title: Chemical Chaperone 4-Phenylbutyric Acid Reduces Cardiac Ischemia/Reperfusion Injury by Alleviating Endoplasmic Reticulum Stress and Oxidative Stress.
abstract: 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.
authors.affiliation: Department of Cardiovascular, Tianjin First Central Hospital, tianjin, China (mainland).
authors.forename: Lian
authors.initials: L
authors.lastname: Jian
authors.affiliation: Department of Cardiovascular, Tianjin First Central Hospital, tianjin, China (mainland).
authors.forename: Yuan
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Department of Radiology, Tianjin Medical University Metabolic Diseases Hospital, Tianjin, China (mainland).
authors.forename: Shan
authors.initials: S
authors.lastname: Lu
authors.affiliation: Department of Cardiovascular, Tianjin First Central Hospital, tianjin, China (mainland).
authors.forename: Chengzhi
authors.initials: C
authors.lastname: Lu
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D002316:Cardiotonic Agents / Q000494:pharmacology; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D006334:Heart Function Tests / Q000187:drug effects; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D018384:Oxidative Stress / Q000187:drug effects*; D010654:Phenylbutyrates / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000975:Antioxidants; D002316:Cardiotonic Agents; D010654:Phenylbutyrates; C075773:4-phenylbutyric acid