title: The Succinate Receptor GPR91 Is Involved in Pressure Overload-Induced Ventricular Hypertrophy.
abstract: BACKGROUND
  Pulmonary arterial hypertension is characterized by increased pressure overload that leads to right ventricular hypertrophy (RVH). GPR91 is a formerly orphan G-protein-coupled receptor (GPCR) that has been characterized as a receptor for succinate; however, its role in RVH remains unknown.
  
  
  RESULTS
  We investigated the role of succinate-GPR91 signaling in a pulmonary arterial banding (PAB) model of RVH induced by pressure overload in SD rats. GPR91 was shown to be located in cardiomyocytes. In the sham and PAB rats, succinate treatment further aggravated RVH, up-regulated RVH-associated genes and increased p-Akt/t-Akt levels in vivo. In vitro, succinate treatment up-regulated the levels of the hypertrophic gene marker anp and p-Akt/t-Akt in cardiomyocytes. All these effects were inhibited by the PI3K antagonist wortmannin both in vivo and in vitro. Finally, we noted that the GPR91-PI3K/Akt axis was also up-regulated compared to that in human RVH.
  
  
  CONCLUSIONS
  Our findings indicate that succinate-GPR91 signaling may be involved in RVH via PI3K/Akt signaling in vivo and in vitro. Therefore, GPR91 may be a novel therapeutic target for treating pressure overload-induced RVH.
authors.affiliation: Department of Gastroenterology, Nanjing Children's Hospital, Affiliated to Nanjing Medical University, Nanjing, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Cardiothoracic Surgery, Nanjing Children's Hospital, Affiliated to Nanjing Medical University, Nanjing, China.
authors.forename: Di
authors.initials: D
authors.lastname: Yu
authors.affiliation: Department of Cardiothoracic Surgery, Nanjing Drum Tower Hospital, the affiliated hospital of Nanjing University Medical School, Nanjing, China.
authors.forename: Ran
authors.initials: R
authors.lastname: Mo
authors.affiliation: Department of Anesthesiology, Affiliated Hospital of Jiangnan University, Wuxi No.4 People's Hospital, Nanjing, China.
authors.forename: Jiru
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Cardiothoracic Surgery, Nanjing Children's Hospital, Affiliated to Nanjing Medical University, Nanjing, China.
authors.forename: Hu
authors.initials: H
authors.lastname: Hua
authors.affiliation: Department of Cardiothoracic Surgery, Nanjing Children's Hospital, Affiliated to Nanjing Medical University, Nanjing, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Hu
authors.affiliation: Department of Cardiothoracic Surgery, Nanjing Children's Hospital, Affiliated to Nanjing Medical University, Nanjing, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Feng
authors.affiliation: Department of Cardiothoracic Surgery, Nanjing Children's Hospital, Affiliated to Nanjing Medical University, Nanjing, China.
authors.forename: Song
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Cardiothoracic Surgery, Nanjing Children's Hospital, Affiliated to Nanjing Medical University, Nanjing, China.
authors.forename: Wei-Yan
authors.initials: WY
authors.lastname: Zhang
authors.affiliation: Department of Anesthesiology, Zhongda Hospital, Southeast University, Nanjing, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Yin
authors.affiliation: Department of Cardiothoracic Surgery, Nanjing Children's Hospital, Affiliated to Nanjing Medical University, Nanjing, China.
authors.forename: Xu-Ming
authors.initials: XM
authors.lastname: Mo
mesh_terms: D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D006352:Heart Ventricles / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D006976:Hypertension, Pulmonary / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D017380:Hypertrophy, Right Ventricular / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D011651:Pulmonary Artery / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013318:Stroke Volume; D019802:Succinic Acid / Q000378:metabolism* / Q000494:pharmacology; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D009320:Atrial Natriuretic Factor; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering; D043562:Receptors, G-Protein-Coupled; D019802:Succinic Acid; D000077191:Wortmannin; C523503:Sucnr1 protein, rat
references.citation: Int J Cardiol. 2013 Oct 9;168(4):3160-72
references.pmid: 23932046
references.citation: Cardiovasc Res. 2008 Jun 1;78(3):505-14
references.pmid: 18281373
references.citation: Respir Res. 2014;15:159
references.pmid: 25551628
references.citation: PLoS One. 2014;9(7):e101438
references.pmid: 25007154
references.citation: J Korean Med Sci. 2012 Jun;27(6):605-13
references.pmid: 22690090
