title: Succinate causes pathological cardiomyocyte hypertrophy through GPR91 activation.
abstract: BACKGROUND
  Succinate is an intermediate of the citric acid cycle as well as an extracellular circulating molecule, whose receptor, G protein-coupled receptor-91 (GPR91), was recently identified and characterized in several tissues, including heart. Because some pathological conditions such as ischemia increase succinate blood levels, we investigated the role of this metabolite during a heart ischemic event, using human and rodent models.
  
  
  RESULTS
  We found that succinate causes cardiac hypertrophy in a GPR91 dependent manner. GPR91 activation triggers the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), the expression of calcium/calmodulin dependent protein kinase IIδ (CaMKIIδ) and the translocation of histone deacetylase 5 (HDAC5) into the cytoplasm, which are hypertrophic-signaling events. Furthermore, we found that serum levels of succinate are increased in patients with cardiac hypertrophy associated with acute and chronic ischemic diseases.
  
  
  CONCLUSIONS
  These results show for the first time that succinate plays an important role in cardiomyocyte hypertrophy through GPR91 activation, and extend our understanding of how ischemia can induce hypertrophic cardiomyopathy.
authors.affiliation: Department of Physiology and Biophysics, Federal University of Minas Gerais, Av. Antônio Carlos 6627, Belo Horizonte, MG - CEP: 31270-901, Brazil. carlajeane33@hotmail.com.
authors.forename: Carla J
authors.initials: CJ
authors.lastname: Aguiar
authors.affiliation: Department of Physiology and Biophysics, Federal University of Minas Gerais, Av. Antônio Carlos 6627, Belo Horizonte, MG - CEP: 31270-901, Brazil. joaoantoniodarochafranco@hotmail.com.
authors.forename: João A
authors.initials: JA
authors.lastname: Rocha-Franco
authors.affiliation: Department of Physiology and Biophysics, Federal University of Minas Gerais, Av. Antônio Carlos 6627, Belo Horizonte, MG - CEP: 31270-901, Brazil. pedro.sousa@yale.edu.
authors.forename: Pedro A
authors.initials: PA
authors.lastname: Sousa
authors.affiliation: Department of Biochemistry and Immunology, Federal University of Minas Gerais, Av. Antônio Carlos 6627, Belo Horizonte, MG - CEP: 31270-901, Brazil. andersonk.santos@hotmail.com.
authors.forename: Anderson K
authors.initials: AK
authors.lastname: Santos
authors.affiliation: Department of Physiology and Biophysics, Federal University of Minas Gerais, Av. Antônio Carlos 6627, Belo Horizonte, MG - CEP: 31270-901, Brazil. marinasladeira@gmail.com.
authors.forename: Marina
authors.initials: M
authors.lastname: Ladeira
authors.affiliation: Department of Physiology and Biophysics, Federal University of Minas Gerais, Av. Antônio Carlos 6627, Belo Horizonte, MG - CEP: 31270-901, Brazil. cibelerr@ufmg.br.
authors.forename: Cibele
authors.initials: C
authors.lastname: Rocha-Resende
authors.affiliation: Department of Physics, Federal University of Minas Gerais, Av. Antônio Carlos 6627, Belo Horizonte, MG - CEP: 31270-901, Brazil. ladeira@fisica.ufmg.br.
authors.forename: Luiz O
authors.initials: LO
authors.lastname: Ladeira
authors.affiliation: Department of Biochemistry and Immunology, Federal University of Minas Gerais, Av. Antônio Carlos 6627, Belo Horizonte, MG - CEP: 31270-901, Brazil. rrresende@hotmail.com.
authors.forename: Rodrigo R
authors.initials: RR
authors.lastname: Resende
authors.affiliation: Department of Medicine, Federal University of Minas Gerais, Av. Antônio Carlos 6627, Belo Horizonte, MG - CEP: 31270-901, Brazil. fabotoni@gmail.com.
authors.forename: Fernando A
authors.initials: FA
authors.lastname: Botoni
authors.affiliation: Department of Physiology and Biophysics, Federal University of Minas Gerais, Av. Antônio Carlos 6627, Belo Horizonte, MG - CEP: 31270-901, Brazil. mbarrouin@gmail.com.
authors.forename: Marcos
authors.initials: M
authors.lastname: Barrouin Melo
authors.affiliation: Department of Medicine, Federal University of Minas Gerais, Av. Antônio Carlos 6627, Belo Horizonte, MG - CEP: 31270-901, Brazil. cristianoxlima@gmail.com.
authors.forename: Cristiano X
authors.initials: CX
authors.lastname: Lima
authors.affiliation: Novartis Institutes for Biomedical Research, Basel, CH-4002, Switzerland. jose.carballido@novartis.com.
authors.forename: José M
authors.initials: JM
authors.lastname: Carballido
authors.affiliation: Department of Pharmacology, Ribeirão Preto, Medical School, University of São Paulo, São Paulo, Brazil. thicunha@usp.br.
authors.forename: Thiago M
authors.initials: TM
authors.lastname: Cunha
authors.affiliation: Department of Morphology, Federal University of Minas Gerais, Av. Antônio Carlos 6627, Belo Horizonte, MG - CEP: 31270-901, Brazil. menezesgb@gmail.com.
authors.forename: Gustavo B
authors.initials: GB
authors.lastname: Menezes
authors.affiliation: Department of Physiology and Biophysics, Federal University of Minas Gerais, Av. Antônio Carlos 6627, Belo Horizonte, MG - CEP: 31270-901, Brazil. silvia.guatimosim@gmail.com.
authors.forename: Silvia
authors.initials: S
authors.lastname: Guatimosim
authors.affiliation: Department of Physiology and Biophysics, Federal University of Minas Gerais, Av. Antônio Carlos 6627, Belo Horizonte, MG - CEP: 31270-901, Brazil. leitemd@ufmg.br.
authors.forename: M Fatima
authors.initials: MF
authors.lastname: Leite
mesh_terms: D000328:Adult; D000818:Animals; D000831:Animals, Newborn; D001794:Blood Pressure / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D006331:Heart Diseases / Q000378:metabolism* / Q000473:pathology; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D008103:Liver Cirrhosis / Q000378:metabolism; D018345:Mice, Knockout; D008875:Middle Aged; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D017208:Rats, Wistar; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D019802:Succinic Acid / Q000097:blood / Q000378:metabolism*
chemical_list: C531499:GPR91 protein, mouse; D043562:Receptors, G-Protein-Coupled; C557078:SUCNR1 protein, human; C523503:Sucnr1 protein, rat; D019802:Succinic Acid; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D020929:Mitogen-Activated Protein Kinase Kinases; C498619:Hdac5 protein, rat; D006655:Histone Deacetylases; D002118:Calcium