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: Carla J Aguiar, João A Rocha-Franco, Pedro A Sousa, Anderson K Santos, Marina Ladeira, Cibele Rocha-Resende, Luiz O Ladeira, Rodrigo R Resende, Fernando A Botoni, Marcos Barrouin Melo, Cristiano X Lima, José M Carballido, Thiago M Cunha, Gustavo B Menezes, Silvia Guatimosim, M Fatima Leite
• Journal: Cell communication and signaling : CCS (Cell Commun Signal) Vol. 12 Pg. 78 (Dec 24 2014) ISSN: 1478-811X [Electronic] England
• PMID: 25539979 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• GPR91 protein, mouse
• Receptors, G-Protein-Coupled
• SUCNR1 protein, human
• Sucnr1 protein, rat
• Succinic Acid
• Calcium-Calmodulin-Dependent Protein Kinase Type 2
• Mitogen-Activated Protein Kinase Kinases
• Hdac5 protein, rat
• Histone Deacetylases
• Calcium

Topics

• Adult
• Animals
• Animals, Newborn
• Blood Pressure (drug effects)
• Calcium (metabolism)
• Calcium-Calmodulin-Dependent Protein Kinase Type 2 (metabolism)
• Heart Diseases (metabolism, pathology)
• Histone Deacetylases (metabolism)
• Humans
• Liver Cirrhosis (metabolism)
• Mice, Knockout
• Middle Aged
• Mitogen-Activated Protein Kinase Kinases (metabolism)
• Myocytes, Cardiac (metabolism, pathology)
• Rats, Wistar
• Receptors, G-Protein-Coupled (metabolism)
• Succinic Acid (blood, metabolism)