Inflammatory Glycoprotein 130 Signaling Links Changes in Microtubules and Junctophilin-2 to Altered Mitochondrial Metabolism and Right Ventricular Contractility.
Animals
Cytokine Receptor gp130
/ drug effects
Heart Failure
/ drug therapy
Heart Ventricles
/ drug effects
Hypertension, Pulmonary
/ drug therapy
Hypertrophy, Right Ventricular
/ drug therapy
Membrane Proteins
/ pharmacology
Microtubules
/ drug effects
Pulmonary Artery
/ drug effects
Rats
Ventricular Dysfunction, Right
/ drug therapy
Ventricular Remodeling
/ drug effects
glycoprotein
interleukin-6
monocrotaline
proteomics
pulmonary arterial hypertension
Journal
Circulation. Heart failure
ISSN: 1941-3297
Titre abrégé: Circ Heart Fail
Pays: United States
ID NLM: 101479941
Informations de publication
Date de publication:
01 2022
01 2022
Historique:
pubmed:
21
12
2021
medline:
23
2
2022
entrez:
20
12
2021
Statut:
ppublish
Résumé
Right ventricular dysfunction (RVD) is the leading cause of death in pulmonary arterial hypertension (PAH), but no RV-specific therapy exists. We showed microtubule-mediated junctophilin-2 dysregulation (MT-JPH2 pathway) causes t-tubule disruption and RVD in rodent PAH, but the druggable regulators of this critical pathway are unknown. GP130 (glycoprotein 130) activation induces cardiomyocyte microtubule remodeling in vitro; however, the effects of GP130 signaling on the MT-JPH2 pathway and RVD resulting from PAH are undefined. Immunoblots quantified protein abundance, quantitative proteomics defined RV microtubule-interacting proteins (MT-interactome), metabolomics evaluated the RV metabolic signature, and transmission electron microscopy assessed RV cardiomyocyte mitochondrial morphology in control, monocrotaline, and monocrotaline-SC-144 (GP130 antagonist) rats. Echocardiography and pressure-volume loops defined the effects of SC-144 on RV-pulmonary artery coupling in monocrotaline rats (8-16 rats per group). In 73 patients with PAH, the relationship between interleukin-6, a GP130 ligand, and RVD was evaluated. SC-144 decreased GP130 activation, which normalized MT-JPH2 protein expression and t-tubule structure in the monocrotaline RV. Proteomics analysis revealed SC-144 restored RV MT-interactome regulation. Ingenuity pathway analysis of dysregulated MT-interacting proteins identified a link between microtubules and mitochondrial function. Specifically, SC-144 prevented dysregulation of electron transport chain, Krebs cycle, and the fatty acid oxidation pathway proteins. Metabolomics profiling suggested SC-144 reduced glycolytic dependence, glutaminolysis induction, and enhanced fatty acid metabolism. Transmission electron microscopy and immunoblots indicated increased mitochondrial fission in the monocrotaline RV, which SC-144 mitigated. GP130 antagonism reduced RV hypertrophy and fibrosis and augmented RV-pulmonary artery coupling without altering PAH severity. In patients with PAH, higher interleukin-6 levels were associated with more severe RVD (RV fractional area change 23±12% versus 30±10%, GP130 antagonism reduces MT-JPH2 dysregulation, corrects metabolic derangements in the RV, and improves RVD in monocrotaline rats.
Sections du résumé
BACKGROUND
Right ventricular dysfunction (RVD) is the leading cause of death in pulmonary arterial hypertension (PAH), but no RV-specific therapy exists. We showed microtubule-mediated junctophilin-2 dysregulation (MT-JPH2 pathway) causes t-tubule disruption and RVD in rodent PAH, but the druggable regulators of this critical pathway are unknown. GP130 (glycoprotein 130) activation induces cardiomyocyte microtubule remodeling in vitro; however, the effects of GP130 signaling on the MT-JPH2 pathway and RVD resulting from PAH are undefined.
METHODS
Immunoblots quantified protein abundance, quantitative proteomics defined RV microtubule-interacting proteins (MT-interactome), metabolomics evaluated the RV metabolic signature, and transmission electron microscopy assessed RV cardiomyocyte mitochondrial morphology in control, monocrotaline, and monocrotaline-SC-144 (GP130 antagonist) rats. Echocardiography and pressure-volume loops defined the effects of SC-144 on RV-pulmonary artery coupling in monocrotaline rats (8-16 rats per group). In 73 patients with PAH, the relationship between interleukin-6, a GP130 ligand, and RVD was evaluated.
RESULTS
SC-144 decreased GP130 activation, which normalized MT-JPH2 protein expression and t-tubule structure in the monocrotaline RV. Proteomics analysis revealed SC-144 restored RV MT-interactome regulation. Ingenuity pathway analysis of dysregulated MT-interacting proteins identified a link between microtubules and mitochondrial function. Specifically, SC-144 prevented dysregulation of electron transport chain, Krebs cycle, and the fatty acid oxidation pathway proteins. Metabolomics profiling suggested SC-144 reduced glycolytic dependence, glutaminolysis induction, and enhanced fatty acid metabolism. Transmission electron microscopy and immunoblots indicated increased mitochondrial fission in the monocrotaline RV, which SC-144 mitigated. GP130 antagonism reduced RV hypertrophy and fibrosis and augmented RV-pulmonary artery coupling without altering PAH severity. In patients with PAH, higher interleukin-6 levels were associated with more severe RVD (RV fractional area change 23±12% versus 30±10%,
CONCLUSIONS
GP130 antagonism reduces MT-JPH2 dysregulation, corrects metabolic derangements in the RV, and improves RVD in monocrotaline rats.
