title: Sodium 4-Phenylbutyrate Attenuates Myocardial Reperfusion Injury by Reducing the Unfolded Protein Response.
abstract: The unfolded protein response (UPR) plays a pivotal role in ischemia-reperfusion (I/R) injury in various organs such as heart, brain, and liver. Sodium 4-phenylbutyrate (PBA) reportedly acts as a chemical chaperone that reduces UPR. In the present study, we evaluated the effect of PBA on reducing the UPR and protecting against myocardial I/R injury in mice.
  
  
  
  Male C57BL/6 mice were subjected to 30-minute myocardial I/R, and were treated with phosphate-buffered saline (as a vehicle) or PBA.
  
  
  
  At 4 hours after reperfusion, mice treated with PBA had reduced serum cardiac troponin I levels and numbers of apoptotic cells in left ventricles (LVs) in myocardial I/R. Infarct size had also reduced in mice treated with PBA at 48 hours after reperfusion. At 2 hours after reperfusion, UPR markers, including eukaryotic initiation of the factor 2α-subunit, activating transcription factor-6, inositol-requiring enzyme-1, glucose-regulated protein 78, CCAAT/enhancer-binding protein (C/EBP) homologous protein, and caspase-12, were significantly increased in mice treated with vehicle compared to sham-operated mice. Administration of PBA significantly reduced the I/R-induced increases of these markers. Cardiac function and dimensions were assessed at 21 days after I/R. Sodium 4-phenylbutyrate dedicated to the improvement of cardiac parameters deterioration including LV end-diastolic diameter and LV fractional shortening. Consistently, PBA reduced messenger RNA expression levels of cardiac remodeling markers such as collagen type 1α1, brain natriuretic peptide, and α skeletal muscle actin in LV at 21 days after I/R.
  
  
  
  Unfolded protein response mediates myocardial I/R injury. Administration of PBA reduces the UPR, apoptosis, infarct size, and preserved cardiac function. Hence, PBA may be a therapeutic option to attenuate myocardial I/R injury in clinical practice.
authors.affiliation: 1 Department of Disease Control and Homeostasis, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Takatori
authors.affiliation: 1 Department of Disease Control and Homeostasis, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.
authors.forename: Soichiro
authors.initials: S
authors.lastname: Usui
authors.affiliation: 1 Department of Disease Control and Homeostasis, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Okajima
authors.affiliation: 1 Department of Disease Control and Homeostasis, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.
authors.forename: Shuichi
authors.initials: S
authors.lastname: Kaneko
authors.affiliation: 1 Department of Disease Control and Homeostasis, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ootsuji
authors.affiliation: 1 Department of Disease Control and Homeostasis, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.
authors.forename: Shin-Ichiro
authors.initials: SI
authors.lastname: Takashima
authors.affiliation: 1 Department of Disease Control and Homeostasis, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Kobayashi
authors.affiliation: 1 Department of Disease Control and Homeostasis, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.
authors.forename: Hisayoshi
authors.initials: H
authors.lastname: Murai
authors.affiliation: 1 Department of Disease Control and Homeostasis, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Furusho
authors.affiliation: 1 Department of Disease Control and Homeostasis, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Takamura
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D008297:Male; D008810:Mice, Inbred C57BL; D009200:Myocardial Contraction / Q000187:drug effects; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D010654:Phenylbutyrates / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020127:Recovery of Function; D015398:Signal Transduction / Q000187:drug effects; D056811:Unfolded Protein Response / Q000187:drug effects*; D016277:Ventricular Function, Left / Q000187:drug effects; D020257:Ventricular Remodeling / Q000187:drug effects
chemical_list: D010654:Phenylbutyrates; D012333:RNA, Messenger; C075773:4-phenylbutyric acid
keywords: apoptosis; myocardial ischemia–reperfusion injury; sodium 4-phenylbutyrate; unfolded protein response