Author + information
- Received January 16, 2019
- Revision received May 29, 2019
- Accepted May 29, 2019
- Published online October 28, 2019.
- Soichi Sano, MD, PhDa,
- Ying Wang, MD, PhDa,
- Yoshimitsu Yura, MD, PhDa,
- Miho Sano, MD, PhDa,
- Kosei Oshima, MD, PhDb,
- Yue Yang, PhDc,
- Yasufumi Katanasaka, PhDd,
- Kyung-Duk Min, MD, PhDa,
- Shinobu Matsuura, DVM, PhDe,
- Katya Ravid, DSce,
- Golam Mohi, PhDc and
- Kenneth Walsh, PhDa,∗ ()
- aHematovascular Biology Center, Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, Virginia
- bMolecular Cardiology, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts
- cBiochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, Virginia
- dDivision of Molecular Medicine, Graduate School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan
- eDepartment of Medicine and Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts
- ↵∗Address for correspondence:
Dr. Kenneth Walsh, University of Virginia, Robert M. Berne Cardiovascular Research Center, 415 Lane Road, PO Box 801394, Suite 1010, Charlottesville, Virginia 22908.
• Clonal hematopoiesis can develop from JAK2V617F mutant cells, but mouse models harboring this mutation are confounded by myeloproliferative disease phenotypes.
• To establish a model of JAK2V617F clonal hematopoiesis, a lentivirus vector was used to transduce hematopoietic stem and progenitor cells with a construct that expresses this mutation from a myeloid-specific promoter.
• When transduced hematopoietic stem and progenitor cells were implanted into mice, JAK2V617F chimerism was achieved in monocytes and neutrophils in the absence of changes in blood cell counts, and these mice exhibited greater myocardial inflammation and accelerated heart failure when subjected to models of cardiac injury.
• These data suggest that clonal hematopoiesis can arise from the acquisition of JAK2V617F mutations in a progenitor cell subpopulation that gives rise to circulating myeloid cells, and that this condition can promote cardiovascular disease through proinflammatory mechanisms.
Janus kinase 2 (valine to phenylalanine at residue 617) (JAK2V617F) mutations lead to myeloproliferative neoplasms associated with elevated myeloid, erythroid, and megakaryocytic cells. Alternatively these same mutations can lead to the condition of clonal hematopoiesis with no impact on blood cell counts. Here, a model of myeloid-restricted JAK2V617F expression from lineage-negative bone marrow cells was developed and evaluated. This model displayed greater cardiac inflammation and dysfunction following permanent left anterior descending artery ligation and transverse aortic constriction. These data suggest that JAK2V617Fmutations arising in myeloid progenitor cells may contribute to cardiovascular disease by promoting the proinflammatory properties of circulating myeloid cells.
This work was supported by National Institutes of Health grant nos. HL138014, HL132564 (to Dr. Walsh), HL139819 (to Dr. Walsh), HL141256 (to Dr. Walsh), HL095685 (to Dr. Mohi), and HL136363 (to Dr. Ravid); American Heart Association Post-Doctoral Fellowship 17POST33670076 and Kanae Foundation for the Promotion of Medical Science (to Dr. Sano), and a China Scholarship Council grant (to Dr. Wang). The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: Basic to Translational Science author instructions page.
- Received January 16, 2019.
- Revision received May 29, 2019.
- Accepted May 29, 2019.
- 2019 The Authors