Basic Study
Copyright ©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. May 21, 2016; 22(19): 4685-4694
Published online May 21, 2016. doi: 10.3748/wjg.v22.i19.4685
Contribution of mammalian target of rapamycin in the pathophysiology of cirrhotic cardiomyopathy
Seyed Soheil Saeedi Saravi, Mahmoud Ghazi-Khansari, Shahram Ejtemaei Mehr, Maliheh Nobakht, Seyyedeh Elaheh Mousavi, Ahmad Reza Dehpour
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
Seyed Soheil Saeedi Saravi, Seyyedeh Elaheh Mousavi, Ahmad Reza Dehpour, Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran 13145, Iran
Seyed Soheil Saeedi Saravi, Department of Toxicology-Pharmacology, Faculty of Pharmacy, Guilan University of Medical Sciences, Rasht 9813, Iran
Maliheh Nobakht, Department of Anatomy, School of Medicine, Iran University of Medical Sciences, Tehran 13145, Iran
Author contributions: Saeedi Saravi SS designed the study as his PhD thesis, wrote the protocol and the first draft of the manuscript, and managed the literature searches and statistical analyses; Ghazi-Khansari M and Ejtemaei Mehr S contributed to literature searches and analyses; Nobakht M performed immunohistochemistry; Mousavi SE performed experiments; and Dehpour AR supervised all procedures and managed the experimental processes, manuscript writing, and correction.
Supported by Tehran University of Medical Sciences and Health Services grant, No. 92033024196.
Institutional animal care and use committee statement: All experiments and manipulations were conducted in Prof. Dehpour’s Hepatological Researches Laboratory in accordance with the institutional animal care and use committee (Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences) guidelines. This study was approved by the Ethics Committee of Tehran University of Medical Sciences.
Conflict-of-interest statement: To the best of our knowledge, no conflict of interest exists.
Data sharing statement: Technical appendix, statistical code, and dataset available from the corresponding author at dehpour@yahoo.com. No additional data are available.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Ahmad Reza Dehpour, PharmD, PhD, Professor, Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, PO Box 13145-784, Tehran 13145, Iran. dehpour@yahoo.com
Telephone: +98-21-66402569 Fax: +98-21-66402569
Received: January 17, 2016
Peer-review started: January 19, 2016
First decision: February 18, 2016
Revised: February 27, 2016
Accepted: March 13, 2016
Article in press: March 14, 2016
Published online: May 21, 2016
Abstract

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 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.

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.

Keywords: Cirrhotic cardiomyopathy; Rat; Mammalian target of rapamycin; Rapamycin; Inotropic effect

Core tip: Enhanced levels of cardiac phosphorylated mammalian target of rapamycin (mTOR) contribute to impairment of electrophysiological and mechanical function induced by cirrhosis, called “cirrhotic cardiomyopathy”. Here, we find that the mTOR inhibitor rapamycin normalized the impaired inotropic responsiveness to β-adrenergic stimulation and prolonged Q-T interval in tetrachloride carbon (CCl4)-induced cirrhotic rats. Cardiac ventricular expression of phosphorylated-mTOR (p-mTOR) was increased in rats with cirrhosis, and this effect was ameliorated by rapamycin. CCl4-induced cirrhosis was associated with an increase in cardiac proinflammatory cytokine tumor necrosis factor-α, and this increase was reversed by rapamycin as well.