Inhibition of JAK2 suppresses myelopoiesis and atherosclerosis in Apoe (−/−) mice Journal Article
| Authors: | Tang, Y.; Liu, W.; Wang, W.; Fidler, T.; Woods, B.; Levine, R. L.; Tall, A. R.; Wang, N. |
| Article Title: | Inhibition of JAK2 suppresses myelopoiesis and atherosclerosis in Apoe (−/−) mice |
| Abstract: | Objective: Increased myelopoiesis has been linked to risk of atherosclerotic cardiovascular disease (ACD). Excessive myelopoiesis can be driven by dyslipidemia and cholesterol accumulation in hematopoietic stem and progenitor cells (HSPC) and may involve increased signaling via Janus kinase 2 (JAK2). Constitutively activating JAK2 mutants drive biased myelopoiesis and promote development of myeloproliferative neoplasms (MPN) or clonal hematopoiesis, conditions associated with increased risk of ACD. JAK2 inhibitors have been developed as a therapy for MPNs. The potential for JAK2 inhibitors to protect against atherosclerosis has not been tested. We therefore assessed the impact of JAK2 inhibition on atherogenesis. Methods: A selective JAK2 inhibitor TG101348 (fedratinib) or vehicle was given to high-fat high-cholesterol Western diet (WD)–fed wild-type (WT) or Apoe−/− mice. Hematopoietic cell profiles, cell proliferation, and atherosclerosis in WT or Apoe−/− mice were assessed. Results: TG101348 selectively reversed neutrophilia, monocytosis, HSPC, and granulocyte-macrophage progenitor (GMP) expansion in Apoe−/− mice with decreased cellular phosphorylated STAT5 and ERK1/2 and reduced cell cycling and BrdU incorporation in HSPCs, indicating inhibition of JAK/STAT signaling and cell proliferation. Ten-week WD feeding allowed the development of marked aortic atherosclerosis in Apoe−/− mice which was substantially reduced by TG101348. Conclusions: Selective JAK2 inhibition reduces atherogenesis by suppressing excessive myelopoiesis in hypercholesterolemic Apoe−/− mice. These findings suggest selective JAK2 inhibition as a potential therapeutic approach to decrease ACD risk in patients with increased myelopoiesis and leukocytosis. © 2020, The Author(s). |
| Keywords: | controlled study; janus kinase 2; nonhuman; treatment indication; cd8 antigen; cell proliferation; mouse; cd34 antigen; enzyme inhibition; clinical assessment; granulocyte macrophage colony stimulating factor; animal experiment; animal model; cd2 antigen; atherosclerosis; cd11b antigen; hematopoietic cell; mitogen activated protein kinase 3; cholesterol; hematopoietic stem cell; cd4 antigen; stat5 protein; cd19 antigen; colony forming unit gm; broxuridine; atherogenesis; monocytosis; jak2 inhibitor; lipid diet; apolipoprotein e; high density lipoprotein; western diet; myelopoiesis; interleukin 3; fibrinogen receptor; cholesterol diet; neutrophilia; cd71 antigen; female; priority journal; article; fedratinib; receptor type tyrosine protein phosphatase c; jak-stat signaling; tg101348 (fedratinib); aortic atherosclerosis |
| Journal Title: | Cardiovascular Drugs and Therapy |
| Volume: | 34 |
| Issue: | 2 |
| ISSN: | 0920-3206 |
| Publisher: | Springer |
| Date Published: | 2020-04-01 |
| Start Page: | 145 |
| End Page: | 152 |
| Language: | English |
| DOI: | 10.1007/s10557-020-06943-9 |
| PUBMED: | 32086626 |
| PROVIDER: | scopus |
| PMCID: | PMC7125070 |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
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