title: Contribution of mammalian target of rapamycin in the pathophysiology of cirrhotic cardiomyopathy.
abstract: OBJECTIVE
  To explore the role of mammalian target of rapamycin (mTOR) in the pathogenesis of cirrhotic cardiomyopathy and the potential of rapamycin to improve this pathologic condition.
  
  
  METHODS
  Male albino Wistar rats weighing 100-120 g were treated with tetrachloride carbon (CCl4) for 8 wk to induce cirrhosis. Subsequently, animals were administered rapamycin (2 mg/kg per day). The QTc intervals were calculated in a 5-min electrocardiogram. Then, the left ventricular papillary muscles were isolated to examine inotropic responsiveness to β-adrenergic stimulation using a standard organ bath equipped by Powerlab system. Phosphorylated-mTOR localization in left ventricles was immunohistochemically assessed, and ventricular tumor necrosis factor (TNF)-α was measured. Western blot was used to measure levels of ventricular phosphorylated-mTOR protein.
  
  
  RESULTS
  Cirrhosis was confirmed by hematoxylin and eosin staining of liver tissues, visual observation of lethargy, weight loss, jaundice, brown urine, ascites, liver stiffness, and a significant increase of spleen weight (P < 0.001). A significant prolongation in QTc intervals occurred in cirrhotic rats exposed to CCl4 (P < 0.001), while this prolongation was decreased with rapamycin treatment (P < 0.01). CCl4-induced cirrhosis caused a significant decrease of contractile responsiveness to isoproterenol stimulation and a significant increase in cardiac TNF-α. These findings were correlated with data from western blot and immunohistochemical studies on phosphorylated-mTOR expression in left ventricles. Phosphorylated-mTOR was significantly enhanced in cirrhotic rats, especially in the endothelium, compared to controls. Rapamycin treatment significantly increased contractile force and myocardial localization of phosphorylated-mTOR and decreased cardiac TNF-α concentration compared to cirrhotic rats with no treatment.
  
  
  CONCLUSIONS
  In this study, we demonstrated a potential role for cardiac mTOR in the pathophysiology of cirrhotic cardiomyopathy. Rapamycin normalized the inotropic effect and altered phosphorylated-mTOR expression and myocardial localization in cirrhotic rats.
authors.affiliation: Seyed Soheil Saeedi Saravi, Mahmoud Ghazi-Khansari, Shahram Ejtemaei Mehr, Seyyedeh Elaheh Mousavi, Ahmad Reza Dehpour, Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran 13145, Iran.
authors.forename: Seyed Soheil
authors.initials: SS
authors.lastname: Saeedi Saravi
authors.affiliation: Seyed Soheil Saeedi Saravi, Mahmoud Ghazi-Khansari, Shahram Ejtemaei Mehr, Seyyedeh Elaheh Mousavi, Ahmad Reza Dehpour, Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran 13145, Iran.
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Ghazi-Khansari
authors.affiliation: Seyed Soheil Saeedi Saravi, Mahmoud Ghazi-Khansari, Shahram Ejtemaei Mehr, Seyyedeh Elaheh Mousavi, Ahmad Reza Dehpour, Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran 13145, Iran.
authors.forename: Shahram
authors.initials: S
authors.lastname: Ejtemaei Mehr
authors.affiliation: Seyed Soheil Saeedi Saravi, Mahmoud Ghazi-Khansari, Shahram Ejtemaei Mehr, Seyyedeh Elaheh Mousavi, Ahmad Reza Dehpour, Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran 13145, Iran.
authors.forename: Maliheh
authors.initials: M
authors.lastname: Nobakht
authors.affiliation: Seyed Soheil Saeedi Saravi, Mahmoud Ghazi-Khansari, Shahram Ejtemaei Mehr, Seyyedeh Elaheh Mousavi, Ahmad Reza Dehpour, Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran 13145, Iran.
authors.forename: Seyyedeh Elaheh
authors.initials: SE
authors.lastname: Mousavi
authors.affiliation: Seyed Soheil Saeedi Saravi, Mahmoud Ghazi-Khansari, Shahram Ejtemaei Mehr, Seyyedeh Elaheh Mousavi, Ahmad Reza Dehpour, Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran 13145, Iran.
authors.forename: Ahmad Reza
authors.initials: AR
authors.lastname: Dehpour
mesh_terms: D000200:Action Potentials; D000818:Animals; D002251:Carbon Tetrachloride; D009202:Cardiomyopathies / Q000201:enzymology / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D002316:Cardiotonic Agents / Q000494:pharmacology; D056486:Chemical and Drug Induced Liver Injury / Q000150:complications* / Q000201:enzymology / Q000473:pathology; D006339:Heart Rate; D007545:Isoproterenol / Q000494:pharmacology; D008106:Liver Cirrhosis, Experimental / Q000150:complications* / Q000201:enzymology / Q000473:pathology; D008297:Male; D009200:Myocardial Contraction; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D010210:Papillary Muscles / Q000187:drug effects / Q000201:enzymology* / Q000503:physiopathology; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017208:Rats, Wistar; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D016277:Ventricular Function, Left / Q000187:drug effects
chemical_list: D002316:Cardiotonic Agents; D047428:Protein Kinase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D002251:Carbon Tetrachloride; C546845:mTOR protein, rat; D058570:TOR Serine-Threonine Kinases; D007545:Isoproterenol; D020123:Sirolimus
keywords: Cirrhotic cardiomyopathy; Inotropic effect; Mammalian target of rapamycin; Rapamycin; Rat