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

Physical Exercise Reduces Cytotoxicity and Up-Regulates Nrf2 and UPR Expression in Circulating Cells of Peripheral Artery Disease Patients: An Hypoxic Adaptation?
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Fratta Pasini AM, Stranieri C, Rigoni AM, De Marchi S, Peserico D, Mozzini C, Cominacini L, Garbin U,


Fratta Pasini AM, Stranieri C, Rigoni AM, De Marchi S, Peserico D, Mozzini C, Cominacini L, Garbin U, (click to view)

Fratta Pasini AM, Stranieri C, Rigoni AM, De Marchi S, Peserico D, Mozzini C, Cominacini L, Garbin U,

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Journal of atherosclerosis and thrombosis 2018 03 13() doi 10.5551/jat.42432
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.

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