title: Antioxidant metallothionein alleviates endoplasmic reticulum stress-induced myocardial apoptosis and contractile dysfunction.
abstract: OBJECTIVE
  Endoplasmic reticulum (ER) stress exerts myocardial oxidative stress, apoptosis, and contractile anomalies, although the precise interplay between ER stress and apoptosis remains elusive. This study was designed to examine the impact of the cysteine-rich free radical scavenger metallothionein on ER stress-induced myocardial contractile defect and underlying mechanisms.
  
  
  RESULTS
  Wild-type friendly virus B and transgenic mice with cardiac-specific overexpression of metallothionein were challenged with the ER stress inducer tunicamycin (1 mg/kg, intraperitoneal, 48 h) prior to the assessment of myocardial function, oxidative stress, and apoptosis. Our results revealed that tunicamycin promoted cardiac remodeling (enlarged left ventricular end systolic/diastolic diameters with little changes in left ventricular wall thickness), suppressed fractional shortening and cardiomyocyte contractile function, elevated resting Ca(2+), decreased stimulated Ca(2+) release, prolonged intracellular Ca(2+) clearance, and downregulated sarco(endo)plasmic reticulum Ca(2+)-ATPase levels, the effects of which were negated by metallothionein. Treatment with tunicamycin caused cardiomyocyte mitochondrial injury, as evidenced by decreased mitochondrial membrane potential (∆Ѱm, assessed by JC-1 staining), the effect of which was negated by the antioxidant. Moreover, tunicamycin challenge dramatically facilitated myocardial apoptosis as manifested by increased Bax, caspase 9, and caspase 12 protein levels, as well as elevated caspase 3 activity. Interestingly, metallothionein transgene significantly alleviated tunicamycin-induced myocardial apoptosis.
  
  
  CONCLUSIONS
  Taken together, our data favor a beneficial effect of metallothionein against ER stress-induced cardiac dysfunction possibly associated with attenuation of myocardial apoptosis.
authors.affiliation: a Department of Anesthesiology , Xijing Hospital, the Fourth Military Medical University , Xi'an , P. R. China.
authors.forename: L
authors.initials: L
authors.lastname: Yang
authors.forename: J
authors.initials: J
authors.lastname: Wang
authors.forename: J
authors.initials: J
authors.lastname: Yang
authors.forename: R
authors.initials: R
authors.lastname: Schamber
authors.forename: N
authors.initials: N
authors.lastname: Hu
authors.forename: S
authors.initials: S
authors.lastname: Nair
authors.forename: L
authors.initials: L
authors.lastname: Xiong
authors.forename: J
authors.initials: J
authors.lastname: Ren
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D015415:Biomarkers; D020013:Calcium Signaling / Q000187:drug effects; D000252:Calcium-Transporting ATPases / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D016166:Free Radical Scavengers / Q000494:pharmacology / Q000627:therapeutic use*; D006321:Heart / Q000187:drug effects*; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008668:Metallothionein / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D008822:Mice, Transgenic; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000473:pathology*; D014415:Tunicamycin / Q000494:pharmacology / Q000627:therapeutic use; D020257:Ventricular Remodeling / Q000187:drug effects
chemical_list: D000975:Antioxidants; D015415:Biomarkers; D016166:Free Radical Scavengers; D014415:Tunicamycin; D008668:Metallothionein; D000252:Calcium-Transporting ATPases
keywords: ER stress; apoptosis; cardiac function; metallothionein; tunicamycin