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Mar. Drugs 2015, 13(4), 2306-2326; doi:10.3390/md13042306

Xyloketal B Attenuates Atherosclerotic Plaque Formation and Endothelial Dysfunction in Apolipoprotein E Deficient Mice

1
Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China
2
Department of Anesthesiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510080, China
3
VIP Healthcare Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
4
Department of Pathophysiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China
5
Department of Pharmacy, The fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou 510182, China
6
Department of Applied Chemistry, School of Chemistry and Chemical Engineering, Sun Yat-sen University, Guangzhou 510080, China
7
Department of Education of Guangdong Province, Guangdong Province Key Laboratory of Functional Molecules in Oceanic Microorganism, Sun Yat-sen University, Guangzhou 510080, China
8
Guangdong Cardiovascular Institute, Guangdong General Hospital, Guangzhou 510080, China
9
Lab for Basic Research of Life Science, School of Medicine, Tibet Institute for Nationalities, Xianyang 712082, China
10
Departments of Surgery and Physiology, Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, ON M5G 1G6, Canada
These authors contributed equally to this work.
*
Authors to whom correspondence should be addressed.
Academic Editor: Peer Jacobson
Received: 13 February 2015 / Revised: 30 March 2015 / Accepted: 3 April 2015 / Published: 14 April 2015
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Abstract

Our previous studies demonstrated that xyloketal B, a novel marine compound with a unique chemical structure, has strong antioxidant actions and can protect against endothelial injury in different cell types cultured in vitro and model organisms in vivo. The oxidative endothelial dysfunction and decrease in nitric oxide (NO) bioavailability are critical for the development of atherosclerotic lesion. We thus examined whether xyloketal B had an influence on the atherosclerotic plaque area in apolipoprotein E-deficient (apoE/−) mice fed a high-fat diet and investigated the underlying mechanisms. We found in our present study that the administration of xyloketal B dose-dependently decreased the atherosclerotic plaque area both in the aortic sinus and throughout the aorta in apoE/− mice fed a high-fat diet. In addition, xyloketal B markedly reduced the levels of vascular oxidative stress, as well as improving the impaired endothelium integrity and NO-dependent aortic vasorelaxation in atherosclerotic mice. Moreover, xyloketal B significantly changed the phosphorylation levels of endothelial nitric oxide synthase (eNOS) and Akt without altering the expression of total eNOS and Akt in cultured human umbilical vein endothelial cells (HUVECs). Here, it increased eNOS phosphorylation at the positive regulatory site of Ser-1177, while inhibiting phosphorylation at the negative regulatory site of Thr-495. Taken together, these findings indicate that xyloketal B has dramatic anti-atherosclerotic effects in vivo, which is partly due to its antioxidant features and/or improvement of endothelial function. View Full-Text
Keywords: xyloketals; atherosclerosis; endothelium; eNOS; apoE-deficient mice xyloketals; atherosclerosis; endothelium; eNOS; apoE-deficient mice
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Zhao, L.-Y.; Li, J.; Yuan, F.; Li, M.; Zhang, Q.; Pang, J.-Y.; Zhang, B.; Sun, F.-Y.; Sun, H.-S.; Li, Q.; Cao, L.; Xie, Y.; Lin, Y.-C.; Liu, J.; Tan, H.-M.; Wang, G.-L.; Huang, Y.-Y. Xyloketal B Attenuates Atherosclerotic Plaque Formation and Endothelial Dysfunction in Apolipoprotein E Deficient Mice. Mar. Drugs 2015, 13, 2306-2326.

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