Erythrocyte-derived microvesicles induce arterial spasms in JAK2V617F myeloproliferative neoplasm

J Clin Invest. 2020 May 1;130(5):2630-2643. doi: 10.1172/JCI124566.

Abstract

Arterial cardiovascular events are the leading cause of death in patients with JAK2V617F myeloproliferative neoplasms (MPNs). However, their mechanisms are poorly understood. The high prevalence of myocardial infarction without significant coronary stenosis or atherosclerosis in patients with MPNs suggests that vascular function is altered. The consequences of JAK2V617F mutation on vascular reactivity are unknown. We observe here increased responses to vasoconstrictors in arteries from Jak2V617F mice resulting from a disturbed endothelial NO pathway and increased endothelial oxidative stress. This response was reproduced in WT mice by circulating microvesicles isolated from patients carrying JAK2V617F and by erythrocyte-derived microvesicles from transgenic mice. Microvesicles of other cellular origins had no effect. This effect was observed ex vivo on isolated aortas, but also in vivo on femoral arteries. Proteomic analysis of microvesicles derived from JAK2V617F erythrocytes identified increased expression of myeloperoxidase as the likely mechanism accounting for their effect. Myeloperoxidase inhibition in microvesicles derived from JAK2V617F erythrocytes suppressed their effect on oxidative stress. Antioxidants such as simvastatin and N-acetyl cysteine improved arterial dysfunction in Jak2V617F mice. In conclusion, JAK2V617F MPNs are characterized by exacerbated vasoconstrictor responses resulting from increased endothelial oxidative stress caused by circulating erythrocyte-derived microvesicles. Simvastatin appears to be a promising therapeutic strategy in this setting.

Keywords: Cancer; Cardiology; Cardiovascular disease; Hematology; endothelial cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antioxidants / pharmacology
  • Aorta, Thoracic / drug effects
  • Aorta, Thoracic / physiopathology
  • Cardiovascular Diseases / etiology
  • Cardiovascular Diseases / genetics
  • Cardiovascular Diseases / physiopathology
  • Cell-Derived Microparticles / physiology
  • Erythrocytes / physiology*
  • Femoral Artery / drug effects
  • Femoral Artery / physiopathology
  • Gain of Function Mutation*
  • Humans
  • In Vitro Techniques
  • Janus Kinase 2 / genetics*
  • Janus Kinase 2 / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Myeloproliferative Disorders / complications
  • Myeloproliferative Disorders / genetics*
  • Myeloproliferative Disorders / physiopathology*
  • Oxidative Stress
  • Simvastatin / pharmacology
  • Vasoconstriction / drug effects
  • Vasoconstriction / physiology

Substances

  • Antioxidants
  • Simvastatin
  • JAK2 protein, human
  • Janus Kinase 2

Grant support

Supported Johanne Poisson