HDL-S1P against pyroptosis damage after Acute Myocardial Infarction

• Grant number: 18/17792-0
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: January 01, 2020
• End date: December 31, 2023
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Andrei Carvalho Sposito
• Grantee: Helison Rafael Pereira Do Carmo
• Host Institution: Faculdade de Ciências Médicas (FCM). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated research grant: 13/07607-8 - OCRC - Obesity and Comorbidities Research Center, AP.CEPID

Abstract

The deleterious effects from Acute Myocardial Infarction (AMI) followed by ischemia and reperfusion injury (IR) has in their genesis the inability to contain the programmed pro-inflammatory cell-death pathway, named pyroptosis. The mechanism of pyroptosis induces pore formation on the plasma membrane surface and release of cytosolic components into the extracellular mean. The spread of contents, affects adjacent cells, triggering the activation of the innate immune system through Damage-Associated Molecular Patterns (DAMP) receptors. Fallowed by the formation of the scaffold protein complex in the form of the inflammasome NLRP3, an inducer of Caspase 1 (CASP1) activity, the main molecule to pyroptosis manifestations. The high proteolytic CASP1 activity promotes irreversible damage to the myocardium through the cleavage of proinflammatory cytokines (IL-1 and IL-18) and proteins that alter cell membrane lipid formation (i.e., Gasdermin D). However, the contribution of the active metabolite sphingosine-1-phosphate (S1P) carried by High-Density Lipoproteins (HDL), contributes to the maintenance of vascular integrity and protection of the myocardium after AMI. Therefore, the process of modulating pyroptosis through the activity of HDL-S1P is presented as a potential therapeutic target after myocardial IR. In the present project, we will evaluate if therapies based on HDL-S1P can prevent the damages associated to pyroptosis after AMI. Studies will be carried out in pre-clinical models, analysis from left ventricular contractility, myocardial infarction size and activity and expression of proteins relevant to the pyroptosis vs. HDL-S1P pathways. (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)

CARMO, HELISON RAFAEL P.; YOSHINAGA, MARCOS Y.; CASTILLO, ALEJANDRO ROSELL; CHAVES-FILHO, ADRIANO BRITTO; BONILHA, ISABELLA; BARRETO, JOAQUIM; MURARO, STEFANIE PRIMON; DE SOUZA, GABRIELA FABIANO; DAVANZO, GUSTAVO GASTAO; PERROUD JR, MAURICIO W.; et al. Phenotypic changes in low-density lipoprotein particles as markers of adverse clinical outcomes in COVID-19. MOLECULAR GENETICS AND METABOLISM, v. 138, n. 4, p. 8-pg., 2023-03-06. (20/04558-0, 20/12649-5, 16/00194-8, 13/07937-8, 18/17792-0)