Contribution of mammalian target of rapamycin in the pathophysiology of cirrhotic cardiomyopathy

• Published in: World journal of gastroenterology : WJG 2016-05, Vol.22 (19), p.4685-4694
• Main Authors: Saeedi Saravi, Seyed Soheil, Ghazi-Khansari, Mahmoud, Ejtemaei Mehr, Shahram, Nobakht, Maliheh, Mousavi, Seyyedeh Elaheh, Dehpour, Ahmad Reza
• Format: Article
• Language: English
• Subjects: Action Potentials; Animals; Basic Study; Carbon Tetrachloride; Cardiomyopathies - enzymology; Cardiomyopathies - etiology; Cardiomyopathies - pathology; Cardiomyopathies - physiopathology; cardiomyopathy; Rat; Mammalian; Cardiotonic Agents - pharmacology; Chemical and Drug Induced Liver Injury - complications; Chemical and Drug Induced Liver Injury - enzymology; Chemical and Drug Induced Liver Injury - pathology; Cirrhotic; effect; Heart Rate; Isoproterenol - pharmacology; Liver Cirrhosis, Experimental - complications; Liver Cirrhosis, Experimental - enzymology; Liver Cirrhosis, Experimental - pathology; Male; Myocardial Contraction; Myocardium - enzymology; Myocardium - pathology; Papillary Muscles - drug effects; Papillary Muscles - enzymology; Papillary Muscles - physiopathology; Phosphorylation; Protein Kinase Inhibitors - pharmacology; rapamycin; Rapamycin; Inotropic; Rats, Wistar; Signal Transduction; Sirolimus - pharmacology; target; TOR Serine-Threonine Kinases - antagonists & inhibitors; TOR Serine-Threonine Kinases - metabolism; Tumor Necrosis Factor-alpha - metabolism; Ventricular Function, Left - drug effects
• ISSN: 1007-9327; 2219-2840
• DOI: 10.3748/wjg.v22.i19.4685

AIM: To explore the role of mammalian target of rapamycin（m TOR） 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 wereisolated to examine inotropic responsiveness to β-adrenergic stimulation using a standard organ bath equipped by Powerlab system. Phosphorylated-m TOR 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-m TOR 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-m TOR expression in left ventricles. Phosphorylated-m TOR was significantly enhanced in cirrhotic rats, especially in the endothelium, compared to controls. Rapamycin treatment significantly increased contractile force and myocardial localization of phosphorylated-m TOR and decreased cardiac TNF-α concentration compared to cirrhotic rats with no treatment. CONCLUSION: In this study, we demonstrated a potential role for cardiac m TOR in the pathophysiology of cirrhotic cardiomyopathy. Rapamycin normalized the inotropic effect and altered phosphorylated-m TOR expression and myocardial localization in cirrhotic rats.