Abstract Number: PB1037
Meeting: ISTH 2021 Congress
Background: Neutrophil extracellular traps (NETs) have been reported to promote the formation of abdominal aortic aneurysms (AAAs) by propagating an inflammatory response. They are formed by the expulsion of nuclear or mitochondrial DNA which implicates the production of reactive oxygen species (ROS). Moreover, oxidized mitochondrial DNA is known to be involved in chronic inflammatory pathologies like systemic lupus erythematosus (SLE).
Aims: The aim of the study was to test the therapeutic capacity of blocking mitochondrial ROS and mitoNET formation on established AAA disease in murine models. mitoTEMPO, a mitoROS scavenger, was previously shown to diminish NET capacity in a mouse model of SLE. Additionally, metformin, which is an anti-diabetic agent acting in a pleiotropic manner, has been proposed to inhibit nuclear as well as mitochondrial NETs by regulating ROS production.
Methods: AAAs are induced in ApoE KO mice by subcutaneous implantation of osmotic pumps releasing angiotensin II over 28 days. Aneurysms develop by day 8, when the animals undergo external jugular vein catheterization with an access port for daily intravenous injections with PBS (as control) or anti-NET therapy with mitoTEMPO (3 µg/g) or metformin (0.2 µg/g mouse weight).
Results: Inhibition of AAA progression revealed a significant difference in percent growth of aortic volume at day 28 (p=0.0177) between the control group treated with daily PBS injections (n=6, 337% growth in aortic volume), and the mitoTEMPO treated group (n=7, 185% growth in aortic volume). Moreover, the application of metformin in the same model showed significant inhibition of AAA progression in the treatment group (n=7/group, 364% vs. 199% growth in aortic volume, p=0.0133).
Conclusions: Both mitoTEMPO and metformin show inhibition of AAA progression in the ApoE KO mouse model. To document the impact of these inhibitors on mitoNETs, reversal of drug effects by injection of oxidized mitochondrial DNA will be attempted.
To cite this abstract in AMA style:Bleichert S, Ibrahim N, Klopf J, Knöbl V, Busch A, Bailey M, Eilenberg W, Neumayer C, Brostjan C. Targeting Pathways of Mitochondrial Neutrophil Extracellular Trap Formation to Inhibit Progression of Abdominal Aortic Aneurysms in Preclinical Models [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/targeting-pathways-of-mitochondrial-neutrophil-extracellular-trap-formation-to-inhibit-progression-of-abdominal-aortic-aneurysms-in-preclinical-models/. Accessed November 28, 2021.
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