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Monday 23 November 2015

Enhanced hypoxic tolerance by Seabuckthorn is due to upregulation of HIF-1α and attenuation of ER stress


Highlights

Seabuckthorn (SBT) leaf extract improves hypoxic tolerance.
Cardioprotective action of SBT may be due to the upregulation of HIF-1α and its regulated proteins.
SBT enhances NO production and reduces endothelin-1 levels.
SBT ameliorates hypoxia induced ER stress.
SBT extracts displays anti-inflammatory and anti-apoptotic properties.

Abstract

An imbalance in the redox homeostasis causes activation of multifaceted signaling responses which may be protective or deleterious. Amelioration of oxidative stress is one of the major modes of action of herbal supplements like Seabuckthorn (SBT). While the antioxidant potential of SBT is known, investigations into its effect on stress inducible signaling cascades are in progress. Here, we examine the impact of SBT on hypoxic tolerance and the mechanism behind its cardioprotective action. The efficacy of SBT was evaluated using the onset of gasping time (GT) at an altitude of 9754 m as the indicator for hypoxic tolerance. SBT led to a 100% increase in GT and curtailed hypoxia induced cardiac damage and free radical production. SBT upregulated HIF-1α and led to a two-fold increase in HO-1. A 100% increase in NO levels was observed. SBT reduced protein carbonylation and enhanced HSP70 levels. A statistically significant decline was seen in the markers of ER stress, GRP78, PERK and CHOP. SBT potentiated anti-inflammatory effects and downregulated NF-κB and TNF-α. Our study provides a novel insight into the mechanism behind the pro-survival effects of SBT against hypoxia, highlighting the cross talk between key adaptive responses mediated by HIF-1α and ER stress.

Graphical abstract

Image for unlabelled figure

Abbreviations

  • AOPP, advanced oxidation protein products;
  • CHOP, C/EBP homologous protein;
  • CK-MB, creatine kinase-MB;
  • DCFH-DA, 2′,7′-dichlorofluorescein-diacetate;
  • eIF2, eukaryotic initiation factor 2;
  • eNOS, endothelial nitric oxide synthase;
  • ER, endoplasmic reticulum;
  • GLUT-1, glucose transporter-1;
  • GRP78, glucose regulated protein 78;
  • HIF-1, hypoxia inducible factor-1α;
  • HO-1, heme oxygenase-1;
  • HSP, heat shock proteins;
  • HSR, heat shock response;
  • iNOS, inducible nitric oxide synthase;
  • NF-κB, nuclear factor-κB;
  • NO, nitric oxide;
  • PERK, protein kinase-like ER kinase;
  • ROS, reactive oxygen species;
  • SBT, Seabuckthorn;
  • UPR, unfolded protein response;
  • VEGF, vascular endothelial growth factor

Keywords

  • Oxidative stress;
  • Hypoxia;
  • HIF-1α;
  • Nitric oxide;
  • Caspase

Corresponding author. Tel.: +91 11 23883311; fax: +91 11 23914790.