references.citation: Nat Immunol. 2008 Nov;9(11):1261-9
references.pmid: 18820681
references.citation: Exp Physiol. 2013 Aug;98(8):1274-8
references.pmid: 23873899
references.citation: Respir Res. 2011;12:159
references.pmid: 22185646
references.citation: Eur J Clin Invest. 2013 Apr;43(4):397-404
references.pmid: 23398121
references.citation: Hepatology. 2015 Jan;61(1):326-36
references.pmid: 25142022
references.citation: J Mol Med (Berl). 2013 Oct;91(10):1185-97
references.pmid: 23794090
references.citation: Nature. 2004 May 13;429(6988):188-93
references.pmid: 15141213
references.citation: Am J Physiol Cell Physiol. 2015 Jan 15;308(2):C155-63
references.pmid: 25377088
references.citation: Free Radic Biol Med. 2012 May 1;52(9):1970-86
references.pmid: 22401856
references.citation: Pathol Res Pract. 2013 May;209(5):302-8
references.pmid: 23582365
references.citation: Diabetologia. 2014 Nov;57(11):2282-95
references.pmid: 25091629
references.citation: Cell Calcium. 2010 Jan;47(1):37-46
references.pmid: 20018372
references.citation: Nature. 2014 Nov 20;515(7527):431-5
references.pmid: 25383517
references.citation: Cell Physiol Biochem. 2014;33(2):310-20
references.pmid: 24525799
references.citation: Med Sci Monit. 2015;21:9-17
references.pmid: 25553410
references.citation: Clin Sci (Lond). 2013 May;124(9):553-66
references.pmid: 23336210
references.citation: Pulm Circ. 2013 Dec;3(4):936-51
references.pmid: 25006410
references.citation: Exp Eye Res. 2013 Apr;109:31-9
references.pmid: 23379999
references.citation: Exp Cell Res. 2014 Oct 15;328(1):143-55
references.pmid: 25102377
references.citation: J Bioenerg Biomembr. 2014 Oct;46(5):357-70
references.pmid: 25104045
references.citation: Cell Biochem Biophys. 2013 Nov;67(2):305-16
references.pmid: 23897578
references.citation: Circ Heart Fail. 2013 Sep 1;6(5):1039-48
references.pmid: 23861485
references.citation: PLoS One. 2012;7(8):e43433
references.pmid: 22912874
references.citation: Pulm Circ. 2011 Oct-Dec;1(4):470-4
references.pmid: 22530102
references.citation: Circulation. 2012 Dec 11;126(24):2859-69
references.pmid: 23124027
references.citation: J Dev Orig Health Dis. 2011 Jun;2(3):184-9
references.pmid: 25141044
references.citation: DNA Repair (Amst). 2014 Oct;22:24-9
references.pmid: 25086499
references.citation: FEBS Lett. 2013 Aug 2;587(15):2399-404
references.pmid: 23770096
references.citation: Int J Cardiol. 2015 Feb 15;181:232-4
references.pmid: 25528526
references.citation: Am J Clin Exp Immunol. 2014 Aug 15;3(2):97-106
references.pmid: 25143870
references.citation: Am J Physiol Renal Physiol. 2013 Aug 15;305(4):F439-44
references.pmid: 23761671
references.citation: Free Radic Biol Med. 2014 Apr;69:35-49
references.pmid: 24423485
references.citation: Semin Nucl Med. 2014 Mar;44(2):110-22
references.pmid: 24484748
references.citation: Oxid Med Cell Longev. 2013;2013:471790
references.pmid: 23533692
references.citation: MBio. 2014;5(4). pii: e01093-14. doi: 10.1128/mBio.01093-14
references.pmid: 25118234
references.citation: Cancer Lett. 2015 Apr 1;359(1):47-56
references.pmid: 25554016
references.citation: Pulm Pharmacol Ther. 2014 Oct;29(1):7-14
references.pmid: 24417910
references.citation: Multimed Man Cardiothorac Surg. 2012 Jan 1;2012:mms010
references.pmid: 24414714
references.citation: PLoS One. 2014;9(8):e105172
references.pmid: 25121974
references.citation: Am J Physiol Heart Circ Physiol. 2012 Apr 15;302(8):H1655-66
references.pmid: 22245771
references.citation: Front Endocrinol (Lausanne). 2012 Feb 16;3:22
references.pmid: 22649411
references.citation: Biochem Biophys Res Commun. 2014 Oct 24;453(3):600-5
references.pmid: 25301555
references.citation: J Exp Biol. 2014 Jul 1;217(Pt 13):2348-57
references.pmid: 25141346
references.citation: J Dev Orig Health Dis. 2014 Feb;5(1):36-44
references.pmid: 24847689
references.citation: Bioorg Med Chem Lett. 2014 Sep 1;24(17):4073-9
references.pmid: 25086683
references.citation: Springerplus. 2014 Jul 14;3:356
references.pmid: 25089247
references.citation: J Pharmacol Exp Ther. 2011 Jan;336(1):56-63
references.pmid: 20947636
references.citation: Handb Exp Pharmacol. 2013;218:105-49
references.pmid: 24092338
references.citation: Life Sci. 2014 Mar 7;98(1):39-43
references.pmid: 24412385
references.citation: J Mol Med (Berl). 2010 Oct;88(10):1011-20
references.pmid: 20820751
references.citation: Circ Cardiovasc Imaging. 2014 Mar;7(2):240-9
references.pmid: 24425501
references.citation: Kaohsiung J Med Sci. 2014 Jun;30(6):267-78
references.pmid: 24835346
references.citation: Am J Physiol Lung Cell Mol Physiol. 2014 Aug 1;307(3):L261-72
references.pmid: 24951776