title: Cardiac-specific catalase overexpression rescues anthrax lethal toxin-induced cardiac contractile dysfunction: role of oxidative stress and autophagy.
abstract: BACKGROUND
  Lethal and edema toxins secreted by Bacillus anthracis during anthrax infection were found to incite serious cardiovascular complications. However, the underlying mechanisms in anthrax lethal toxin-induced cardiac anomalies remain unknown. This study was designed to evaluate the impact of antioxidant enzyme catalase in anthrax lethal toxin-induced cardiomyocyte contractile dysfunction.
  
  
  METHODS
  Wild type (WT) and cardiac-specific catalase overexpression mice were challenged with lethal toxin (2 μg/g, intraperotineally (i.p.)). Cardiomyocyte contractile and intracellular Ca(2+) properties were assessed 18 h later using an IonOptix edge-detection system. Proteasome function was assessed using chymotrypsin-like and caspase-like activities. GFP-LC3 puncta and Western blot analysis were used to evaluate autophagy and protein ubiquitination.
  
  
  RESULTS
  Lethal toxin exposure suppressed cardiomyocyte contractile function (suppressed peak shortening, maximal velocity of shortening/re-lengthening, prolonged duration of shortening/re-lengthening, and impaired intracellular Ca(2+) handling), the effects of which were alleviated by catalase. In addition, lethal toxin triggered autophagy, mitochondrial and ubiquitin-proteasome defects, the effects of which were mitigated by catalase. Pretreatment of cardiomyocytes from catalase mice with the autophagy inducer rapamycin significantly attenuated or ablated catalase-offered protection against lethal toxin-induced cardiomyocyte dysfunction. On the other hand, the autophagy inhibitor 3-MA ablated or significantly attenuated lethal toxin-induced cardiomyocyte contractile anomalies.
  
  
  CONCLUSIONS
  Our results suggest that catalase is protective against anthrax lethal toxin-induced cardiomyocyte contractile and intracellular Ca(2+) anomalies, possibly through regulation of autophagy and mitochondrial function.
authors.affiliation: Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY 82071, USA.
authors.forename: Machender R
authors.initials: MR
authors.lastname: Kandadi
authors.forename: Xuejun
authors.initials: X
authors.lastname: Yu
authors.forename: Arthur E
authors.initials: AE
authors.lastname: Frankel
authors.forename: Jun
authors.initials: J
authors.lastname: Ren
mesh_terms: D000818:Animals; D000942:Antigens, Bacterial / Q000633:toxicity*; D001343:Autophagy; D001408:Bacillus anthracis / Q000472:pathogenicity*; D001427:Bacterial Toxins / Q000633:toxicity*; D002118:Calcium / Q000032:analysis; D002374:Catalase / Q000378:metabolism*; D003593:Cytoplasm / Q000737:chemistry; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009200:Myocardial Contraction / Q000187:drug effects*; D018384:Oxidative Stress; D010447:Peptide Hydrolases / Q000032:analysis; D054875:Ubiquitination
chemical_list: D000942:Antigens, Bacterial; D001427:Bacterial Toxins; C030325:anthrax toxin; D002374:Catalase; D010447:Peptide Hydrolases; D002118:Calcium