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

2020 ◽  
Vol 10 ◽  
Author(s):  
Camila A. Pereira ◽  
Daniela Carlos ◽  
Nathanne S. Ferreira ◽  
Josiane F. Silva ◽  
Camila Z. Zanotto ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Mitochondrial Dna ◽  
Endothelial Dysfunction ◽  
Nlrp3 Inflammasome ◽  
Inflammasome Activation ◽  
Nlrp3 Inflammasome Activation

scholarly journals H3 relaxin alleviated vascular injury  in rats with type 1 diabetes by inhibiting endoplasmic reticulum stress and inflammation

2021 ◽  
Author(s):  
Xiaohui Zhang ◽  
Kelaier Yang ◽  
Jinyu Chi ◽  
Wenjia Chen ◽  
Xiao Ma ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Type 1 Diabetes ◽  
Endoplasmic Reticulum Stress ◽  
Nlrp3 Inflammasome ◽  
Vascular Function ◽  
Diabetic Rats ◽  
Inflammasome Activation ◽  
Type I ◽  
Nlrp3 Inflammasome Activation

Abstract Human recombinant relaxin-3 (H3 relaxin ),a small molecule peptide hormone, ameliorated myocardial injury after myocardial infarction or isoprenaline injection by inhibiting apoptosis and fibrosis. However, whether H3 relaxin protects vascular function in rats with type 1 diabetes and its mechanism are unknown. In type 1 diabetes rats model induced by streptozotocin (STZ), rats were subcutaneously injected H3 relaxin (2 µg/kg/d or 0.2 µg/kg/d) for 2 weeks. At 4 or 8 weeks after STZ injection, we detected the expression of fibrosis (type I and III collagen), ERS (endoplasmic reticulum stress) and NLRP3 inflammasome activation in the aortas and inflammation markers in the plasma from rats with diabetes. Compared with the diabetic rats, H3 relaxin treatment exhibited markedly decreased plasma oxidative stress markers (TNF-a and MDA) levels. The protein expression levels of type I and III collagen in the aortas were increased in rats with diabetes, inhibited by H3 relaxin. H3 relaxin treatment inhibited ERS (GRP78 and CHOP) and NLRP3 inflammasome activation in the aortas of diabetic rats. These results suggest that H3 relaxin inhibited fibrosis, ERS and inflammation activation in the aortas of type 1 diabetic rats.

Abstract 11852: Role of Lox-1 in Mitochondrial Dna Damage and NLRP3 Inflammasome Activation

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Zufeng Ding ◽  
Sadip Pant ◽  
Abhishek Deshmukh ◽  
Jawahar L Mehta
Keyword(s):  
Dna Damage ◽  
Mitochondrial Dna ◽  
Nlrp3 Inflammasome ◽  
Ros Generation ◽  
Inflammasome Activation ◽  
Mtdna Damage ◽  
Mitochondrial Dna Damage ◽  
Mitochondrial Ros ◽  
Nlrp3 Inflammasome Activation

Objective: This study tested the hypothesis that mitochondrial DNA damage could trigger NLRP3 inflammasome activation during inflammation, and LOX-1 may play a critical role in this process. Methods and Results: We performed studies in cultured human THP1 macrophages exposed to ox-LDL or LPS,which are often used as inflammation stimuli in vitro . We examined and confirmed the increase in LOX-1 expression when cells were treated with ox-LDL or LPS. Parallel groups of cells were treated with LOX-1 Ab to bind LOX-1. In accordance with our previous studies in endothelial cells and smooth muscle cells, LOX-1 Ab markedly reduced ox-LDL- as well as LPS-stimulated LOX-1 expression. To assess mitochondrial ROS generation, MitoSOX™ Red mitochondrial superoxide indicator was used. Both fluorescence staining and flow cytometry analysis showed that LPS induced (more than ox-LDL) mitochondrial ROS generation. Pretreatment with LOX-1 Ab significantly attenuated mitochondrial ROS generation in response to ox-LDL or LPS. Then we observed mtDNA damage in THP1 cells exposed to ox-LDL or LPS. Importantly, pretreatment with LOX-1 Ab protected mtDNA from damage in response to both stimuli. This was also confirmed by q-PCR (mtDNA/nDNA ratio) analysis. Further, ox-LDL or LPS induced the expression of phos-NF-kB p65, caspase-1 p10 and p20, and cleaved proteins IL-1β and IL-18. Of note, NLRP3 inflammasome was activated in response to ox-LDL or LPS in a similar manner. Pretreatment of cells with LOX-1 Ab treatment blocked or significantly attenuated these inflammatory responses. Conclusions: These observations based on in vitro observations indicate that LOX-1 via ROS generation plays a key role in mtDNA damage which then leads to NLRP3 inflammasome activation during inflammation.

scholarly journals New mitochondrial DNA synthesis enables NLRP3 inflammasome activation

