Abstract 15575: The Clonal Hematopoiesis Mutation Jak2 V617F Aggravates NETosis and Endothelial Injury in Mouse Arteries With Erosion-like Intimas

• DOI: 10.1161/circ.142.suppl_3.15575
• Publication Date: 2021-05-10T17:09:12Z
• Authors: Roberto Molinaro; Rob S Sellar; Grasiele Sausen; Amelie Vromman; Eduardo Folco; Galina K Sukhova; Benjamin Ebert; Peter Libby
• Keywords: Neutrophil Extracellular Traps; Endothelial Dysfunction

Introduction: In the current era of intense LDL lowering, superficial erosion may be on rise as a cause ACS (25-30%). Experimental data human atheromata support role for neutrophils and formation neutrophil extracellular traps (NETs) in pathogenesis subsequent thrombosis. The common mutation Janus kinase 2 ( Jak2 V617F ) borne by clones leukocytes derived from bone marrow stem cells sensitizes to undergo NETosis linked NET increased associates with accelerated atherosclerosis venous thrombosis patients myeloproliferative neoplasms (MPN) individuals harboring this but without demonstrable MPN. Hypothesis We hypothesized that i) associated clonal hematopoiesis atherosclerotic thrombotic risk humans, predisposes endothelial injury at sites flow disturbance arteries erosion-like intimas; ii) clinically approved Jak-1,2 inhibitor, ruxolitinib (Rux), can preserve integrity reduce mice myeloid . Methods: generated cohorts or wild-type used surgical preparation recapitulating features assessed integrity, thrombosis, relation genotype vivo Rux treatment. Results Conclusions: Evans blue extravasation following introduction erosion-prone intimas showed significant impairment barrier group bearing compared control (WT) ** p<0.005). further observed more mutation. Immunohistochemical evaluation regions experimental revealed reduced continuity accumulation vs. WT mice. treatment mitigated adverse effects both supporting translational potential these observations due acute coronary syndromes.