The Succinate Receptor GPR91 Is Involved in Pressure Overload-Induced Ventricular Hypertrophy

PLoS One. 2016 Jan 29;11(1):e0147597. doi: 10.1371/journal.pone.0147597. eCollection 2016.

Abstract

Background: Pulmonary arterial hypertension is characterized by increased pressure overload that leads to right ventricular hypertrophy (RVH). GPR91 is a formerly orphan G-protein-coupled receptor (GPCR) that has been characterized as a receptor for succinate; however, its role in RVH remains unknown.

Methods and results: We investigated the role of succinate-GPR91 signaling in a pulmonary arterial banding (PAB) model of RVH induced by pressure overload in SD rats. GPR91 was shown to be located in cardiomyocytes. In the sham and PAB rats, succinate treatment further aggravated RVH, up-regulated RVH-associated genes and increased p-Akt/t-Akt levels in vivo. In vitro, succinate treatment up-regulated the levels of the hypertrophic gene marker anp and p-Akt/t-Akt in cardiomyocytes. All these effects were inhibited by the PI3K antagonist wortmannin both in vivo and in vitro. Finally, we noted that the GPR91-PI3K/Akt axis was also up-regulated compared to that in human RVH.

Conclusions: Our findings indicate that succinate-GPR91 signaling may be involved in RVH via PI3K/Akt signaling in vivo and in vitro. Therefore, GPR91 may be a novel therapeutic target for treating pressure overload-induced RVH.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Androstadienes / pharmacology
  • Animals
  • Atrial Natriuretic Factor / genetics
  • Atrial Natriuretic Factor / metabolism
  • Gene Expression Regulation
  • Heart Ventricles / metabolism
  • Heart Ventricles / pathology
  • Heart Ventricles / physiopathology
  • Humans
  • Hypertension, Pulmonary / genetics
  • Hypertension, Pulmonary / metabolism*
  • Hypertension, Pulmonary / pathology
  • Hypertension, Pulmonary / physiopathology
  • Hypertrophy, Right Ventricular / genetics
  • Hypertrophy, Right Ventricular / metabolism*
  • Hypertrophy, Right Ventricular / pathology
  • Hypertrophy, Right Ventricular / physiopathology
  • Myocytes, Cardiac / cytology
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / metabolism
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphoinositide-3 Kinase Inhibitors
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Pulmonary Artery / metabolism
  • Pulmonary Artery / pathology
  • Pulmonary Artery / surgery
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Rats
  • Receptors, G-Protein-Coupled / antagonists & inhibitors
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism*
  • Signal Transduction
  • Stroke Volume
  • Succinic Acid / metabolism*
  • Succinic Acid / pharmacology
  • Wortmannin

Substances

  • Androstadienes
  • Phosphoinositide-3 Kinase Inhibitors
  • RNA, Small Interfering
  • Receptors, G-Protein-Coupled
  • Sucnr1 protein, rat
  • Atrial Natriuretic Factor
  • Succinic Acid
  • Proto-Oncogene Proteins c-akt
  • Wortmannin

Grants and funding

This work was supported by the National Natural Science Foundation of China (81370277, 81500243), the National 12th Five-Year technology based plan topic (2011BAI11B22), was sponsored by the Research and Innovation Project for College Graduates of Jiangsu Province (CXLX-0560), and by Young talent of Nanjing Children's Hospital Affiliated to Nanjing Medical University and Key Project supported by Medical Science and technology development Foundation, Nanjing Department of Health (YKK14116) and Hospital Management Center Project of Wuxi (YGZXY1307). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.