Proteic nitrosylation: a critical mechanism and pharmacological target in severe sepsis

• Grant number: 17/07570-8
• Support Opportunities: Research Grants - Young Investigators Grants
• Start date: February 01, 2018
• End date: September 30, 2021
• Field of knowledge: Biological Sciences - Pharmacology - General Pharmacology
• Principal Investigator: Lucas Cezar Pinheiro
• Grantee: Lucas Cezar Pinheiro
• Host Institution: Escola de Enfermagem de Ribeirão Preto (EERP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated researchers: Carlos Renato Tirapelli ; Fernando de Queiroz Cunha ; José Carlos Toledo Junior ; Jose Eduardo Tanus dos Santos ; Riccardo Lacchini
• Associated scholarship(s): 19/03334-3 - Evaluation of total vascular S-nitrosylation in CLP septic animals, BP.IC; 18/00343-9 - Proteic nitrosylation: a critical mechanism and pharmacological target in severe sepsis, BP.JP

Abstract

Sepsis is a complex syndrome with problematic definition and diagnosis. Sepsis treatment is complex, generally expensive and ineffective in sight of the high mortality rate of the septic patient. Recent data indicate, in Brazil, mortality due to sepsis of approximately 43.8%. During sepsis there is a significant increase in the production of nitric oxide (NO). The systemic increase of NO results in a myriad of effects. NO derived from macrophages and polymorphonucleated cells is essential for the control of infection, but also exerts vascular effects. The increases in vasodilatation can result in septic shock, a complication in which blood pressure is below 65 mmHg and with a high mortality rate. Treatment for reversion of septic shock usually requires the infusion of vasoconstrictors, often with low efficacy. NO, in addition to the above effects, may form S-nitrosothiols that would result in long-term protein modifications, which in general result in inhibition thereof. We believe that the reversal or impairment of S-nitrosylation during Sepsis improves the response to vasoconstrictors with consequent improvement in survival. In this context, recent studies only demonstrate the generalized increase of S-nitrosylation in Sepsis. Therefore, the proposal of this project is the discrimination and quantification of S-nitrosylation of key proteins in vasculature for vasoconstriction, followed by the attempt of reversion or impediment of S-nitrosylation. For this, Sepsis will be induced in rats by CLP and followed by analysis of total S-nitrosylated proteins, followed by identification of the main targets involved in the compromised vasoconstriction. Subsequently the septic animals will be treated with drugs to prevent or reverse nitrosylation, followed by analysis of possible improvement in response to vasoconstrictor agents as well as the alteration of S-nitrosylation of the proteins identified at the beginning. In this way we will be able to identify a possible new therapeutic target as well as to have real chances of improving the response to vasoconstrictors and of survival. (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)

NUNES, PRISCILA REZECK; PINHEIRO, LUCAS CEZAR; MARTINS, LAISLA ZANETONI; DIAS-JUNIOR, CARLOS ALAN; PALEI, ANA CAROLINA TAVEIROS; SANDRIM, VALERIA CRISTINA. A new look at the role of nitric oxide in preeclampsia: Protein S-nitrosylation. PREGNANCY HYPERTENSION-AN INTERNATIONAL JOURNAL OF WOMENS CARDIOVASCULAR HEALTH, v. 29, p. 7-pg., 2022-08-01. (20/14610-9, 17/07570-8, 18/24484-0, 19/07230-8)