Secreted Monocyte miR-27a, via Mesenteric Arterial Mas Receptor-eNOS Pathway, Causes Hypertension

Am J Hypertens. 2020 Jan 1;33(1):31-42. doi: 10.1093/ajh/hpz112.

Abstract

Background: Essential hypertension is associated with increased plasma concentrations of extracellular vesicles (EVs). We aimed to determine the role of monocyte miR-27a in EVs on arterial Mas receptor expression, and its involvement in the pathogenesis of hypertension.

Methods: THP-1 cells were transfected with miR-27a mimic and miR-27a inhibitor, and EVs were collected. Mas receptor expression and endothelial nitric oxide synthase (eNOS) phosphorylation were determined by immunoblotting. Sprague-Dawley (SD) rats received EVs via tail-vein injection. Blood pressure (BP) was measured with the tail-cuff method. The vasodilatory response of mesenteric arteries was measured using a small vessel myograph.

Results: EVs from THP-1 cells increased rat BP by impairing Ang-(1-7)-mediated vasodilation in mesenteric arteries, which was further exaggerated by EVs from lipopolysaccharides-treated THP-1 cells. As the receptor and key signaling of Ang-(1-7), next experiments found that Mas receptor expression and eNOS phosphorylation were decreased in mesenteric arteries from EVs-treated SD rats. Screening studies found miR-27a in EVs may be involved in this process. Through transfection with miR-27a inhibitor or miR-27a mimic, we found that miR-27a downregulates Mas receptor expression in endothelial cells. Injection of EVs from miR-27a-transfected HEK-293 cells decreased Mas receptor and eNOS phosphorylation in mesenteric arteries, impaired Ang-(1-7)-mediated vasodilation and increased BP. Earlier effects were reversed using cells with downregulation of miR-27 in EVs.

Conclusions: Monocyte miR-27a in EVs decreases Mas receptor expression and eNOS phosphorylation in endothelium, impairs Ang-(1-7)-mediated vasodilation, and causes hypertension. Understanding the contributions of EVs in the pathogenesis of hypertension may facilitate their use as a diagnostic biomarker.

Keywords: Mas receptor; blood pressure; eNOS; extracellular vesicles; hypertension; miR-27a.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Pressure*
  • Disease Models, Animal
  • Extracellular Vesicles / genetics
  • Extracellular Vesicles / metabolism*
  • Extracellular Vesicles / transplantation
  • HEK293 Cells
  • Humans
  • Hypertension / enzymology*
  • Hypertension / genetics
  • Hypertension / physiopathology
  • Male
  • Mesenteric Arteries / enzymology*
  • Mesenteric Arteries / physiopathology
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Monocytes / metabolism*
  • Monocytes / transplantation
  • Nitric Oxide Synthase Type III / metabolism*
  • Phosphorylation
  • Proto-Oncogene Mas
  • Proto-Oncogene Proteins / metabolism*
  • Rats, Sprague-Dawley
  • Receptors, G-Protein-Coupled / metabolism*
  • Signal Transduction
  • THP-1 Cells
  • Vasodilation

Substances

  • MIRN27 microRNA, human
  • MicroRNAs
  • Proto-Oncogene Mas
  • Proto-Oncogene Proteins
  • Receptors, G-Protein-Coupled
  • Nitric Oxide Synthase Type III
  • Nos3 protein, rat