PMID- 27217700 OWN - NLM STAT- MEDLINE DCOM- 20170410 LR - 20211203 IS - 2219-2840 (Electronic) IS - 1007-9327 (Print) IS - 1007-9327 (Linking) VI - 22 IP - 19 DP - 2016 May 21 TI - Contribution of mammalian target of rapamycin in the pathophysiology of cirrhotic cardiomyopathy. PG - 4685-94 LID - 10.3748/wjg.v22.i19.4685 [doi] AB - AIM: 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 beta-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)-alpha 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-alpha. 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-alpha concentration compared to cirrhotic rats with no treatment. CONCLUSION: 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. FAU - Saeedi Saravi, Seyed Soheil AU - Saeedi Saravi SS AD - 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. FAU - Ghazi-Khansari, Mahmoud AU - Ghazi-Khansari M AD - 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. FAU - Ejtemaei Mehr, Shahram AU - Ejtemaei Mehr S AD - 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. FAU - Nobakht, Maliheh AU - Nobakht M AD - 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. FAU - Mousavi, Seyyedeh Elaheh AU - Mousavi SE AD - 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. FAU - Dehpour, Ahmad Reza AU - Dehpour AR AD - 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. LA - eng PT - Journal Article PL - United States TA - World J Gastroenterol JT - World journal of gastroenterology JID - 100883448 RN - 0 (Cardiotonic Agents) RN - 0 (Protein Kinase Inhibitors) RN - 0 (Tumor Necrosis Factor-alpha) RN - CL2T97X0V0 (Carbon Tetrachloride) RN - EC 2.7.1.1 (mTOR protein, rat) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - L628TT009W (Isoproterenol) RN - W36ZG6FT64 (Sirolimus) SB - IM MH - Action Potentials MH - Animals MH - Carbon Tetrachloride MH - Cardiomyopathies/enzymology/*etiology/pathology/physiopathology MH - Cardiotonic Agents/pharmacology MH - Chemical and Drug Induced Liver Injury/*complications/enzymology/pathology MH - Heart Rate MH - Isoproterenol/pharmacology MH - Liver Cirrhosis, Experimental/*complications/enzymology/pathology MH - Male MH - Myocardial Contraction MH - Myocardium/*enzymology/pathology MH - Papillary Muscles/drug effects/*enzymology/physiopathology MH - Phosphorylation MH - Protein Kinase Inhibitors/pharmacology MH - Rats, Wistar MH - Signal Transduction MH - Sirolimus/pharmacology MH - TOR Serine-Threonine Kinases/antagonists & inhibitors/*metabolism MH - Tumor Necrosis Factor-alpha/metabolism MH - *Ventricular Function, Left/drug effects PMC - PMC4870075 OTO - NOTNLM OT - Cirrhotic cardiomyopathy OT - Inotropic effect OT - Mammalian target of rapamycin OT - Rapamycin OT - Rat EDAT- 2016/05/25 06:00 MHDA- 2017/04/11 06:00 PMCR- 2016/05/21 CRDT- 2016/05/25 06:00 PHST- 2016/01/17 00:00 [received] PHST- 2016/02/27 00:00 [revised] PHST- 2016/03/13 00:00 [accepted] PHST- 2016/05/25 06:00 [entrez] PHST- 2016/05/25 06:00 [pubmed] PHST- 2017/04/11 06:00 [medline] PHST- 2016/05/21 00:00 [pmc-release] AID - 10.3748/wjg.v22.i19.4685 [doi] PST - ppublish SO - World J Gastroenterol. 2016 May 21;22(19):4685-94. doi: 10.3748/wjg.v22.i19.4685.