Succinate causes pathological cardiomyocyte hypertrophy through GPR91 activation

被引：108

作者：

Aguiar, Carla J. ^{[1
]}

Rocha-Franco, Joao A. ^{[1
]}

Sousa, Pedro A. ^{[1
]}

Santos, Anderson K. ^{[2
]}

Ladeira, Marina ^{[1
]}

Rocha-Resende, Cibele ^{[1
]}

Ladeira, Luiz O. ^{[3
]}

Resende, Rodrigo R. ^{[2
]}

Botoni, Fernando A. ^{[4
]}

Melo, Marcos Barrouin ^{[1
]}

Lima, Cristiano X. ^{[4
]}

Carballido, Jose M. ^{[5
]}

Cunha, Thiago M. ^{[6
]}

Menezes, Gustavo B. ^{[7
]}

Guatimosim, Silvia ^{[1
]}

Leite, M. Fatima ^{[1
]}

机构：

[1] Univ Fed Minas Gerais, Dept Physiol & Biophys, BR-31270901 Belo Horizonte, MG, Brazil

[2] Univ Fed Minas Gerais, Dept Biochem & Immunol, BR-31270901 Belo Horizonte, MG, Brazil

[3] Univ Fed Minas Gerais, Dept Phys, BR-31270901 Belo Horizonte, MG, Brazil

[4] Univ Fed Minas Gerais, Dept Med, BR-31270901 Belo Horizonte, MG, Brazil

[5] Novartis Inst Biomed Res, CH-4002 Basel, Switzerland

[6] Univ Sao Paulo, Sch Med, Dept Pharmacol, Sao Paulo, Brazil

[7] Univ Fed Minas Gerais, Dept Morphol, BR-31270901 Belo Horizonte, MG, Brazil

来源：

CELL COMMUNICATION AND SIGNALING | 2014年 / 12卷

关键词：

Succinate; Cardiomyocyte; Hypertrophy; CARDIAC GENE-EXPRESSION; VENTRICULAR HYPERTROPHY; SIGNALING PATHWAYS; RECEPTOR GPR91; PROTEIN-KINASE; HEART-FAILURE; LIVER-TRANSPLANTATION; MYOCARDIAL-INFARCTION; HISTONE DEACETYLASE-5; CALCINEURIN-NFAT;

D O I：

10.1186/s12964-014-0078-2

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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 II delta (CaMKII delta) 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.

引用

页数：17

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