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

• Published in: Journal of Atherosclerosis and Thrombosis Vol. 25; no. 9; pp. 808 - 820
• Main Authors: Pasini, Anna Maria Fratta, Stranieri, Chiara, Rigoni, Anna Maria, Marchi, Sergio De, Peserico, Denise, Mozzini, Chiara, Cominacini, Luciano, Garbin, Ulisse
• Format: Journal Article
• Language: English; Japanese
• Published: Japan Japan Atherosclerosis Society 01.09.2018
• Subjects: Aged; Aged, 80 and over; Apoptosis; Cell Nucleus - metabolism; eIF-2 Kinase - metabolism; Endoribonucleases - metabolism; Exercise; Exercise Test; Female; Humans; Ischemic Preconditioning; Leukocytes, Mononuclear - cytology; Leukocytes, Mononuclear - metabolism; Male; Middle Aged; NF-E2-Related Factor 2 - blood; Nrf2; Original; Outpatients; Oxidative Stress; PAD; Peripheral Arterial Disease - blood; Protein Denaturation; Protein-Serine-Threonine Kinases - metabolism; Transcription Factors - metabolism; Unfolded Protein Response; Up-Regulation; UPR; Walking; Oxidative stress; PAD; Nrf2; UPR
• ISSN: 1340-3478; 1880-3873
• DOI: 10.5551/jat.42432

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.