Limb Ischemic Conditioning Induces Oxidative Stress Followed by a Correlated Increase of HIF-1α in Healthy Volunteers

Ann Vasc Surg. 2020 Jan:62:412-419. doi: 10.1016/j.avsg.2019.06.033. Epub 2019 Aug 23.

Abstract

Background: Local and remote ischemic preconditioning has been used as a protective intervention against ischemia/reperfusion (I/R) damage in several preclinical and clinical studies. However, its physiological mechanisms are not completely known. I/R increases the production of reactive oxygen species, which also serve as messengers for a variety of functions. Hypoxia-inducible factor 1 alpha (HIF-1α) is probably the most important transcription factor mediator of hypoxic signaling.

Objective: We hypothesized that limb ischemic conditioning (LIC) induces a local oxidative/nitrosative stress and a correlated increase of HIF-1α plasma levels.

Methods: An observational, prospective, and single-center study has been conducted in 27 healthy volunteers. LIC was applied: three cycles (5 min of ischemia followed by 5 min of reperfusion) using an ischemia cuff placed on the upper left arm. Time course of 8-isoprostane, nitrite, and HIF-1α levels was measured in blood plasma. Venous blood was sampled from the left arm before tourniquet inflation (basal) and after LIC: 1 min and 2 hr for 8-isoprostane and nitrite; and 1 min, 2 hr, 8 hr, 24 hr, and 48 hr for HIF-1α.

Results: After LIC, we have found an early increase of 8-isoprostane and nitrite. HIF-1α increased at 2 and 8 hr after LIC. We found a direct correlation between HIF-1α and 8-isoprostane and nitrite plasma levels.

Conclusions: We concluded that LIC induces an early oxidative/nitrosative stress in the arm followed by an increase of HIF-1α plasma levels correlated with 8-isoprostane and nitrite levels, possibly as a local response.

Publication types

  • Observational Study

MeSH terms

  • Adult
  • Biomarkers / blood
  • Dinoprost / analogs & derivatives
  • Dinoprost / blood
  • Female
  • Healthy Volunteers
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / blood*
  • Ischemic Preconditioning / methods*
  • Male
  • Nitrites / blood
  • Nitrosative Stress
  • Oxidative Stress*
  • Prospective Studies
  • Regional Blood Flow
  • Spain
  • Therapeutic Occlusion*
  • Time Factors
  • Up-Regulation
  • Upper Extremity / blood supply*
  • Young Adult

Substances

  • Biomarkers
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Nitrites
  • 8-epi-prostaglandin F2alpha
  • Dinoprost