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American Heart Association

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Final ID: Tu032

LRRC8 complex regulates platelet activation and thrombosis

Abstract Body: During activation, platelets undergo both shape and volumetric changes which are mechanical events essential for thrombosis. Volume-Regulated Anion Channels (VRACs) are ubiquitously expressed mechanoresponsive, heterohexameric anion channels comprised of leucine-rich repeat containing protein 8 (LRRC8) A (essential for channel activity) in combination with B, C, D and/or E subunits. In this study, we identify single-nucleotide polymorphisms (SNPs) in three LRRC8 subunits (LRRC8A, C, and D) which are expressed in human platelets and are independently associated with altered mean platelet volume in human genetic studies – implicating the volume-sensing LRRC8 channel complex as a regulator of platelet function in humans. We show that LRRC8A is required for functional LRRC8/VRAC in megakaryocytes (MKs). MK-specific LRRC8A conditional knockout (cKO) mice give rise to LRRC8A-null platelets with larger mean volumes. LRRC8A-null platelets and CRISPR-edited human LRRC8A KO MKs (hiPSC MKs) have reduced agonist-stimulated P-selectin exposure and aIIbb3 integrin activation. LRRC8A-null platelets exhibit impaired adhesion to collagen-coated surfaces and reduced agonist-stimulated aggregation and ATP secretion. Additionally, VRAC in MKs mediate ATP currents which are abolished in LRRC8A-null MKs. In vivo, MK-specific LRRC8A cKO mice have reduced platelet thrombus formation in laser-induced cremaster arteriolar thrombosis, and prolonged occlusion times in FeCl3-induced carotid arterial thrombosis, compared to control mice, without affecting tail bleeding times. Mechanistically, platelet LRRC8A mediates swell-induced ATP release to amplify agonist-stimulated calcium influx and platelet aggregation. Small-molecule LRRC8 channel inhibitors largely recapitulate the defects observed in LRRC8A-null platelets. These studies identify the mechanoresponsive LRRC8 channel complex as an ATP release channel in platelets which regulates platelet function and arterial thrombosis, providing a proof-of-concept for a novel anti-thrombotic drug target.
  • Tranter, John  ( Washington University in St. Louis , St. Louis , Missouri , United States )
  • Ashworth, Katrina  ( Washington University in St. Louis , St. Louis , Missouri , United States )
  • Hong, Juan  ( Washington University in St. Louis , St. Louis , Missouri , United States )
  • Zhang, Haixia  ( Washington University in St. Louis , St. Louis , Missouri , United States )
  • Kumari, Tripti  ( Washington University in St. Louis , St. Louis , Missouri , United States )
  • Balutowski, Adam  ( Washington University in St. Louis , St. Louis , Missouri , United States )
  • Liu, Alice  ( Washington University in St. Louis , St. Louis , Missouri , United States )
  • Bark, David  ( Washington University in St. Louis , St. Louis , Missouri , United States )
  • Nair, Vinayak  ( Washington University in St. Louis , St. Louis , Missouri , United States )
  • Lasky, Nina  ( Washington University in St. Louis , St. Louis , Missouri , United States )
  • Feng, Yongmei  ( Washington University in St. Louis , St. Louis , Missouri , United States )
  • Kumar, Ashutosh  ( Washington University in St. Louis , St. Louis , Missouri , United States )
  • Stitziel, Nathan  ( Washington University in St. Louis , St. Louis , Missouri , United States )
  • Lerner, Daniel  ( Senseion Therapeutics , St. Louis , Missouri , United States )
  • Campbell, Robert  ( University of Utah , Salt Lake City , Utah , United States )
  • Di Paola, Jorge  ( Washington University in St. Louis , St. Louis , Missouri , United States )
  • Cho, Jaehyung  ( Washington University in St. Louis , St. Louis , Missouri , United States )
  • Sah, Rajan  ( Washington University in St. Louis , St. Louis , Missouri , United States )
  • Brown, Gavriel  ( Washington University in St. Louis , St. Louis , Missouri , United States )
  • Mikami, Ryan  ( Washington University in St. Louis , St. Louis , Missouri , United States )
  • Zhao, Yonghui  ( Washington University in St. Louis , St. Louis , Missouri , United States )
  • Abraham, Nihil  ( Washington University in St. Louis , St. Louis , Missouri , United States )
  • Abd El-aziz, Tarek  ( Washington University in St. Louis , St. Louis , Missouri , United States )
  • Ajanel Gomez, Jehiel Abigail  ( University of Utah , Salt Lake City , Utah , United States )
  • Xie, Litao  ( Washington University in St. Louis , St. Louis , Missouri , United States )
  • Author Disclosures:
    John Tranter: DO NOT have relevant financial relationships | Katrina Ashworth: DO NOT have relevant financial relationships | Juan Hong: DO NOT have relevant financial relationships | Haixia Zhang: No Answer | Tripti Kumari: DO NOT have relevant financial relationships | Adam Balutowski: No Answer | Alice Liu: DO NOT have relevant financial relationships | David Bark: No Answer | Vinayak Nair: No Answer | Nina Lasky: No Answer | Yongmei Feng: No Answer | Ashutosh Kumar: No Answer | Nathan Stitziel: DO have relevant financial relationships ; Consultant:Novo Nordisk:Active (exists now) | Daniel Lerner: DO have relevant financial relationships ; Ownership Interest:Senseion Therapeutics:Active (exists now) | Robert Campbell: No Answer | Jorge Di Paola: No Answer | Jaehyung Cho: DO NOT have relevant financial relationships | Rajan Sah: DO have relevant financial relationships ; Ownership Interest:Senseion Therapeutics Inc.:Active (exists now) | Gavriel Brown: DO NOT have relevant financial relationships | Ryan Mikami: No Answer | Yonghui Zhao: DO NOT have relevant financial relationships | Nihil Abraham: DO NOT have relevant financial relationships | Tarek Abd El-Aziz: DO NOT have relevant financial relationships | Jehiel Abigail Ajanel Gomez: DO NOT have relevant financial relationships | Litao Xie: No Answer
Meeting Info:

Basic Cardiovascular Sciences

2024

Chicago, Illinois

Session Info:

Poster Session and Reception 2

Tuesday, 07/23/2024 , 04:30PM - 07:00PM

Poster Session and Reception

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