Succinate causes pathological cardiomyocyte hypertrophy through GPR91 activation

Abstract

BackgroundSuccinate 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.ResultsWe 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.ConclusionsThese 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12964-014-0078-2) contains supplementary material, which is available to authorized users.

Metabolomic Profiling in Acute ST‐Segment–Elevation Myocardial Infarction Identifies Succinate as an Early Marker of Human Ischemia–Reperfusion Injury

“…Another reason for reduced myocardial succinate release was that NSTEMI patients underwent PCI (and, therefore, blood sampling) within 72 hours of hospital admission, which allowed time for succinate accumulation to resolve, unlike the STEMI patients, who underwent emergency PCI on arrival. Only 1 previous study described succinate concentration in PVs of myocardial infarction patients 10 . In that study, the peripheral blood succinate concentration was assessed in only 3 patients with acute myocardial infarction and was shown to be significantly higher than in healthy volunteers.…”

“…Because of ethical considerations, blood samples of the CS and aortic root could not be obtained from healthy volunteers; therefore, the level of succinate under these conditions is unknown. However, in a study that investigated the role of succinate in cardiac hypertrophy, the authors were unable to detect succinate in peripheral blood, 10 suggesting that the succinate concentration in the CS and aortic root is likely to be low in healthy participants.…”

Insight into SUCNR1 (GPR91) structure and function

“…However, this does not preclude a local signaling role of succinate, which may not be reflected by the circulating levels. Hence, as an indirect example of chronic hypertension, serum succinate levels are increased in patients suffering from cardiac hypertrophy (CH) (Aguiar et al, 2014). Activated SUCNR1 may indirectly contribute to CH by inducing hypertension but might also have a direct action because it is expressed at protein level in ventricular cardiomyocytes (in sarcolemmal membrane and T-tubules) (Aguiar et al, 2010;Aguiar et al, 2014).…”

“…Hence, as an indirect example of chronic hypertension, serum succinate levels are increased in patients suffering from cardiac hypertrophy (CH) (Aguiar et al, 2014). Activated SUCNR1 may indirectly contribute to CH by inducing hypertension but might also have a direct action because it is expressed at protein level in ventricular cardiomyocytes (in sarcolemmal membrane and T-tubules) (Aguiar et al, 2010;Aguiar et al, 2014). In these cells, SUCNR1 activation triggers hypertrophic gene expression via ERK1/2 phosphorylation, increased expression of calcium/calmodulin-dependent protein kinase IIδ (CaMKIIδ) and the translocation of histone deacetylase 5 (HDAC5) into the cytoplasm (Aguiar et al, 2014).…”

“…Activated SUCNR1 may indirectly contribute to CH by inducing hypertension but might also have a direct action because it is expressed at protein level in ventricular cardiomyocytes (in sarcolemmal membrane and T-tubules) (Aguiar et al, 2010;Aguiar et al, 2014). In these cells, SUCNR1 activation triggers hypertrophic gene expression via ERK1/2 phosphorylation, increased expression of calcium/calmodulin-dependent protein kinase IIδ (CaMKIIδ) and the translocation of histone deacetylase 5 (HDAC5) into the cytoplasm (Aguiar et al, 2014). Moreover, it was shown in another study by the same group as for cardiomyocytes, SUCNR1 alters Ca 2+ transient via AC and protein kinase A (PKA) activation that phosphorylate phospholamban (PLN) and ryanodine receptor 2 (RyR2), two well-known Ca 2+ handling proteins (Aguiar et al, 2010).…”