Physical Exercise Reduces Cytotoxicity and Up-Regulates Nrf2 and UPR Expression in Circulating Cells of Peripheral Artery Disease Patients: An Hypoxic Adaptation?

Abstract

AIM:

Ischemia-reperfusion (I-R) produces reactive oxygen species (ROS) that damage cells and favour cytotoxicity and apoptosis in peripheral artery disease (PAD) patients. Since brief episodes of I-R (ischemic conditioning) protect cells against ischemic harms, we evaluated whether a short-course of supervised treadmill training, characterized by repeated episodes of I-R, makes peripheral blood mononuclear cells (PBMCs) from PAD patients with intermittent claudication more resistant to I-R injuries by reducing oxidative stress and by inducing an adaptative response of unfolded protein response (UPR) and nuclear factor-E2-related factor (Nrf2) pathway expression.

METHODS:

24 PAD patients underwent 21 sessions of treadmill training and a treadmill test as indicator of acute response to I-R.

RESULTS:

Maximal and pain free walking distance improved (p＜0.01), whereas LDH leakage and apoptosis of PBMCs decreased (p＜0.01); plasma malondialdehyde and ROS generation in PBMCs declined, while plasma glutathione augmented (p＜0.01). Moreover we demonstrated an up-regulation of UPR and Nrf2 expression in PBMCs (p＜0.01). To understand whether treadmill training may act as a trigger of ischemic conditioning, we examined the effect of repeated episodes of I-R on adaptative response in PBMCs derived from the patients. We showed an up-regulation of UPR and Nrf2 gene expression (p＜0.01), while oxidative stress and cytotoxicity, after an initial increase, declined (p＜0.01). This positive effect on cytotoxicity was reduced after inhibition of UPR and Nrf2 pathways.

CONCLUSIONS:

Treadmill training in PAD patients through UPR and Nrf2 up-regulation may trigger hypoxic adaptation similar to conditioning, thus modifying cell survival.

• Authors: Anna Maria Fratta Pasini, Chiara Stranieri, Anna Maria Rigoni, Sergio De Marchi, Denise Peserico, Chiara Mozzini, Luciano Cominacini, Ulisse Garbin
• Journal: Journal of atherosclerosis and thrombosis (J Atheroscler Thromb) Vol. 25 Issue 9 Pg. 808-820 (Sep 01 2018) ISSN: 1880-3873 [Electronic] Japan
• PMID: 29540636 (Publication Type: Journal Article)

Chemical References

• NF-E2-Related Factor 2
• NFE2L2 protein, human
• Transcription Factors
• EIF2AK3 protein, human
• ERN1 protein, human
• Protein Serine-Threonine Kinases
• eIF-2 Kinase
• Endoribonucleases

Topics

• Aged
• Aged, 80 and over
• Apoptosis
• Cell Nucleus (metabolism)
• Endoribonucleases (metabolism)
• Exercise
• Exercise Test
• Female
• Humans
• Ischemic Preconditioning
• Leukocytes, Mononuclear (cytology, metabolism)
• Male
• Middle Aged
• NF-E2-Related Factor 2 (blood)
• Outpatients
• Oxidative Stress
• Peripheral Arterial Disease (blood)
• Protein Denaturation
• Protein Serine-Threonine Kinases (metabolism)
• Transcription Factors (metabolism)
• Unfolded Protein Response
• Up-Regulation
• Walking
• eIF-2 Kinase (metabolism)