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Role of microRNA-205 in the angiogenic deficit mediated by FAK signaling in hypertension: effect of exercise training and perspective of the therapeutic potential

Grant number: 15/17275-8
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): November 01, 2015
Effective date (End): May 23, 2019
Field of knowledge:Biological Sciences - Physiology
Principal Investigator:Edilamar Menezes de Oliveira
Grantee:Tiago Fernandes
Home Institution: Escola de Educação Física e Esporte (EEFE). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Associated scholarship(s):17/04899-9 - Investigation of the functional and molecular mechanism of RNA-binding protein PCBP1 in the heart, BE.EP.PD

Abstract

Hypertension is a multifactorial syndrome characterized by sustained high levels of blood pressure (BP). Aerobic exercise training (ET) has been used as an important non-pharmacological treatment of hypertension, since it corrects microvascular rarefaction and reduces BP; however, the mechanisms involved are poorly understood. A new class of small RNAs, called microRNAs (miRNAs), has been extensively studied because they regulate their target gene expression at the post-transcriptional level. Studies evaluating the role of miRNAs in the angiogenic process both in hypertension and exercise training are unknown. Based on the profile analysis of miRNA expression by microarray, we selected miRNA-205 for this study to be one of most miRNAs differentially expressed in HA and target a large number of genes involved in the angiogenic process; considered a potential therapeutic target across the vascular damage in the HA. Therefore, we aim to investigate the role of miRNA-205 in reduced angiogenic capacity mediated by signaling FAK/ integrin in spontaneously hypertensive rats (SHR) and check the therapeutic role of ET in correcting these parameters. In the first stage of the project, spontaneously hypertensive rats (SHR) aged 6 months at the beginning of the protocol and the respective controls Wistar Kyoto (WKY) will be divided into four experimental groups (n = 7/ group): SHR, trained SHR (SHR -T), WKY and trained WKY (WKY-T). The swimming ET will consist of 10-week, 1x day/ 5x a week/ 10 weeks. They will be analyzed BP and resting hear rate by tail plethysmography, the ability to exercise tolerance and VO2 peak post ET. After sacrifice, the morphological analysis will be made of the soleus muscle as the cross-sectional area, capillary to fiber ratio and profile of fiber types by histochemical method. Analyzes shall be performed miRNA-205 expression and their targets related to the control of the angiogenic process and vascular integrity. In the second stage of the project, we evaluate gain and loss of function of endothelial cell (HUVEC) in vitro by transfection antagomiR/ miRmimic-205 or a mismatched oligonucleotide with the miRNA studied as a control (scramble) on the proliferation, migration and formation of capillary tubes on matrigel; and expression of miRNA-205 and its target genes validated and predicted. The validation of Itga5 target gene will be held for miRNA-205 through the luciferase assay and analysis of protein expression of FAK mediated by integrin signaling. In the third stage, we evaluate the angiogenic response in aortic rings of WKY and SHR ex vivo by transfection antagomiR/ miRmimic-205 and FAK inhibitor. So, we will test the hypothesis of participation of miRNA-205 in regulating the angiogenic process, which could be further used as a therapeutic source for HA.

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)
FERNANDES, TIAGO; BARRETTI, DIEGO LOPES; PHILLIPS, M. IAN; OLIVEIRA, EDILAMAR MENEZES. Exercise training prevents obesity-associated disorders: Role of miRNA-208a and MED13. Molecular and Cellular Endocrinology, v. 476, p. 148-154, NOV 15 2018. Web of Science Citations: 1.
FERNANDES, TIAGO; CASAES, LILIAN; SOCI, URSULA; SILVEIRA, ANDRE; GOMES, JOAO; BARRETTI, DIEGO; ROQUE, FERNANDA; OLIVEIRA, EDILAMAR. Exercise Training Restores the Cardiac Microrna-16 Levels Preventing Microvascular Rarefaction in Obese Zucker Rats. Obesity Facts, v. 11, n. 1, p. 15-24, 2018. Web of Science Citations: 4.

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