title: β-adrenergic receptor blockade reduces endoplasmic reticulum stress and normalizes calcium handling in a coronary embolization model of heart failure in canines.
abstract: OBJECTIVE
  Alterations in calcium homeostasis in the endoplasmic/sarcoplasmic reticulum (ER) cause ER stress that ultimately may affect ventricular function. However, the role of ER stress in β-blocker therapy for congestive heart failure (CHF) has not been studied. This study examined ER stress in CHF and evaluated its role in β-blocker therapy in a canine model of ischaemic CHF.
  
  
  RESULTS
  CHF was created by daily coronary embolization in chronically instrumented dogs. After oral administration of β-blocker metoprolol or vehicle for 12 weeks, Ca(2+) transport proteins including sarcoplasmic reticulum Ca(2+)-ATPase (SERCA), ryanodine receptor (RyR2), Na(+)-Ca(2+) exchanger (NCX1), Ca(2+) storage protein calreticulin (CRT), and phospholamban were evaluated by Western blot analysis. Cellular levels of ER stress marker, phosphorylated eukaryotic initiation factor 2α (eIF2α-P), were also examined. Compared with the vehicle-treated group, metoprolol caused significantly improved cardiac function, restored the proteins of SERCA2a, NCX1, and CRT, increased phosphorylated phospholamban, reversed protein kinase A hyperphosphorylation of RyR2, and resulted in normalized ER stress marker eIF2α-P and reduced DNA damage.
  
  
  CONCLUSIONS
  Our results suggest that ER stress could be induced by abnormal Ca(2+) homeostasis in CHF. The restoration of calcium-handling protein function and resultant decrease in ER stress might, in part, explain the beneficial effects of β-blockade observed in CHF. Whether this mechanism occurs in other animal CHF models or human CHF warrants further study.
authors.affiliation: Division of Cardiothoracic Surgery, College of Physicians and Surgeons of Columbia University, New York, NY, USA.
authors.forename: Isaac
authors.initials: I
authors.lastname: George
authors.forename: Hani N
authors.initials: HN
authors.lastname: Sabbah
authors.forename: Kai
authors.initials: K
authors.lastname: Xu
authors.forename: Nan
authors.initials: N
authors.lastname: Wang
authors.forename: Jie
authors.initials: J
authors.lastname: Wang
mesh_terms: D000284:Administration, Oral; D000319:Adrenergic beta-Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000378:metabolism; D037282:Calreticulin / Q000378:metabolism; D004195:Disease Models, Animal; D004285:Dogs; D004621:Embolization, Therapeutic; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D005260:Female; D006333:Heart Failure / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D006439:Hemodynamics / Q000187:drug effects; D006706:Homeostasis; D020287:In Situ Nick-End Labeling; D008297:Male; D008790:Metoprolol / Q000008:administration & dosage / Q000494:pharmacology*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D020127:Recovery of Function; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D019831:Sodium-Calcium Exchanger / Q000378:metabolism; D013312:Stress, Physiological / Q000187:drug effects*; D013997:Time Factors; D014463:Ultrasonography; D016277:Ventricular Function, Left / Q000187:drug effects; D017725:Ventricular Pressure / Q000187:drug effects; D000099211:Phospholamban
chemical_list: D000319:Adrenergic beta-Antagonists; D002118:Calcium; D002135:Calcium-Binding Proteins; D037282:Calreticulin; D015852:Eukaryotic Initiation Factor-2; D008790:Metoprolol; D019837:Ryanodine Receptor Calcium Release Channel; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D019831:Sodium-Calcium Exchanger; D000099211:Phospholamban; C110374:sodium-calcium exchanger 1