The role of the beta-arrestin signaling pathway in the control of cardiac muscle mass and cardiomyocytes culture of rodents

• Grant number: 13/08553-9
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Effective date (Start): December 01, 2013
• Effective date (End): July 25, 2017
• Field of knowledge: Biological Sciences - Biochemistry - Metabolism and Bioenergetics
• Principal Investigator: Isis Do Carmo Kettelhut
• Grantee: Sílvia de Paula Gomes
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated research grant: 12/24524-6 - Control of muscle mass by cAMP signaling pathway, AP.TEM
• Associated scholarship(s): 15/01156-0 - The role of PDE4D5 in the beta-arrestin signaling pathway in the control of cardiac muscle mass and cardiomyocytes culture of rodents, BE.EP.PD

Abstract

The heart failure is one of the most prevalent cardiovascular disease in the world which could explain the great interest in the knowledge of the cardiac mass regulation. Our previous studies revealed the role of SNS in the regulation of protein metabolism in the heart through the inhibition of the Ub-proteasome and lysosomal /autophagic proteolytic activities, which are primarily involved in the increase of heart mass. This effect is due to the inhibition of atrophic genes involving the participation of intracellular signaling pathways such as PI3K/Akt and cAMP / PKA. Recent studies have demonstrated that ²-arrestin, a protein previously known as responsible for the internalization and desensitization of G-protein coupled receptors, can anchor Akt, EPAC e ERK1/2 and activates a signaling pathway independent of G protein. Furthermore, preliminary data from our laboratory shows that mice treated with carvedilol, a ²-adrenoceptor blocker, widely used in patients with heart failure, and recently featured as a selective activator of ²-arrestin signaling pathway, increases the expression of atrogenes, whereas treatment with propranolol, wich does not activate ²-arrestin, does not activate the expression of atrogenes. Our hypothesis is that the ²-arrestin increase the expression of atrophic genes by a pathway independent of the G protein, which can reduce cardiac hypertrophy mediated by SNS. We propose to investigate in vivo and in vitro the involvement of ²-arrestin and its G protein-independent signaling pathway in the control of the atrogenes in the cardiac muscle of normal mice, cardiomyocyte culture and in the rat´s experimental model of heart failure, which present a sympathetic hyperactivation, since it appears that ²-arrestin acts as a regulatory mechanism aiming to attenuate cardiac hypertrophy mediated by SNS. In the present work, we intend to correlate the recruitment of ²-arrestin to the membrane and the subsequent activation of atrogenes both in cardiomyocytes as well as in heart of mice treated with carvedilol. In addition, it will be implemented in our laboratory the FRET technique (Fluorescence Resonance Energy Transfer), that is a very interesting tool to investigate, for example, alterations in the cAMP intracellular levels.

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)

FORESTO, CAMILA SILVA; PAULA-GOMES, SILVIA; SILVEIRA, WILIAN ASSIS; GRACA, FLAVIA APARECIDA; KETTELHUT, ISIS DO CARMO; PINHEIRO GONCALVES, DAWIT ALBIEIRO; MATTIELLO-SVERZUT, ANA CLAUDIA. Morphological and molecular aspects of immobilization-induced muscle atrophy in rats at different stages of postnatal development: the role of autophagy. Journal of Applied Physiology, v. 121, n. 3, p. 646-660, SEP 1 2016. (10/11015-0, 12/24524-6, 12/18861-0, 13/08553-9)

FERREIRA, GRAZIELLA NASCIMENTO; ROSSI-VALENTIM, RAFAEL; BUZELLE, SAMYRA LOPES; PAULA-GOMES, SILVIA; ZANON, NEUSA MARIA; RISSATO GAROFALO, MARIA ANTONIETA; FRASSON, DANUBIA; CARVALHO NAVEGANTES, LUIZ CARLOS; CHAVES, VALERIA ERNESTANIA; KETTELHUT, ISIS DO CARMO. Differential regulation of glyceroneogenesis by glucocorticoids in epididymal and retroperitoneal white adipose tissue from rats. ENDOCRINE, v. 57, n. 2, p. 287-297, AUG 2017. (13/08553-9)