Aorta
Autophagy
/ physiology
Benzoates
/ metabolism
Biphenyl Compounds
/ metabolism
Cardiomegaly
/ metabolism
Constriction, Pathologic
Cyclic GMP-Dependent Protein Kinase Type I
/ genetics
Cysteine
/ metabolism
Endothelin-1
/ pharmacology
Enzyme Activation
Everolimus
/ pharmacology
Gene Knock-In Techniques
Guanylate Cyclase
/ metabolism
Hydrocarbons, Fluorinated
/ metabolism
Mechanistic Target of Rapamycin Complex 1
/ antagonists & inhibitors
Mice
Mice, Inbred C57BL
Myocytes, Cardiac
/ drug effects
Oxidation-Reduction
Oxidative Stress
Phosphorylation
Pressure
Proteostasis
Rats
Tuberous Sclerosis Complex 2 Protein
/ genetics
autophagy
heart failure
hypertrophy
mice
phosphorylation
Journal
Circulation research
ISSN: 1524-4571
Titre abrégé: Circ Res
Pays: United States
ID NLM: 0047103
Informations de publication
Date de publication:
31 07 2020
31 07 2020
Historique:
pubmed:
13
5
2020
medline:
22
5
2021
entrez:
13
5
2020
Statut:
ppublish
Résumé
Stimulated PKG1α (protein kinase G-1α) phosphorylates TSC2 (tuberous sclerosis complex 2) at serine 1365, potently suppressing mTORC1 (mechanistic [mammalian] target of rapamycin complex 1) activation by neurohormonal and hemodynamic stress. This reduces pathological hypertrophy and dysfunction and increases autophagy. PKG1α oxidation at cysteine-42 is also induced by these stressors, which blunts its cardioprotective effects. We tested the dependence of mTORC1 activation on PKG1α C42 oxidation and its capacity to suppress such activation by soluble GC-1 (guanylyl cyclase 1) activation. Cardiomyocytes expressing wild-type (WT) PKG1α (PKG1α Oxidation of PKG1α at C42 reduces its phosphorylation of TSC2, resulting in amplified PO-stimulated mTORC1 activity and associated hypertrophy, dysfunction, and depressed autophagy. This is ameliorated by direct GC-1 stimulation.
Identifiants
pubmed: 32393148
doi: 10.1161/CIRCRESAHA.119.315714
pmc: PMC7416445
mid: NIHMS1593956
doi:
Substances chimiques
4-(((4-carboxybutyl) (2- (5-fluoro-2-((4'-(trifluoromethyl) biphenyl-4-yl)methoxy)phenyl)ethyl) amino)methyl)benzoic acid
0
Benzoates
0
Biphenyl Compounds
0
Endothelin-1
0
Hydrocarbons, Fluorinated
0
Tsc2 protein, mouse
0
Tuberous Sclerosis Complex 2 Protein
0
Everolimus
9HW64Q8G6G
Mechanistic Target of Rapamycin Complex 1
EC 2.7.11.1
Cyclic GMP-Dependent Protein Kinase Type I
EC 2.7.11.12
Guanylate Cyclase
EC 4.6.1.2
Cysteine
K848JZ4886
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
522-533Subventions
Organisme : American Heart Association-American Stroke Association
ID : 16POST29090003
Pays : United States
Organisme : NHLBI NIH HHS
ID : F31 HL134196
Pays : United States
Organisme : NHLBI NIH HHS
ID : T32 HL007227
Pays : United States
Organisme : American Heart Association-American Stroke Association
ID : 11POST7730049
Pays : United States
Organisme : NHLBI NIH HHS
ID : R35 HL135827
Pays : United States
Organisme : American Heart Association-American Stroke Association
ID : 18CDA34110140
Pays : United States
Organisme : NHLBI NIH HHS
ID : F31 HL143905
Pays : United States
Organisme : NHLBI NIH HHS
ID : HHSN268201000032C
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL119012
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL089297
Pays : United States
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