Nature ◽  
2018 ◽  
Vol 560 (7717) ◽  
pp. 198-203 ◽  
Author(s):  
Zhenyu Zhong ◽  
Shuang Liang ◽  
Elsa Sanchez-Lopez ◽  
Feng He ◽  
Shabnam Shalapour ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Dna Synthesis ◽  
Nlrp3 Inflammasome ◽  
Inflammasome Activation ◽  
Nlrp3 Inflammasome Activation ◽  
Mitochondrial Dna Synthesis

scholarly journals Extracellular mitochondrial DNA promote NLRP3 inflammasome activation and induce acute lung injury through TLR9 and NF-κB

2019 ◽  
Vol 11 (11) ◽  
pp. 4816-4828 ◽  
Author(s):  
Guannan Wu ◽  
Qingqing Zhu ◽  
Junli Zeng ◽  
Xiaoling Gu ◽  
Yingying Miao ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Acute Lung Injury ◽  
Lung Injury ◽  
Nlrp3 Inflammasome ◽  
Inflammasome Activation ◽  
Nlrp3 Inflammasome Activation

scholarly journals Mitochondrial DNA Activates NLRP3 Inflammasome and Contributes to Endothelial Dysfunction and Inflammation in Type 1 Diabetic Mice

2018 ◽  
Vol 32 (S1) ◽  
Author(s):  
Camila André Pereira ◽  
Nathanne Santos Ferreira ◽  
Camila Zillioto Zanotto ◽  
Daniela Carlos ◽  
Rita Tostes
Keyword(s):  
Mitochondrial Dna ◽  
Endothelial Dysfunction ◽  
Nlrp3 Inflammasome ◽  
Diabetic Mice

Abstract P075: Angiotensin II Induces Endothelial Dysfunction And Vascular Remodeling Dependent Of Nlrp3 Inflammasome

Hypertension ◽  
2020 ◽  
Vol 76 (Suppl_1) ◽  
Author(s):  
Stefany B Cau ◽  
Marcondes da Silva ◽  
Nathanne d Ferreira ◽  
Rita C Tostes ◽  
Thiago Bruder-Nascimento
Keyword(s):  
Angiotensin Ii ◽  
Endothelial Dysfunction ◽  
Nlrp3 Inflammasome ◽  
Vascular Remodeling ◽  
Vascular Diseases ◽  
Vascular Damage ◽  
Mesenteric Arteries ◽  
Cell Counting ◽  
Inflammasome Activation ◽  
Nlrp3 Inflammasome Activation

The NLRP3 inflammasome is a multimeric protein complex constituted by NLRP3, Asc and Capase-1 (Casp1). It triggers an inflammatory response by releasing the pro-inflammatory cytokines IL-1β and IL-18. NLRP3 inflammasome is expressed in different cells and its activation has been associated with several diseases including atherosclerosis and hypertension. Herein we tested the hypothesis that angiotensin II (AngII) induces vascular damage by activating the NLPR3 inflammasome in the vasculature. C57BL/6J male mice (Ctrl) and Casp-1 deficient mice (Casp1-/-) were treated with AngII (490 ng/min/kg/14 days by osmotic mini pump). In Ctrl mice, AngII treatment impaired the vascular relaxation to acetylcholine in mesenteric arteries, increased aorta media thickness [Ctrl: 49.4 ± 2.5 vs AngII: 62.3 ± 2.3* (μm), *P<0.05] and cross-sectional area [Ctrl: 0.11 ± 0.1 vs AngII: 0.15 ± 0.2* (mm), *P<0.05] and triggered NLRP3 inflammasome activation in aorta and mesenteric arteries, analyzed by caspase-1 cleavage and IL-1B maturation via western blot and casp1 activity - FAM-FLICA assay. Fascinatingly, Casp1-/- mice were protected from AngII-induced endothelial dysfunction and vascular remodeling. Furthermore, AngII (0.1uM) incubation, combined or not with lipopolysaccharide (500 ng.ml –1 ultrapure) or Nigericin (20 μM), elevated Casp1 cleavage and IL-1B maturation in Rat Aortic Smooth Muscle Cells (RASMC). Moreover, AngII elevated PCNA (~2.5-fold) and CyclinD1 (~2.1-fold) protein expression and induced vascular migration and proliferation measured by scratch assay and cell counting kit-8 (CCK-8) assay respectively. Interestingly NLRP3 antagonist incubation (MCC950, 1uM) abolished PCNA expression and attenuated the vascular migration and proliferation produced by AngII incubation. Our data suggest that AngII induces vascular damage by activating NLPR3 inflammasome directly in the vasculature. We place this innate immune receptor as a master regulator of the vascular phenotype and as a target for therapeutic strategies for vascular diseases. Future studies will be helpful providing a better understanding into the molecular mechanism of NLRP3 inflammasome activation and regulation in the control of vascular diseases.

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