Urolithin A alleviates myocardial ischemia/reperfusion injury via PI3K/Akt pathway
Introduction
Myocardial reperfusion injury is the tissue damage that occurs when the blood supply returns to the heart tissue after a period of ischemia or lack of oxygen, resulting in additional damage to the myocardium [1]. Ischemia/reperfusion (I/R) injury has been shown to play a role in strokes and brain trauma, and the death of myocytes (either necrotic or apoptotic) is a feature of many pathological heart conditions. I/R injury is therefore responsible for significant morbidity and mortality worldwide [2].
Myocardial I/R injury is a complex phenomenon involving many players, all contributing to the final damage inflicted on the heart [3]. In recent years, enormous efforts have been made to explore the rescue approaches of I/R myocardium. However, further studies are needed to seek novel strategies and targets to reduce myocardial I/R injury. Activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway, an intracellular signaling pathway important in regulating a vast array of cellular processes involved in the cell cycle, has been shown to promote cellular survival of cardiomyocytes and protect the heart from I/R injury [4].
Ellagitannins are hydrolyzable tannins present in pomegranate, walnuts, berries such as raspberries, strawberries, and blackberries, and oak-aged wines. Once consumed, ellagitannins are hydrolyzed in the gut to release ellagic acid, which is further processed by the intestinal microflora into urolithins [5]. In the species investigated to date (including humans), urolithin A (UA) (Fig. 1A), urolithin B (UB), urolithin C (UC) and urolithin D (UD) are the redundant measurable metabolites that are thought to be the end products of both ellagitannins and ellagic acid [6].
Until now, a few studies have documented biological effects of urolithins, including anti-proliferation in cancer cell models, anti-inflammation, benefits on lipid metabolism, and improves endothelial function [7]. Nevertheless, the potential role of urolithins in modulating I/R injury has been scarcely investigated to date. The present study is designed to investigate cardioprotective effects of urolithin A (UA) against I/R injury in vivo and in vitro and the underlying mechanisms.
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Animals model of myocardial ischemia/reperfusion injury
Male adult C57BL/6 mice (20–25 g) were obtained from the Laboratory Animal Center of Guangdong Province (Guangdong, China). All animals received humane care in accordance with the Guide for the Care and Use of Laboratory Animals published by the United States National Institute of Health (NIH Publication No. 85–23, revised 1996). All experiments were performed according to the protocols approved by the Institute Animal Care Committee, Southern Medical University. Before surgery, mice were
UA alleviates hypoxia/reoxygenation injury
We assessed cell viability in every group via MTT assay. UA (1, 10, 20 μM) ameliorated cell viability in a concentration dependent manner (Fig. 1B). Since lactate dehydrogenase (LDH) leakage is widely used as a marker of cellular damage, cardiomyocyte cells injury was assessed by determining LDH activity in culture medium at the end of reoxygenation. LDH leakage increased in the H/R group compared with the Control group, but was significantly decreased by UA pretreatment especially with 10 μM (
Discussion
In the present study, we provided direct in vivo and in vitro evidence that UA protected the heart against I/R injury by significantly improved cardiac function and reduced myocardial apoptosis. Our findings firstly showed that UA attenuated myocardial ischemia/reperfusion injury possibly through its anti-apoptotic effect via activating PI3K/Akt signaling.
Urolithin A (UA) is one ingredient of urolithins, which are the redundant measurable metabolites that are thought to be the end products of
Conflict of interest
The authors declare no potential conflicts of interest were disclosed.
Acknowledgements
This work was in part supported by the National Natural Science Foundation of China (grant numbers 81270218 to A.C.) and the Scientific and Technological Research Project of the Education Department in Hunan Province in China (project number 14C1129 to Yingli Mo).
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These authors contributed equally to this work.