Background and Purpose
Microsomal prostaglandin E synthase-1 (mPGES-1) is an inducible isomerase responsible for prostaglandin E2 production in inflammatory conditions. We evaluated the role of mPGES-1 in the development and the metabolic and cardiovascular alterations of obesity.
Experimental Approach
mPGES-1+/+ and mPGES-1−/− mice were fed with normal or high fat diet (HFD, 60% fat). The glycaemic and lipid profile was evaluated by glucose and insulin tolerance tests and colorimetric assays. Vascular function, structure and mechanics were assessed by myography. Histological studies, q-RT-PCR, and western blot analyses were performed in adipose tissue depots and cardiovascular tissues. Gene expression in abdominal fat and perivascular adipose tissue (PVAT) from patients was correlated with vascular damage.
Key Results
Male mPGES-1−/− mice fed with HFD were protected against body weight gain and showed reduced adiposity, better glucose tolerance and insulin sensitivity, lipid levels and less white adipose tissue and PVAT inflammation and fibrosis, compared with mPGES-1+/+ mice. mPGES-1 knockdown prevented cardiomyocyte hypertrophy, cardiac fibrosis, endothelial dysfunction, aortic insulin resistance, and vascular inflammation and remodelling, induced by HFD. Obesity-induced weight gain and endothelial dysfunction of resistance arteries were ameliorated in female mPGES-1−/− mice. In humans, we found a positive correlation between mPGES-1 expression in abdominal fat and vascular remodelling, vessel stiffness, and systolic blood pressure. In human PVAT, there was a positive correlation between mPGES-1 expression and inflammatory markers.
Conclusions and Implications
mPGES-1 inhibition might be a novel therapeutic approach to the management of obesity and the associated cardiovascular and metabolic alterations.
Date: First published: 07 December 2021
Author: Constanza Ballesteros-Martínez,Raquel Rodrigues-Díez,Luis M. Beltrán,Rosa Moreno-Carriles,Ernesto Martínez-Martínez,María González-Amor,Jose Martínez-González … See all authors
Constanza Ballesteros-Martínez and Raquel Rodrigues-Díez contributed equally to this study.
https://doi.org/10.1111/bph.15776
Funding information: Ministerio Ciencia e Innovación. Programa Juan de la Cierva, Grant/Award Number: IJCI-2017-31399; Comunidad de Madrid, Grant/Award Number: B2017/BMD-3676 AORTASANA, FEDER-a way to build Europe; Fondo Europeo de Desarrollo Regional, Grant/Award Number: SAF2016-80305P; Ministerio de Ciencia e Innovación, Grant/Award Number: FIS PI18/0257
