MOLECULAR MECANISMS OF PULMONARY ARTERIAL HYPERTENSION ASSOCIATED TO INSULIN RESISTANCE: STUDIES IN ANIMAL MODEL OF OBESITY.

• Grant number: 12/02669-2
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: August 01, 2012
• End date: July 31, 2016
• Field of knowledge: Biological Sciences - Physiology - General Physiology
• Principal Investigator: Mario Jose Abdalla Saad
• Grantee: Any Elisa de Souza Schmidt Gonçalves
• Host Institution: Faculdade de Ciências Médicas (FCM). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated research grant: 13/07607-8 - OCRC - Obesity and Comorbidities Research Center, AP.CEPID

Abstract

Endoplasmic reticulum (ER) stress on smooth muscle cells is considered a factor for developing PAH. Obesity has been associated with induction of ER stress predominantly in liver and adipose tissues. The fact of PAH has been recently related to diabetes supports the hypothesis of a strong connection between ER stress and PAH. Based on previous data, the aims of this study are:1.Establish animals models of insulin resistance induced by high fat diet and explore the development of PAH;2.Investigate if there is any link between obesity and PAH RE stress (pPERK, ATF6, Ire-1 and JNK) and if it is associated to insulin resistance on pulmonary artery; 3.Evaluate if RE stress modulators, such as such as 4-phenyl butyric acid and ursodeoxycholic acid and its taurine-conjugated derivative, are able to reverse PAH developed in obesity state; Patients with PAH presented decreased expression of BMP-2, PPAR³ e apolipoprotein E (apoE). It has been demonstrated that insulin resistance, low plasma adiponectin levels, and deficiency of apoE may be risk factors for PAH and that PPAR³ activation can reverse PAH in an animal model There is emerging evidence that many key genes involved in PAH development are targets of the insulin-sensitizing transcription factor PPAR³, and that pharmacological PPAR³ activation would lead to their beneficial induction or repression and subsequent antiproliferative, anti-inflammatory, proapoptotic, and direct vasodilatory effects in the vasculature. These findings suggest that BMP-RII dysfunction decreases endogenous PPAR³ activity and enhances PDGF-BB/MAPK (e.g., ERK) pathways and associated vascular remodeling. Thus, the last aim of this study is:4.Evaluate PPAR³ (peroxisome proliferator-activated receptor ³) expression in pulmonary artery of obese animals and determine if PPAR³ agonist drugs can reverse PAH.

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

SCHMIDT GONCALVES, ANY ELISA DE SOUZA; ROCHA, GUILHERME ZWEIG; MARIN, RODRIGO; CAMARGO, RAFAEL LUDEMANN; DOS SANTOS, ANDREY; DO CARMO, HELISON; GUADAGNINI, DIOZE; PETRUCCI, ORLANDO; MOYSES, ZENAIDE PROVIDELLO; CURY SALEMI, VERA MARIA; et al. Pulmonary Hypertension in Obese Mice Is Accompanied by a Reduction in PPAR-gamma Expression in Pulmonary Artery. FRONTIERS IN ENDOCRINOLOGY, v. 12, SEP 6 2021. (12/02669-2)