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.
Highlights
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
We observed a significant increase in myocyte nuclear diameter in succinate treated groups (4.3 ± 0.12 μm in cardiomyocytes from control animals vs 5.6 ± 0.2 μm in succinate treated rats, p < 0.001), (Figure 1B), suggesting that high circulating succinate levels might cause cardiac hypertrophy
Since sustained increase in blood pressure is know to cause cardiac hypertrophy [27,28], we investigated whether the hypertrophy induced by high levels of succinate in the blood stream was a consequence of succinate triggering changes in the arterial blood pressure
Summary
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. Cardiac hypertrophy is an adaptive response to biomechanical overload or extracellular stimuli and it is associated with augmented risk of heart failure and sudden death [1,2,3]. Several pathologies including hypertension and ischemic diseases are known to cause hypertrophy [6,7,8,9,10]. Succinate is an important intermediate metabolite of the citric acid cycle and in conditions linked with insufficient blood supply, such as ischemia, succinate blood The exact mechanism is poorly understood [11,12,13].
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call