title: Apoptosis contributes to septic cardiomyopathy and is improved by simvastatin therapy.
abstract: Bacterial toxins cause cardiac dysfunction and death through an inflammatory process, but the mechanism remains unclear. Simvastatin is recognized as having anti-inflammatory properties beyond its lipid-lowering effects. We examined Staphylococcus aureus alpha-toxin in isolated heart and in vivo models and tested simvastatin's effects in sepsis. Isolated Langendorff-perfused rat hearts were exposed to a recirculating perfusate containing alpha-toxin (0.5 microg mL(-1)). Compared with controls, there was a significant increase in coronary perfusion pressure and fall in myocardial performance. Significant increases in p53 expression and apoptosis (1.3 +/- 0.5 to 7.1 +/- 1.4 terminal deoxynucleaotidyl transferase nick end labeling-positive cells; P < 0.05) compared with controls were observed, but markers of necrosis were similar. In parallel experiments, anaesthetized rats receiving alpha-toxin (40 microg kg(-1), i.v.) had in vivo hemodynamic parameters and serum markers of necrosis monitored for 4 h before the hearts were analyzed for histological change, p53 expression, and apoptosis. Over 4 h, alpha-toxin exposure produced substantial hemodynamic effects. In addition, p53 expression (0.2 +/- 0.2 to 7.1 +/- 0.5 p53-positive myocytes; P < 0.05), TNF-alpha levels, the degree of apoptosis, and markers of necrosis were all significantly increased compared with control animals. Pretreatment with simvastatin protected against alpha-toxin-induced sepsis associated with reduced p53, TNF-alpha, apoptosis, and necrosis. We found significant changes in systemic hemodynamics, coronary perfusion pressure, myocardial function, and increased p53 expression with apoptosis due to bacterial exotoxin. In vivo changes were significantly inhibited by pretreatment with simvastatin. We provide novel evidence for the mechanisms by which septicemia causes myocardial depression and hint at a potential role for simvastatin as an inhibitor of apoptosis in sepsis.
authors.affiliation: Department of Medicine III, Martin Luther-University, Halle (Saale), Germany.
authors.forename: Ute
authors.initials: U
authors.lastname: Buerke
authors.forename: Justin M
authors.initials: JM
authors.lastname: Carter
authors.forename: Axel
authors.initials: A
authors.lastname: Schlitt
authors.forename: Martin
authors.initials: M
authors.lastname: Russ
authors.forename: Hendrik
authors.initials: H
authors.lastname: Schmidt
authors.forename: Ulf
authors.initials: U
authors.lastname: Sibelius
authors.forename: Ulrich
authors.initials: U
authors.lastname: Grandel
authors.forename: Friedrich
authors.initials: F
authors.lastname: Grimminger
authors.forename: Werner
authors.initials: W
authors.lastname: Seeger
authors.forename: Ursula
authors.initials: U
authors.lastname: Mueller-Werdan
authors.forename: Karl
authors.initials: K
authors.lastname: Werdan
authors.forename: Michael
authors.initials: M
authors.lastname: Buerke
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D009202:Cardiomyopathies / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D005098:Exotoxins / Q000633:toxicity; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D006439:Hemodynamics / Q000187:drug effects; D020287:In Situ Nick-End Labeling; D066298:In Vitro Techniques; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009336:Necrosis; D051381:Rats; D018805:Sepsis / Q000139:chemically induced / Q000150:complications / Q000188:drug therapy*; D019821:Simvastatin / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D005098:Exotoxins; D014409:Tumor Necrosis Factor-alpha; D016159:Tumor Suppressor Protein p53; D019821:Simvastatin