Triggering the succinate receptor GPR91 enhances pressure overload-induced right ventricular hypertrophy.

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.

Methods And 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.