Abstract
Abstract 107: PKM2 Promotes Neutrophil Activation And Cerebral Thrombo-inflammation: Therapeutic Implications For Ischemic Stroke
Arteriosclerosis, thrombosis, and vascular biology, Vol.41(Suppl_1)
09/2021
DOI: 10.1161/atvb.41.suppl_1.107
Abstract
In recent years compelling evidence has emerged that implicates role of metabolic reprogramming in the modulation of thrombosis and inflammation. The dimeric form of the metabolic enzyme pyruvate kinase muscle 2 (PKM2) enters nucleus and exerts protein kinase activity. We found that nuclear PKM2 levels were upregulated in neutrophils after the onset of ischemic stroke both in humans and in mice. Therefore, we evaluated the role of PKM2 in promoting thrombo-inflammation and ischemic brain injury.We generated novel myeloid cell-specific
PKM2
-/-
mice on wild-type (
PKM2
fl/fl
LysMCre
+
) and hyperlipidemic background (
PKM2
fl/fl
LysMCre
+
Apoe
-/-
). We observed that genetic deletion of PKM2 in myeloid cells limited inflammatory response in peripheral neutrophils and reduced neutrophil extracellular traps following cerebral ischemia/reperfusion. In the filament and autologous clot/rtPA stroke models, irrespective of sex, deletion of PKM2 in myeloid cells either in wild-type or hyperlipidemic mice reduced infarcts and enhanced long-term sensorimotor recovery. Laser speckle imaging revealed improved regional cerebral blood flow in myeloid cell-specific PKM2-deficient mice that was concomitant with reduced post-ischemic cerebral thrombo-inflammation (intracerebral fibrin(ogen), platelet (CD41- positive) deposition, neutrophil infiltration, and inflammatory cytokines). Mechanistically, PKM2 regulates post-ischemic inflammation in peripheral neutrophils by promoting STAT3 phosphorylation. Utilizing small molecule inhibitor (ML265) that inhibits PKM2 dimerization, we evaluated ex vivo thrombosis using human whole blood in a microfluidic flow chamber system. We observed a fivefold reduction in the thrombus growth rate in ML265-treated group. Similarly, ML265 treatment in mice resulted into significantly reduced poststroke neutrophil hyperactivation and improved short-term and long-term functional outcomes following stroke. Collectively, these findings identify PKM2 as a novel therapeutic target to improve brain salvage and recovery following reperfusion.
Details
- Title: Subtitle
- Abstract 107: PKM2 Promotes Neutrophil Activation And Cerebral Thrombo-inflammation: Therapeutic Implications For Ischemic Stroke
- Creators
- Nirav Dhanesha - University of IowaRakeshkumar Patel - University of IowaManish Jain - University of IowaMariia Kumskova - University of IowaDaniel Thedens - Univ Iowa, Iowa City, IAHeena M Olalde - Univ of Iowa Hosp, Iowa City, IAManasa Nayak - University of IowaPrakash Doddapattar - University of IowaEnrique C. C Leira - University of IowaAnil K Chauhan - University of Iowa
- Resource Type
- Abstract
- Publication Details
- Arteriosclerosis, thrombosis, and vascular biology, Vol.41(Suppl_1)
- DOI
- 10.1161/atvb.41.suppl_1.107
- ISSN
- 1079-5642
- eISSN
- 1524-4636
- Language
- English
- Date published
- 09/2021
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Radiology; Electrical and Computer Engineering; Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine; Neurology; Epidemiology; Iowa Neuroscience Institute; Neurosurgery
- Record Identifier
- 9984274854802771
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