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

• Published in: Frontiers in physiology Vol. 10; p. 1557
• Main Authors: Pereira, Camila A, Carlos, Daniela, Ferreira, Nathanne S, Silva, Josiane F, Zanotto, Camila Z, Zamboni, Dario S, Garcia, Valéria D, Ventura, Dora Fix, Silva, João S, Tostes, Rita C
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 17.01.2020
• Subjects: endothelial dysfunction; inflammation; mitochondrial DNA; NLRP3 inflammasome; Physiology; reactive oxygen species; type 1 diabetes; type 1 diabetes; NLRP3 inflammasome; inflammation; endothelial dysfunction; mitochondrial DNA; reactive oxygen species
• ISSN: 1664-042X; 1664-042X
• DOI: 10.3389/fphys.2019.01557

NLRP3 inflammasome activation in response to several signals, including mitochondrial DNA (mDNA), regulates inflammatory responses by caspase-1 activation and interleukin-1β (IL-1β) 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. Vascular reactivity, reactive oxygen species (ROS) generation, calcium (Ca ) influx and caspase-1 and IL-1β activation were determined in mesenteric resistance arteries from normoglicemic and streptozotocin-induced diabetic C57BL/6 and NLRP3 knockout ( ) mice. Endothelial cells and mesenteric arteries were stimulated with mDNA from control (cmDNA) and diabetic (dmDNA) mice. Diabetes reduced endothelium-dependent vasodilation and increased vascular ROS generation and caspase-1 and IL-1β activation in C57BL/6, but not in mice. Diabetes increased pancreatic cytosolic mDNA. dmDNA decreased endothelium-dependent vasodilation. In endothelial cells, dmDNA activated NLRP3 via mitochondrial ROS and Ca influx. Patients with type 1 diabetes exhibited increased circulating mDNA as well as caspase-1 and IL-1β activation. dmDNA activates endothelial NLRP3 inflammasome by mechanisms that involve Ca 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.