The clonal hematopoiesis mutation Jak2V617F aggravates endothelial injury and thrombosis in arteries with erosion-like intimas

Roberto Molinaro; Rob S Sellar; Amélie Vromman; Grasiele Sausen; Eduardo Folco; Galina K Sukhova; Marie E McConke; Claudia Corbo; Benjamin L Ebert; Peter Libby

doi:10.1016/j.ijcard.2024.132184

The clonal hematopoiesis mutation Jak2^V617F aggravates endothelial injury and thrombosis in arteries with erosion-like intimas

Int J Cardiol. 2024 May 16:409:132184. doi: 10.1016/j.ijcard.2024.132184. Online ahead of print.

Authors

Affiliations

¹ Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States of America.
² Department of Haematology, UCL Cancer Institute, London, UK; Dana-Farber Cancer Institute, Boston, MA, USA; Broad Institute of Harvard and MIT, Cambridge, MA, USA.
³ Dana-Farber Cancer Institute, Boston, MA, USA; Broad Institute of Harvard and MIT, Cambridge, MA, USA.
⁴ University of Milano-Bicocca, Department of Medicine and Surgery, NANOMIB Center, Monza 20900, Italy; IRCCS Istituto Ortopedico Galeazzi, Milan 20161, Italy.
⁵ Dana-Farber Cancer Institute, Boston, MA, USA; Broad Institute of Harvard and MIT, Cambridge, MA, USA; Howard Hughes Medical Institute, Boston, MA, USA.
⁶ Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States of America. Electronic address: plibby@bwh.harvard.edu.

PMID: 38759798
DOI: 10.1016/j.ijcard.2024.132184

Abstract

Background: Superficial plaque erosion causes many acute coronary syndromes. However, mechanisms of plaque erosion remain poorly understood, and we lack directed therapeutics for thrombotic complication. Human eroded plaques can harbor neutrophil extracellular traps (NETs) that propagate endothelial damage at experimental arterial lesions that recapitulate superficial erosion. Clonal Hematopoiesis of Indeterminate Potential (CHIP) denotes age-related clonal expansion of bone marrow-derived cells harboring somatic mutations in the absence of overt hematological disease. CHIP heightens the risk of cardiovascular disease, with the greatest increase seen in individuals with JAK2^V617F. Neutrophils from mice and humans with JAK2^V617F undergo NETosis more readily than Jak2^WT (wild-type) cells. We hypothesized that JAK2^V617F, by increasing propensity to NETosis, exacerbates aspects of superficial erosion.

Methods and results: We generated Jak2^V617F and Jak2^WT mice with heterozygous Jak2^V617F in myeloid cells. We induced areas of denuded endothelium that recapitulate features of superficial erosion and assessed endothelial integrity, cellular composition of the erosion, thrombosis rates, and response to ruxolitinib, a clinically available JAK1/2 inhibitor, in relation to genotype. Following experimental erosion, Jak2^V617F mice have greater impairment of endothelial barrier function and increased rates of arterial thrombosis. Neointimas in Jak2^V617F mice exhibit increased apoptosis, NETosis, and platelet recruitment. Jak2^V617F mice treated with ruxolitinib show increased endothelial continuity and reduced apoptosis in the neointima comparable to levels in Jak2^WT.

Conclusions: These observations provide new mechanistic insight into the pathophysiology of superficial erosion, the heightened risk for myocardial infarction in JAK2^V617F CHIP, and point the way to personalized therapeutics based on CHIP status.

Keywords: Acute coronary syndromes; Clonal hematopoiesis; Endothelial dysfunction; Janus kinase; Neutrophil extracellular traps; Superficial erosion.