Abstract
Abstract 247: Mitochondrial Damage Associated Molecular Patterns Promotes Endothelial Dysfunction in the Microcirculation
Circulation research, Vol.123(Suppl_1)
08/03/2018
DOI: 10.1161/res.123.suppl_1.247
Abstract
Vascular endothelial dysfunction is an early event in the development of atherosclerosis. Flow-mediated dilation (FMD) can be used to identify such endothelial dysfunction which is characterized by a decrease of nitric oxide (NO). Indeed, in subjects with coronary artery disease (CAD), microvascular FMD switches from a NO-mediated to a H
2
O
2
-mediated mechanism with corresponding elevations in mitochondrial reactive oxygen species (ROS). Recent evidence has shown an increase circulating mitochondrial DNA Damage-Associated Molecular Patterns (
mt
DAMPs) in Coronary Heart Disease subjects and has been linked to vascular dysfunction.
mt
DAMPs signaling can activate the inflammatory response directly through activation of Toll Like Receptors 9 (TLR9). The effect of
mt
DAMPs on the endothelial function in the human microcirculation and the potential role for TLR9- mtDNA signaling axis to affect microvascular FMD, is unknown. In this study, we hypothesized that increased levels of
mt
DAMPs result in changes in microvascular redox environment that promote a loss of NO mediated dilation and elevation in mitochondrial derived ROS
The incubation of cultured endothelial cells (ECs) with
mt
DAMPs decreased the ratio peNOS:teNOS in a time-dependent manner supporting the idea that
mt
DAMPs reduce NO bioavailability. This effect was eliminated when the ECs were pre-incubated with TLR9-targeted si-RNA. Prolonged (15-20H) ex vivo exposure to low dose of
mt
DAMPs (1ug/mL) changed the mechanism of FMD from NO to compensatory increase in H
2
O
2
to preserve overall dilator capacity
in non-CAD human adipose micro-arterioles (% Max Diameter: Control 84.7±8.2; + L-NAME: 89.4±5.5; + Peg-Cat 35.4±10.8*; N=5, *p<0.05). With higher dose of
mt
DAMPs (2.5ug/mL), the magnitude of the FMD was however significantly altered (% Max Diameter: high dose: 42.8 ±9.1* vs. low dose of
mt
DAMPs 84.7±8.2; N=4; p<0.05).
Our data suggest a potential pathogenic role of
mt
DAMPs in microvascular function through TLR9 to reduce NO bioavailability and induce endothelial dysfunction.
Details
- Title: Subtitle
- Abstract 247: Mitochondrial Damage Associated Molecular Patterns Promotes Endothelial Dysfunction in the Microcirculation
- Creators
- Karima Ait-Aissa - Medical College of WisconsinAndrew O Kadlec - Medical College of WisconsinDawid S Chabowski - Medical College of WisconsinJoseph C Hockenberry - Medical College of WisconsinJasmine M Linn - Medical College of WisconsinDavid D Gutterman - Medical College of WisconsinAndreas M Beyer - Medical College of Wisconsin
- Resource Type
- Abstract
- Publication Details
- Circulation research, Vol.123(Suppl_1)
- DOI
- 10.1161/res.123.suppl_1.247
- ISSN
- 0009-7330
- eISSN
- 1524-4571
- Language
- English
- Date published
- 08/03/2018
- Academic Unit
- Cardiovascular Medicine; Internal Medicine
- Record Identifier
- 9984361575202771
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