Abstract
Abstract 4136786: Prediabetes increases platelet activation and thrombotic susceptibility via mitochondrial oxidants
Circulation (New York, N.Y.), Vol.150(Suppl_1)
11/12/2024
DOI: 10.1161/circ.150.suppl_1.4136786
Abstract
Abstract only Recent studies suggest that prediabetes is not only a prelude to diabetes, but also is an independent risk factor for cardiovascular thrombotic events in young and aged people. However, the mechanisms that may promote platelet activation and thrombosis during prediabetes have not been studied. We hypothesized that in prediabetes, dysregulation of electron transfer and accumulation of mitochondrial oxidants promotes platelet activation and thrombosis, and that aging exacerbates the phenotype. We recruited young (18-50 year) and middle-aged (51-64 year) Veterans with prediabetes and age- and BMI- matched healthy Veterans. Compared to healthy cohort, platelets from prediabetes exhibited enhanced agonist induced platelet activation, mitochondrial oxidants, membrane potential and thrombus formation ex vivo in both young and middle-aged cohorts to a similar extent. Preincubation of platelets with either a mitochondria targetable superoxide dismutase (SOD) mimetic or MitoQ (transfers electrons from Complex I/II to complex III to lower superoxide generation within mitochondria), rescued the prothrombotic phenotype. We confirmed these platelet phenotypes in C57BL6/J mice fed high fat (HF) diet for 2 weeks (model of early diabetes). Importantly, HF-fed mice showed increased susceptibility to carotid artery and pulmonary thrombosis in vivo . Pharmacological treatment of HF-fed mice with SOD-mimetic or MitoQ, or genetic overexpression of catalase within mitochondria, rescued the prothrombotic state. This is the first report showing platelet hyperactivity and enhanced thrombotic susceptibility in prediabetes. Further, our findings suggest that enhanced mitochondrial oxidants due to the premature electron escape contribute to the phenotype. Our data imply a therapeutic potential of SOD-mimetic and MitoQ in lowering thrombotic burden in prediabetes.
Details
- Title: Subtitle
- Abstract 4136786: Prediabetes increases platelet activation and thrombotic susceptibility via mitochondrial oxidants
- Creators
- Azaj Ahmed - University of Iowamelissa jensen - University of IowaKatharine Geasland - University of Iowa, Clinical Research UnitJagadish Swamy - University of IowaDouglas Spitz - University of IowaE. Dale Abel - Department of Medicine, LA, California, United StatesDiana Jalal - University of IowaSanjana Dayal - University of Iowa
- Resource Type
- Abstract
- Publication Details
- Circulation (New York, N.Y.), Vol.150(Suppl_1)
- Publisher
- LIPPINCOTT WILLIAMS & WILKINS
- DOI
- 10.1161/circ.150.suppl_1.4136786
- ISSN
- 0009-7322
- eISSN
- 1524-4539
- Language
- English
- Date published
- 11/12/2024
- Academic Unit
- Pathology; Fraternal Order of Eagles Diabetes Research Center; Endocrinology and Metabolism; Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine; Clinical Research Unit; Nephrology; Iowa Neuroscience Institute; Radiation Oncology
- Record Identifier
- 9984749558602771
Metrics
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