The role of PDE4D5 in the beta-arrestin signaling pathway in the control of cardiac muscle mass and cardiomyocytes culture of rodents

• Grant number: 15/01156-0
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor
• Effective date (Start): June 01, 2015
• Effective date (End): May 31, 2016
• Field of knowledge: Biological Sciences - Biochemistry - Metabolism and Bioenergetics
• Principal Investigator: Isis Do Carmo Kettelhut
• Grantee: Sílvia de Paula Gomes
• Supervisor: Frank Lezoualc’h
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Research place: Université Paul Sabatier - Toulouse III, France
• Associated to the scholarship: 13/08553-9 - The role of the beta-arrestin signaling pathway in the control of cardiac muscle mass and cardiomyocytes culture of rodents, BP.PD

Abstract

The knowledge of mechanisms that regulate cardiac mass is of great relevancedue to the fact that nowadays many people suffer from cardiovascular diseases that leadto heart failure.Our previous results demonstrated that the sympathetic nervous system (SNS)regulates the metabolism of heart proteins through the inhibition of Ub-proteasome andlysosomal/autophagic proteolytic systems activities which are primarily involved in themaintenance of cardiac muscle. This effect is due to atrogenes inhibition through theparticipation of intracellular signaling pathways such as PI3K/Akt/EPAC1 andcAMP/PKA. Recent studies have demonstrated that ²-arrestin can anchors Akt, PI3K,EPAC1 and cAMP phosphodiesterases (PDEs). In our post doc project, we observedthat mice and cardiomyocytes treated with carvedilol, a ²-blocker widely used in heartfailure patients and also recently featured as a selective ²-arrestin activator, increasesthe atrogenes expression and also the phosphorylation of ²2 adrenergic receptor inserine355/356 residues, whereas treatment with propranolol (a ²-blocker that does notstimulate ²-arrestin) does not change the atrogenes expression. The ²2-receptorphosphorylation of these specific serine residues is important for ²-arrestin binding andanchoring other proteins, such as EPAC1 and PDEsWe believe that ²-arrestin controls the expression of atrogenes by a pathwayindependent of the G protein, which can reduces cardiac hypertrophy induced by SNSactivation. This effect might be due to PDE4D5 and EPAC1 competition for binding to²-arrestin, which once recruits and anchors PDE4D5, promotes the decrease of cAMPintracellular level and the increase of atrogenes expression, resulting in cardiacremodeling. We propose to investigate in vivo and in vitro the involvement of ²-arrestin/PDE4D5 in the control of atrogenes in cardiac muscle, since it seems that ²-arrestin signaling pathway acts as a regulatory mechanism aiming to attenuate thecardiac hypertrophy mediated by the SNS. Thus we can correlate the recruitment of ²-arrestin to the membrane, the binding to PDE4D5 and its subsequent inducement ofatrogenes both in cardiomyocytes as well as in heart of mice treated with carvedilol. (AU)