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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

Mitochondrial DNA Promotes NLRP3 Inflammasome Activation and Contributes to Endothelial Dysfunction and Inflammation in Type 1 Diabetes

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Author(s):
Pereira, Camila A. [1] ; Carlos, Daniela [2] ; Ferreira, Nathanne S. [1] ; Silva, Josiane F. [1] ; Zanotto, Camila Z. [1] ; Zamboni, Dario S. [3] ; Garcia, Valeria D. [4] ; Ventura, Dora Fix [4] ; Silva, Joao S. [2] ; Tostes, Rita C. [1]
Total Authors: 10
Affiliation:
[1] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Pharmacol, Ribeirao Preto - Brazil
[2] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Biochem & Immunol, Ribeirao Preto - Brazil
[3] Univ Sao Paulo, Ribeirao Preto Med Sch, Cell & Mol Biol & Pathogen Bioagents, Ribeirao Preto - Brazil
[4] Univ Sao Paulo, Inst Psychol, Dept Expt Psychol, Sao Paulo - Brazil
Total Affiliations: 4
Document type: Journal article
Source: FRONTIERS IN PHYSIOLOGY; v. 10, JAN 17 2020.
Web of Science Citations: 0
Abstract

Background: NLRP3 inflammasome activation in response to several signals, including mitochondrial DNA (mDNA), regulates inflammatory responses by caspase1 activation and interleukin-1 beta (IL-1 beta) release. Circulating mDNA is linked to micro and macrovascular complications in diabetes. However, a role for mDNA in endothelial dysfunction is not clear. We tested the hypothesis that mDNA contributes to diabetes-associated endothelial dysfunction and vascular inflammation via NLRP3 activation. Methods: Vascular reactivity, reactive oxygen species (ROS) generation, calcium (Ca2+) influx and caspase-1 and IL-1 beta activation were determined in mesenteric resistance arteries from normoglicemic and streptozotocin-induced diabetic C57BL/6 and NLRP3 knockout (Nlrp3) mice. Endothelial cells and mesenteric arteries were stimulated with mDNA from control (cmDNA) and diabetic (dmDNA) mice. Results: Diabetes reduced endothelium-dependent vasodilation and increased vascular ROS generation and caspase-1 and IL-1 beta activation in C57BL/6, but not in Nlrp3 mice. Diabetes increased pancreatic cytosolic mDNA. dmDNA decreased endothelium-dependent vasodilation. In endothelial cells, dmDNA activated NLRP3 via mitochondrial ROS and Ca2+ influx. Patients with type 1 diabetes exhibited increased circulating mDNA as well as caspase-1 and IL-1 beta activation. Conclusion: dmDNA activates endothelial NLRP3 inflammasome by mechanisms that involve Ca2+ influx and mitochondrial ROS generation. NLRP3 deficiency prevents diabetes-associated vascular inflammatory damage and endothelial dysfunction. Our study highlights the importance of NLRP3 inflammasome in diabetes-associated vascular dysfunction, which is key to diabetic complications. (AU)

FAPESP's process: 13/08216-2 - CRID - Center for Research in Inflammatory Diseases
Grantee:Fernando de Queiroz Cunha
Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
FAPESP's process: 16/17303-4 - Role of inflammasome NLRP3 in vascular changes promoted by Type 1 diabetes in streptozotocin-induced model
Grantee:Camila André Pereira
Support Opportunities: Scholarships in Brazil - Doctorate