AUTHOR=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.
TITLE=Mitochondrial DNA Promotes NLRP3 Inflammasome Activation and Contributes to Endothelial Dysfunction and Inflammation in Type 1 Diabetes
JOURNAL=Frontiers in Physiology
VOLUME=10
YEAR=2020
URL=https://www.frontiersin.org/journals/physiology/articles/10.3389/fphys.2019.01557
DOI=10.3389/fphys.2019.01557
ISSN=1664-042X
ABSTRACT=Background: 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.
Methods: Vascular reactivity, reactive oxygen species (ROS) generation, calcium (Ca2+) 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 (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-1β 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-1β 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.