Pulmonary Hypertension in Obese Mice Is Accompanied by a Reduction in PPAR-γ Expression in Pulmonary Artery.

Any Elisa De Souza Schmidt Gonçalves,Dioze Guadagnini,Orlando Petrucci,Rodrigo Marin,Vera Maria Cury Salemi,Helison Do Carmo,Zenaide Providello Moysés,Rafael Ludemann Camargo,Mario José Abdalla Saad,Alexandre Gabarra Oliveira,Andrey Dos Santos,Guilherme Zweig Rocha

doi:10.3389/fendo.2021.701994

Abstract

Obesity and insulin resistance (IR) are well-studied risk factors for systemic cardiovascular disease, but their impact on pulmonary hypertension (PH) is not well clarified. This study aims to investigate if diet-induced obesity induces PH and if peroxisome-proliferator-activated receptor (PPAR-γ) and/or endoplasmic reticulum (ER) stress are involved in this process. Mice were maintained on a high-fat diet (HFD) for 4 months, and IR and PH were confirmed. In a separate group, after 4 months of HFD, mice were treated with pioglitazone (PIO) or 4-phenylbutyric acid for the last month. The results demonstrated that HFD for at least 4 months is able to increase pulmonary artery pressure, which is maintained, and this animal model can be used to investigate the link between IR and PH, without changes in ER stress in the pulmonary artery. There was also a reduction in circulating adiponectin and in perivascular adiponectin expression in the pulmonary artery, associated with a reduction in PPAR-γ expression. Treatment with PIO improved IR and PH and reversed the lower expression of adiponectin and PPAR-γ in the pulmonary artery, highlighting this drug as potential benefit for this poorly recognized complication of obesity.

Highlights

Pulmonary hypertension (PH) is a disease of the pulmonary circulation associated with an excessive proliferation of vascular cells that may induce alterations in the resistance of the pulmonary arteries (PAs), but systemic vessels are spared [1, 2]
We measured the circulating levels of adiponectin, an adipokine that is secreted by adipose tissue and shows an inverse correlation to the amount of adipose tissue, and here, we show a decrease in adiponectin levels in high-fat diet (HFD) group when compared to control group (CTL) group (Figure 1G)
To investigate if the molecular mechanism of pulmonary hypertension (PH) could be associated to the deleterious effects of obesity, we evaluated the gene expression of endoplasmic reticulum (ER) stress markers ATF6, Ire1a, CHOP, PERK, and eIF2a in the pulmonary artery of CTL and HFD animals fed for 4 months (Figures 3A–E)

Summary

Introduction

Pulmonary hypertension (PH) is a disease of the pulmonary circulation associated with an excessive proliferation of vascular cells that may induce alterations in the resistance of the pulmonary arteries (PAs), but systemic vessels are spared [1, 2]. It may be idiopathic or familial, which are rare forms, but most often, PH is associated with more common diseases such as left heart failure, collagen vascular diseases, congenital heart disease, and AIDS, among others [1, 3]. Sutendra and collaborators considered the ER stress present in endothelial muscle cells of the pulmonary artery as a factor for the development of PH, placing ER stress as a common molecular hypotheses among IR and PH [13]

Objectives

Methods

Results

Discussion

Conclusion