RETRACTED ARTICLE: pNaKtide Attenuates Steatohepatitis and Atherosclerosis by Blocking Na/K-ATPase/ROS Amplification in C57Bl6 and ApoE Knockout Mice Fed a Western Diet

Komal Sodhi,Alexandra Nichols,Saroj Sigdel,Perrine Goguet-Rubio,Athar Nawab,Mehiar El-Hamdani,Rebecca Martin,Preeya T Shah,Amrita Mallick,Jiang Liu,Joseph I Shapiro,Muhammad Chaudhry,Krithika Srikanthan,Zijian Xie,Nader G Abraham

doi:10.1038/s41598-017-00306-5

Komal Sodhi, Alexandra Nichols + Show 13 more

Open Access

https://doi.org/10.1038/s41598-017-00306-5

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Journal: Scientific Reports	Publication Date: Mar 15, 2017
Citations: 42	License type: open-access

Affiliation: Marshall University, New York Medical College

Abstract

We have previously reported that the α1 subunit of sodium potassium adenosine triphosphatase (Na/K-ATPase), acts as a receptor and an amplifier for reactive oxygen species, in addition to its distinct pumping function. On this background, we speculated that blockade of Na/K-ATPase-induced ROS amplification with a specific peptide, pNaKtide, might attenuate the development of steatohepatitis. To test this hypothesis, pNaKtide was administered to a murine model of NASH: the C57Bl6 mouse fed a “western” diet containing high amounts of fat and fructose. The administration of pNaKtide reduced obesity as well as hepatic steatosis, inflammation and fibrosis. Of interest, we also noted marked improvement in mitochondrial fatty acid oxidation, insulin sensitivity, dyslipidemia and aortic streaking in this mouse model. To further elucidate the effects of pNaKtide on atherosclerosis, similar studies were performed in ApoE knockout mice also exposed to the western diet. In these mice, pNaKtide not only improved steatohepatitis, dyslipidemia, and insulin sensitivity, but also ameliorated significant aortic atherosclerosis. Collectively, this study demonstrates that the Na/K-ATPase/ROS amplification loop contributes significantly to the development and progression of steatohepatitis and atherosclerosis. And furthermore, this study presents a potential treatment, the pNaKtide, for the metabolic syndrome phenotype.

Highlights

Recent studies have demonstrated that oxidative stress and inflammation underlie the pathogenesis of metabolic syndrome and, by extension, NASH and atherosclerosis[5,6,7]
This study demonstrates that Na/K-ATPase amplification of oxidant signaling is important in the pathophysiology of NASH and atherosclerosis in the murine models studied
We report that the metabolic syndrome phenotype, present in both C57Bl6 and ApoE−/− mice fed a western diet, improved with pNaKtide treatment which attenuated Na/K-ATPase induced oxidant amplification[20]

Summary

Introduction

Recent studies have demonstrated that oxidative stress and inflammation underlie the pathogenesis of metabolic syndrome and, by extension, NASH and atherosclerosis[5,6,7]. It is believed that NASH predisposes to atherosclerosis through the systemic release of inflammatory and oxidative-stress mediators[9]. We have previously noted that Na/K-ATPase signaling can serve as a feed-forward amplifier for oxidant signaling[12,13,14,15]. We have recently shown that pNaKtide, by restoring redox balance in adipocytes, attenuates obesity in mice fed a high fat diet[20]. Given the aforementioned importance of oxidative stress in the pathophysiology of NASH, we chose to examine whether pNaKtide might be effective in ameliorating NASH in C57Bl6 mice fed a western diet. As the effects of pNaKtide detailed in this report extended to the vascular system, additional studies were performed in the ApoE knockout mouse

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