Identifiants
pubmed: 34923829
doi: 10.1161/CIRCHEARTFAILURE.121.008574
pmc: PMC8766918
mid: NIHMS1751346
doi:
Substances chimiques
Membrane Proteins
0
junctophilin
0
Cytokine Receptor gp130
133483-10-0
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
e008574Subventions
Organisme : NHLBI NIH HHS
ID : F32 HL154533
Pays : United States
Organisme : NHLBI NIH HHS
ID : K08 HL140100
Pays : United States
Organisme : NHLBI NIH HHS
ID : T32 HL144472
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR002494
Pays : United States
Commentaires et corrections
Type : CommentIn
Type : CommentIn
Type : CommentIn
Références
JCI Insight. 2019 Oct 17;4(20):
pubmed: 31550236
J Mol Med (Berl). 2017 Apr;95(4):381-393
pubmed: 28265681
Eur Respir J. 2014 Mar;43(3):912-4
pubmed: 24136333
Cytoskeleton (Hoboken). 2013 Nov;70(11):677-85
pubmed: 24039085
Cardiovasc Res. 2017 Oct 1;113(12):1441-1452
pubmed: 28957536
Sci Rep. 2016 Mar 14;6:23010
pubmed: 26972749
Circulation. 2010 Aug 31;122(9):920-7
pubmed: 20713898
Am J Physiol Cell Physiol. 2015 Feb 1;308(3):C237-45
pubmed: 25394469
Pulm Circ. 2016 Dec;6(4):576-585
pubmed: 28090301
Mol Cancer Ther. 2013 Jun;12(6):937-49
pubmed: 23536726
Eur Respir J. 2020 Apr 16;55(4):
pubmed: 32029443
J Clin Invest. 2018 May 1;128(5):1956-1970
pubmed: 29629897
Science. 2015 Dec 4;350(6265):aad0116
pubmed: 26785494
J Am Heart Assoc. 2017 May 31;6(6):
pubmed: 28566298
Am J Physiol Lung Cell Mol Physiol. 2010 Sep;299(3):L401-12
pubmed: 20581101
J Biol Chem. 2019 Mar 8;294(10):3385-3396
pubmed: 30602572
Hypertension. 2012 Feb;59(2):355-62
pubmed: 22203744
Proc Natl Acad Sci U S A. 2013 Feb 19;110(8):2846-51
pubmed: 23386722
J Biol Chem. 2011 Jan 14;286(2):1576-87
pubmed: 21056972
Eur Respir J. 2019 Jan 24;53(1):
pubmed: 30545968
Front Cell Dev Biol. 2016 Mar 22;4:19
pubmed: 27047941
Metabolites. 2019 Mar 22;9(3):
pubmed: 30909447
J Mol Med (Berl). 2013 Oct;91(10):1185-97
pubmed: 23794090
Anal Chem. 2009 Aug 15;81(16):6656-67
pubmed: 19624122
Exp Biol Med (Maywood). 2019 Nov;244(15):1255-1272
pubmed: 31398994
Proc Natl Acad Sci U S A. 1996 Oct 15;93(21):11664-8
pubmed: 8876193
Cardiovasc Res. 2014 Jul 15;103(2):198-205
pubmed: 24935431
Eur Respir J. 2019 Jan 24;53(1):
pubmed: 30545976
JACC Basic Transl Sci. 2020 Dec 28;5(12):1244-1260
pubmed: 33426379
J Mol Med (Berl). 2013 Mar;91(3):333-46
pubmed: 23247844
Ann Am Thorac Soc. 2016 Feb;13(2):276-84
pubmed: 26848601
Circ Heart Fail. 2021 Feb;14(2):e007058
pubmed: 33541093
Eur Respir J. 2020 Apr 16;55(4):
pubmed: 32300021
Biochem J. 1998 Sep 1;334 ( Pt 2):297-314
pubmed: 9716487
Int J Mol Sci. 2020 Oct 01;21(19):
pubmed: 33019763
BMC Bioinformatics. 2012 Jun 18;13:134
pubmed: 22708584
Basic Res Cardiol. 2014 Jan;109(1):396
pubmed: 24292852
Cold Spring Harb Perspect Biol. 2013 Jun 01;5(6):
pubmed: 23732472
Nature. 2020 Dec;588(7838):466-472
pubmed: 32971526
JACC Basic Transl Sci. 2016 Apr;1(3):122-130
pubmed: 27482548
Immunity. 2019 Apr 16;50(4):812-831
pubmed: 30995501
J Am Heart Assoc. 2019 Jan 8;8(1):e011343
pubmed: 30590974
J Heart Lung Transplant. 2018 Mar;37(3):376-384
pubmed: 28893516
Int J Mol Sci. 2018 Sep 12;19(9):
pubmed: 30213070
Cytokine Growth Factor Rev. 2012 Jun;23(3):85-97
pubmed: 22595692
Am J Physiol Lung Cell Mol Physiol. 2009 Dec;297(6):L1013-32
pubmed: 19748998
Science. 2016 Apr 22;352(6284):aaf0659
pubmed: 27102488
Database (Oxford). 2016 Jul 03;2016:
pubmed: 27374120
Circulation. 2016 May 17;133(20):1936-44
pubmed: 27006481
DNA Cell Biol. 2015 Apr;34(4):290-5
pubmed: 25621430
Ann Neurol. 2008 Nov;64(5):555-65
pubmed: 19067348
JCI Insight. 2019 Apr 25;5:
pubmed: 31021818
J Mol Cell Cardiol. 2011 Apr;50(4):634-41
pubmed: 21223972
Circulation. 2014 Apr 29;129(17):1742-50
pubmed: 24519927
Int J Cardiol. 2016 Dec 15;225:371-380
pubmed: 27760414
J Cell Biol. 2009 Aug 10;186(3):363-9
pubmed: 19651889