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Chemical Chaperone 4-Phenylbutyric Acid Reduces Cardiac Ischemia/Reperfusion Injury by Alleviating Endoplasmic Reticulum Stress and Oxidative Stress

Lian Jian, Yuan Lu, Shan Lu, Chengzhi Lu

Department of Cardiovascular, Tianjin First Central Hospital, Tianjin, China (mainland)

Med Sci Monit 2016; 22:5218-5227

DOI: 10.12659/MSM.898623

Available online:

Published: 2016-12-30

BACKGROUND: Cardiovascular diseases are the leading cause of death in many countries and myocardial ischemia-reperfusion (I/R) injury is the cause of many serious heart diseases. Recent reports suggested that endoplasmic reticulum (ER) stress is associated with the progress of ischemia/reperfusion (I/R) injury. In a previous study, we illustrated that 4-phenylbutyric acid (4-PBA) reduces I/R-induced cell death in vitro through inhibiting the ER stress-initiated cell apoptosis. In the present study we investigated whether 4-PBA improves heart function in isolated rat hearts subjected to I/R and elucidated the potential mechanisms involved in 4-PBA-induced cardioprotective effects.
MATERIAL AND METHODS: The isolated rat hearts were subjected to global ischemia and reperfusion in the absence or presence of 4-PBA. Hemodynamic parameters (LVSP, LVEDP, ±dP/dtmax, and HR) were monitored and histopathological examination was applied. The biomarkers related to oxidative stress were detected by LDH, ROS, MDA, CK, SOD, and GSH-Px kits. A TUNEL apoptosis assay kit was used to detect apoptosis. The expression levels of ER stress and apoptosis proteins were evaluated by Western blotting.
RESULTS: We found that 4-PBA (5 mM, 10 mM) pretreatment significantly attenuated cardiac dysfunction and depressed oxidative stress induced by I/R. Moreover, I/R activated the ER stress proteins Grp78 and PERK, which are all decreased by 4-PBA. 4-PBA pretreatment also inhibited the expression of CHOP, Caspase-12, and Bax, reduced the phosphorylation of JNK, and enhanced the expression of anti-apoptotic protein Bcl-2.
CONCLUSIONS: We elucidated the significant protective effects of 4-PBA against I/R injuries by inhibition of ER stress, oxidative stress, and their associated apoptosis.

Keywords: Apoptosis - drug effects, Antioxidants - metabolism, Animals, Cardiotonic Agents - pharmacology, Endoplasmic Reticulum Stress - drug effects, Heart - physiopathology, Heart Function Tests - drug effects, Myocardial Reperfusion Injury - physiopathology, Oxidative Stress - drug effects, Phenylbutyrates - therapeutic use, Rats, Sprague-Dawley, Signal Transduction - drug effects