1. Succinate causes pathological cardiomyocyte hypertrophy through GPR91 activation.
- Author
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Aguiar CJ, Rocha-Franco JA, Sousa PA, Santos AK, Ladeira M, Rocha-Resende C, Ladeira LO, Resende RR, Botoni FA, Barrouin Melo M, Lima CX, Carballido JM, Cunha TM, Menezes GB, Guatimosim S, and Leite MF
- Subjects
- Adult, Animals, Animals, Newborn, Blood Pressure drug effects, Calcium metabolism, Calcium-Calmodulin-Dependent Protein Kinase Type 2 metabolism, Heart Diseases pathology, Histone Deacetylases metabolism, Humans, Liver Cirrhosis metabolism, Mice, Knockout, Middle Aged, Mitogen-Activated Protein Kinase Kinases metabolism, Myocytes, Cardiac metabolism, Myocytes, Cardiac pathology, Rats, Wistar, Succinic Acid blood, Heart Diseases metabolism, Receptors, G-Protein-Coupled metabolism, Succinic Acid metabolism
- 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.
- Published
- 2014
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