Study of the role of O-glycosylation with N-acetyl-glucosamine (O-GlcNAc) in vascular stress induced by supraphysiological aldosterone concentrations

• Grant number: 21/09273-6
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Start date: January 01, 2022
• Status: Discontinued
• Field of knowledge: Biological Sciences - Pharmacology - Cardiorenal Pharmacology
• Principal Investigator: Rita de Cassia Aleixo Tostes Passaglia
• Grantee: Daniel Rodrigues
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated scholarship(s): 23/10877-9 - The role of protein O-GlcNAcylation on primary aldosteronism, BE.EP.DD

Abstract

Aldosterone (Aldo) is a mineralocorticoid hormone that regulates the renal transport of sodium (Na+) and potassium (K+) ions. However, Aldo has extrarenal effects, especially at supraphysiologic concentrations, which contribute to cardiovascular disease. Aldo, due to its pro-fibrotic, pro-inflammatory and pro-oxidative properties, promotes several changes in target organs, such as the heart and blood vessels. Oxidative stress, i.e. exacerbated generation of Reactive Oxygen Species (ROS), represents an important mechanism in vascular changes associated with cardiovascular disease. O-glycosylation of proteins with N-acetylglucosamine (O-GlcNAc) or, more specifically, the addition of an N-acetylglucosamine monomer to serine and threonine residues of cytoplasmic and nuclear proteins, is a post-translational modification that can alter the location and function of various proteins, thus modulating cell signaling and stress responses. O-GlcNAc is important in the cardiovascular context and recent studies demonstrate that ROS can stimulate modification by O-GlcNAc in the vasculature. Considering that Aldo is a hormone with pro-oxidative properties and that ROS can interfere with protein modification by O-GlcNAc, this study will test the hypothesis that supraphysiologic Aldo concentrations promote a global increase in O-glycosylated vascular proteins, an event mediated by oxidation and reduced activity of OGA (enzyme that removes O-GlcNAc from glycosylated proteins), contributing to vascular dysfunction induced by this mineralocorticoid hormone. Also considering recent evidence that I) Aldo modulates autophagy, an important intracellular process activated in response to different stressful stimuli; and II) MPT by O-GlcNAc regulates proteins that control autophagic flow, our study will also assess whether Aldo induces vascular dysfunction by compromising the autophagy process and whether the modification of autophagic proteins by O-GlcNAc represents a mechanism involved in the effects of Aldo. (AU)

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)

RODRIGUES, DANIEL; MACHADO, MIRELE R.; ALVES, JULIANO V.; FRAGA-SILVA, THAIS F. C.; MARTINS, RONALDO B.; CAMPOS, LIGIA C. B.; FRANCISCO, DANIELY F.; COUTO, ARIEL E. S.; BONATO, VANIA L. D.; ARRUDA, EURICO; et al. Cytokine storm in individuals with severe COVID-19 decreases endothelial cell antioxidant defense via downregulation of the Nrf2 transcriptional factor. AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY, v. 325, n. 2, p. 12-pg., 2023-08-01. (13/08216-2, 19/11213-1, 21/08847-9, 21/09273-6)