Decoding Endothelial MPL and JAK2V617F Mutation: Insight Into Cardiovascular Dysfunction in Myeloproliferative Neoplasms.

Autor:	Zhang H; Department of Medicine, Stony Brook School of Medicine, NY (H. Zhang, N.K., K.M., X.Y., H. Zhan).; The Graduate Program in Molecular and Cellular Biology (H. Zhang), Stony Brook University, NY., Kafeiti N; Department of Medicine, Stony Brook School of Medicine, NY (H. Zhang, N.K., K.M., X.Y., H. Zhan)., Masarik K; Department of Medicine, Stony Brook School of Medicine, NY (H. Zhang, N.K., K.M., X.Y., H. Zhan)., Lee S; Department of Molecular and Cellular Pharmacology (S.L.), Stony Brook University, NY., Yang X; Department of Medicine, Stony Brook School of Medicine, NY (H. Zhang, N.K., K.M., X.Y., H. Zhan).; Division of Rheumatology, Peking Union Medical College Hospital, Beijing, China (X.Y.)., Zheng H; Cardiac Imaging, The Heart Center, Saint Francis Hospital, Roslyn, NY (H. Zheng)., Zhan H; Department of Medicine, Stony Brook School of Medicine, NY (H. Zhang, N.K., K.M., X.Y., H. Zhan).; Medical Service, Northport VA Medical Center, NY (H. Zhan).
Jazyk:	angličtina
Zdroj:	Arteriosclerosis, thrombosis, and vascular biology [Arterioscler Thromb Vasc Biol] 2024 Sep; Vol. 44 (9), pp. 1960-1974. Date of Electronic Publication: 2024 Jul 11.
DOI:	10.1161/ATVBAHA.124.321008
Abstrakt:	Background: Patients with JAK2V617F-positive myeloproliferative neoplasms (MPNs) and clonal hematopoiesis of indeterminate potential face a significantly elevated risk of cardiovascular diseases. Endothelial cells carrying the JAK2V617F mutation have been detected in many patients with MPN. In this study, we investigated the molecular basis for the high incidence of cardiovascular complications in patients with MPN. Methods: We investigated the impact of endothelial JAK2V617F mutation on cardiovascular disease development using both transgenic murine models and MPN patient-derived induced pluripotent stem cell lines. Results: Our investigations revealed that JAK2V617F mutant endothelial cells promote cardiovascular diseases under stress, which is associated with endothelial-to-mesenchymal transition and endothelial dysfunction. Importantly, we discovered that inhibiting the endothelial TPO (thrombopoietin) receptor MPL (myeloproliferative leukemia virus oncogene) suppressed JAK2V617F-induced endothelial-to-mesenchymal transition and prevented cardiovascular dysfunction caused by mutant endothelial cells. Notably, the endothelial MPL receptor is not essential for the normal physiological regulation of blood cell counts and cardiac function. Conclusions: JAK2V617F mutant endothelial cells play a critical role in the development of cardiovascular diseases in JAK2V617F-positive MPNs, and endothelial MPL could be a promising therapeutic target for preventing or ameliorating cardiovascular complications in these patients. Competing Interests: None.
Databáze:	MEDLINE
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