Role of inflammasome NLRP3 in vascular changes promoted by Type 1 diabetes in streptozotocin-induced model

• Grant number: 16/17303-4
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: December 01, 2016
• End date: May 31, 2018
• Field of knowledge: Biological Sciences - Pharmacology - Cardiorenal Pharmacology
• Principal Investigator: Rita de Cassia Aleixo Tostes Passaglia
• Grantee: Camila André Pereira
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Diabetes mellitus (DM) is associated with several micro and macrovascular complications directly related to cardiovascular disease. Prolonged exposure to hyperglycaemia and insulin resistance induces these complications, which are exacerbated by endothelial dysfunction. Inflammatory mediators potentially contribute to the development of endothelial dysfunction by the generation of reactive oxygen species (ROS). In turn, the increase of ROS and oxidative stress stimulates the transcription of proinflammatory factors and the inflammatory responses. Specific receptors, such as NLRs (NOD-like receptors), especially NLRP subfamily, contribute significantly to installation of the inflammatory process by activating the inflammasome complex. This regulates the activation of caspase-1 and proteolytic processing of pro-IL-1b and pro-IL-18 in mature cytokines. Little is known about the involvement of NLR receptors on vascular dysfunction associated with DM. We test the hypothesis that genetic deficiency of NLRP3 and inflammasome key components confers resistance to inflammatory activation process and dysfunction in the vasculature of animals with type 1 diabetes, chemically induced by streptozotocin (STZ). And yet, molecular patterns associated with tissue injury (Mitochondrial DAMPs) contribute to these vascular changes. For that they will be used wild-type mice (WT) and knock-out to NLRP3, which will be submitted to a protocol for induction of STZ-DM1. Vascular smooth muscle cell cultures and co-culture with macrophages are carried out to evaluate the activation of NLRP3 inflammasome. ROS generation and caspase-1 activation will also be evaluated in these cells. Functional vascular parameters are determined in mesenteric resistance arteries. Diabetes reduced endothelium-dependent vasodilation, which was not observed in arteries from NLRP3 animals. Diabetic animals showed increased vascular expression of NLRP3 receptor, caspase-1 and IL-1b. There was an increase of mitochondrial DNA release in arteries from diabetic animals. Diabetic mitochondrial DNA promoted activation of the inflammasome in VSMC. These partial results demonstrate that the NLRP3 inflammasome participates in endothelial dysfunction process promoted by diabetes and even mitochondrial DNA is involved in this process.

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)

PEREIRA, CAMILA A.; CARLOS, DANIELA; FERREIRA, NATHANNE S.; SILVA, JOSIANE F.; ZANOTTO, CAMILA Z.; ZAMBONI, DARIO S.; GARCIA, VALERIA D.; VENTURA, DORA FIX; SILVA, JOAO S.; TOSTES, RITA C.. Mitochondrial DNA Promotes NLRP3 Inflammasome Activation and Contributes to Endothelial Dysfunction and Inflammation in Type 1 Diabetes. FRONTIERS IN PHYSIOLOGY, v. 10, JAN 17 2020. (13/08216-2, 16/17303-4)

Academic Publications

(References retrieved automatically from State of São Paulo Research Institutions)

PEREIRA, Camila André. Role of the NLRP3 inflammasome in the vascular alterations induced by type 1 diabetes in a streptozotocin-induced model. 2018. Doctoral Thesis - Universidade de São Paulo (USP). Faculdade de Medicina de Ribeirão Preto (PCARP/BC) Ribeirão Preto.