title: Triggering the succinate receptor GPR91 enhances pressure overload-induced right ventricular hypertrophy.
abstract: BACKGROUND
  Pulmonary arterial hypertension (PAH) leads to pressure overload in the right ventricle (RV) and induces right ventricular hypertrophy (RVH). GPR91 is an orphan G-protein-coupled receptor (GPCR) that has been characterized as a receptor for succinate, which increases in RVH; however, its role remains unknown.
  
  
  RESULTS
  We studied succinate-GPR91 signaling in a pulmonary arterial banding (PAB) model of RVH in the SD rats due to pressure overload. We report that GPR91 was located in cardiomyocytes. We found that the expressions of GPR91 and p-Akt in the RV significantly increased in the PAB model compared with the sham. In the PAB rats, the treatment of succinate further increased the p-Akt levels and aggravated RVH in vivo. In in vitro studies, succinate stimulated the up-regulation of the hypertrophic gene marker anp. All these effects were inhibited by the antagonist of PI3K, wortmannin, both in vivo and in vitro. Finally, we found that the GPR91-PI3K/Akt axis was also up-regulated compared with the sham in human RVH.
  
  
  CONCLUSIONS
  Our results suggest that succinate-GPR91 is involved in RVH via PI3K/Akt signaling in vivo and in vitro. GPR91 may be a novel therapeutic target for RVH induced by pressure overload.
authors.affiliation: Department of Cardiothoracic Surgery, Nanjing Children's Hospital Affiliated of Nanjing Medical University Jiangsu Province, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Cardiothoracic Surgery, Nanjing Children's Hospital Affiliated of Nanjing Medical University Jiangsu Province, China.
authors.forename: Di
authors.initials: D
authors.lastname: Yu
authors.affiliation: Department of Gynaecology, Jiangsu Province Hospital of TCM Jiangsu Province, China.
authors.forename: Huan-Huan
authors.initials: HH
authors.lastname: Fan
authors.affiliation: Department of Cardiothoracic Surgery, Nanjing Children's Hospital Affiliated of Nanjing Medical University Jiangsu Province, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Feng
authors.affiliation: Department of Cardiothoracic Surgery, Nanjing Children's Hospital Affiliated of Nanjing Medical University Jiangsu Province, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Hu
authors.affiliation: Department of Cardiothoracic Surgery, Nanjing Children's Hospital Affiliated of Nanjing Medical University Jiangsu Province, China.
authors.forename: Wei-Yan
authors.initials: WY
authors.lastname: Zhang
authors.affiliation: Department of Cardiothoracic Surgery, Nanjing Children's Hospital Affiliated of Nanjing Medical University Jiangsu Province, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Zhou
authors.affiliation: Department of Cardiothoracic Surgery, Nanjing Children's Hospital Affiliated of Nanjing Medical University Jiangsu Province, China.
authors.forename: Xu-Ming
authors.initials: XM
authors.lastname: Mo
mesh_terms: D000818:Animals; D009320:Atrial Natriuretic Factor; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006976:Hypertension, Pulmonary / Q000150:complications* / Q000378:metabolism / Q000503:physiopathology; D017380:Hypertrophy, Right Ventricular / Q000139:chemically induced / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D019802:Succinic Acid / Q000633:toxicity*; D013997:Time Factors; D014162:Transfection
chemical_list: D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D043562:Receptors, G-Protein-Coupled; C523503:Sucnr1 protein, rat; D009320:Atrial Natriuretic Factor; D019802:Succinic Acid; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt
keywords: PI3K/Akt; Succinate G-protein-receptor 91; right ventricular hypertrophy