MicroRNA-142-3p improves vascular relaxation in uremia

Atherosclerosis. 2019 Jan:280:28-36. doi: 10.1016/j.atherosclerosis.2018.11.024. Epub 2018 Nov 10.

Abstract

Background and aims: Chronic kidney disease (CKD) is strongly associated with a high burden of cardiovascular morbidity and mortality. Therefore, we aimed to characterize the putative role of microRNAs (miR)s in uremic vascular remodelling and endothelial dysfunction.

Methods: We investigated the expression pattern of miRs in two independent end-stage renal disease (ESRD) cohorts and in the animal model of uremic DBA/2 mice via quantitative RT-PCR. Moreover, DBA/2 mice were treated with intravenous injections of synthetic miR-142-3p mimic and were analysed for functional and morphological vascular changes by mass spectrometry and wire myography.

Results: The expression pattern of miRs was regulated in ESRD patients and was reversible after kidney transplantation. Out of tested miRs, only blood miR-142-3p was negatively associated with carotid-femoral pulse-wave velocity in CKD 5D patients. We validated these findings in a murine uremic model and found similar suppression of miR-142-3p as well as decreased acetylcholine-mediated vascular relaxation of the aorta. Therefore, we designed experiments to restore bioavailability of aortic miR-142-3p in vivo via intravenous injection of synthetic miR-142-3p mimic. This intervention restored acetylcholine-mediated vascular relaxation.

Conclusions: Taken together, we provide compelling evidence, both in humans and in mice, that miR-142-3p constitutes a potential pharmacological agent to prevent endothelial dysfunction and increased arterial stiffness in ESRD.

Keywords: Arterial stiffness; Endothelium dysfunction; Pulse wave velocity; Vascular calcification.

Publication types

  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholine / metabolism*
  • Adult
  • Animals
  • Aorta / metabolism
  • Case-Control Studies
  • Endothelium, Vascular / pathology*
  • Female
  • Humans
  • Kidney Failure, Chronic / metabolism
  • Kidney Transplantation
  • Male
  • Mice
  • Mice, Inbred DBA
  • MicroRNAs / metabolism*
  • Middle Aged
  • Muscle, Smooth, Vascular / metabolism
  • Peritoneal Dialysis
  • Phenotype
  • Prospective Studies
  • Pulse Wave Analysis
  • Renal Dialysis
  • Uremia / blood*
  • Uremia / genetics*
  • Vascular Stiffness*

Substances

  • MIRN142 microRNA, human
  • MicroRNAs
  • Mirn142 microRNA, mouse
  • Acetylcholine