Advanced search
Start date
Betweenand

The role of PPAR gamma in sphingosine-1-phosphate enrichment of HDL in ischemia reperfusion injury of vascular endothelial cells

Grant number: 19/09159-9
Support type:Regular Research Grants
Duration: March 01, 2020 - February 28, 2022
Field of knowledge:Health Sciences - Medicine - Medical Clinics
Principal researcher:Andrei Carvalho Sposito
Grantee:Andrei Carvalho Sposito
Home Institution: Faculdade de Ciências Médicas (FCM). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
Assoc. researchers:Ângela Saito ; Thiago Quinaglia Araujo Costa Silva

Abstract

Acute myocardial infarction (AMI) is the leading cause of death worldwide. Coronary reperfusion is the most effective therapy in this scenario, aimed at preserving the left ventricular ejection fraction and improving clinical outcomes in patients with AMI. Paradoxically, however, such a strategy leads to a deleterious phenomenon called ischemia reperfusion injury (IRI), which induces additional tissue damage representing up to 50% of the final infarct size. Experiments on ex vivo and in vivo models of IRI have clearly shown that one of the most successful approaches to mitigating the deleterious effects of IRI on cardiac function involves infusion of high-density lipoprotein (HDL). In addition, HDL protects endothelial cells, limiting local inflammation and activating cell survival pathways. HDL particles are highly complex composed of apolipoproteins (e.g., ApoA-I, ApoA-II, and ApoM), antioxidant enzymes such as paraoxonase, and various lipid species, including bioactive sphingolipids. Sphingosine-1-phosphate (S1P), the primary sphingolipid in HDL, activates signaling pathways that promote cell survival during IRI. This lipid mediator, carried in the plasma by HDL (HDL/S1P) and generated mainly in platelets, endothelial cells, and erythrocytes through sphingosine phosphorylation by sphingosine kinase, is an enzyme encoded by the highly conserved sphingosine kinase 1 and 2 (Sphk1 and Sphk2). The former plays a critical role in metabolic pathways, controlling the balance between pro-apoptotic sphingolipid levels and S1P, which promotes cell survival. Thus, it is plausible that transcriptional regulation of Sphk1 during IRI or in vitro hypoxia/reoxygenation (H/R) occurs during cellular generation of S1P, subsequent enrichment of HDL, and endothelial homeostasis. However, regulation of the Sphk1 gene during endothelial H/R remains poorly understood. In preliminary in silico analyses conducted in concert with preliminary in vitro experiments, we identified PPAR gamma as an important candidate transcription factor for Sphk1 regulation. In this way, using an in vitro reporter system in human coronary endothelial cells, we propose to validate PPAR gamma targets in the regulatory region of Sphk1. Additionally, we will investigate the role of synthetic PPAR gamma agonists and antagonists in Sphk1 expression, in vitro and in vivo activity in IRI, cellular generation of S1P, and subsequent enrichment of HDL. Finally, we will conduct a trial- of-concept clinical study with a PPAR gamma agonist (pioglitazone) versus placebo, measuring enrichment of HDL with S1P and in vivo endothelium function after IRI. (AU)

Articles published in Agência FAPESP Newsletter about the research grant:
Articles published in other media outlets (0 total):
More itemsLess items
VEICULO: TITULO (DATA)
VEICULO: TITULO (DATA)