Resveratrol Prevented Lipopolysaccharide-Induced Endothelial Dysfunction in Rat Thoracic Aorta Through Increased eNOS Expression

Abstract

Background: The cardiovascular benefits of Resveratrol (RVT) have been well established by previous experimental and clinical studies. Aims: The goal of this study was to test the effectiveness of RVT administration on the impaired endothelial function induced by lipopolysaccharide (LPS), and to elucidate the role of endothelial nitric oxide synthase (eNOS)/ Sirtuin 1 (SIRT1) pathway. Study Design: Animal experiment. Methods: Endotoxemia was induced by intraperitoneal injection of 10mg/kg LPS, and the thoracic aorta was isolated six hours later. RVT was injected intraperitoneally 15 minutes before LPS administration. Six hours after LPS injection, potassium chloride (KCl), phenylephrine (Phe), acetylcholine (ACh), and sodium nitroprusside (SNP) were used to examine to vascular reactivity and endothelial function. eNOS, phospho-eNOS (p-eNOS) (Ser 1177), and SIRT1 expressions in thoracic aorta were evaluated by Western blot. Results: LPS administration significantly inhibited the relaxation response induced by ACh, while the relaxation to SNP was not significantly altered. Phe- and KClinduced contractile responses in the thoracic aorta significantly decreased in LPS-injected group. eNOS and p-eNOS expression decreased significantly in arteries obtained from LPS group rats. The impaired vasoreactivity as well as decreased expressions of eNOS, p-eNOS, and SIRT1 in vessels from LPS-injected rats were improved by RVT treatment. Conclusion: The endothelium-dependent vasodilatation of the thoracic aorta was significantly inhibited by LPS administration, and RVT treatment may improve vascular endothelial function. The protective effect of RVT might be associated with increased eNOS expression and activity

Keywords

• Endothelial dysfunction, nitric oxide synthase type III, lipopolysaccharides, resveratrol, Sirtuin 1

References

1. 1. Peters K, Unger RE, Brunner J, Kirkpatrick CJ. Molecular basis of endothelial dysfunction in sepsis. Cardiovasc Res 2003;60:49-57. [CrossRef]
2. 2. Poredos P. Endothelial dysfunction and cardiovascular disease. Pathophysiol Haemost Thromb 2002;32:274-7. [CrossRef]
3. 3. Aird WC. Endothelium as a therapeutic target in sepsis. Curr Drug Targets 2007;8:501-7. [CrossRef]
4. 4. Wu JM, Wang ZR, Hsieh, TC, Bruder JL, Zou JG, Huang YZ. Mechanism of cardioprotection by resveratrol, a phenolic antioxidantpresent in red wine (Review). Int J Mol Med 2001;8:3-17.
5. 5. Mattagajasingh I, Kim CS, Naqvi A, Yamamori T, Hoffman TA, Jung SB, et al. SIRT1 promotes endothelium-dependent vascular relaxation by activating endothelial nitric oxide synthase. Proc Natl Acad Sci U S A 2007;104:14855-60. [CrossRef]
6. 6. Wallerath T, Deckert G, Ternes T, Anderson H, Li H, Witte K, et al. Resveratrol, a polyphenolic phytoalexin present in red wine, enhances expression and activity of endothelial nitric oxide synthase. Circulation 2002;106:1652-8. [CrossRef]
7. 7. Takahashi S, Nakashima Y. Repeated and long-term treatment with physiological concentrations of resveratrol promotes NO production in vascular endothelial cells. Br J Nutr 2012;107:774-80. [CrossRef]
8. 8. Lalu MM, Csont T, Schulz R. Matrix metalloproteinase activities are altered in the heart and plasma during endotoxemia. Crit Care Med 2004;32:1332-7. [CrossRef]

9. 9. Khadour FH, Panas D, Ferdinandy P, Schulze C, Csont T, Lalu MM, et al. Enhanced NO and superoxide generation in dysfunctional hearts from endotoxemic rats. Am J Physiol Heart Circ Physiol 2002;283:H1108-15. [CrossRef]
10. 10. Lalu MM, Gao CQ, Schulz R. Matrix metalloproteinase inhibitors attenuate endotoxemia induced cardiac dysfunction: a potential role for MMP-9. Mol Cell Biochem 2003;251:61-6. [CrossRef]
11. 11. Lalu MM, Cena J, Chowdhury R, Lam A, Schulz R. Matrix metalloproteinases contribute to endotoxin and interleukin-1beta induced vascular dysfunction. Br J Pharmacol 2006;149:31-42. [CrossRef]
12. 12. Parker JL, Adams HR. Selective inhibition of endothelium-dependent vasodilator capacity by Escherichia coli endotoxemia. Circ Res 1993;72:539-55. [CrossRef]
13. 13. Umans JG, Wylam ME, Samsel RW, Edwards J, Schumacker PT. Effects of endotoxin in vivo on endothelial and smoothmuscle function in rabbit and rat aorta. Am Rev Respir Dis 1993;148:1638-45. [CrossRef]
14. 14. Salzman AL, Wang H, Wollert PS, Vandermeer TJ, Compton CC, Denenberg AG, et al. Endotoxin-induced ileal mucosal hyperpermeability in pigs: role of tissue acidosis. Am J Physiol 1994;266:G633-46.
15. 15. Zhou M, Wang P, Chaudry IH. Endothelial nitric oxide synthase is downregulated during hyperdynamic sepsis. Biochim Biophys Acta 1997;1335:182-90. [CrossRef]
16. 16. Matsuda N, Hattori Y, Zhang XH, Fukui H, Kemmotsu O, Gando S. Contractions to histamine in pulmonary and mesenteric arteries from endotoxemic rabbits: Modulation by vascular expressions of inducible nitric-oxide synthase and histamine H1- receptors. J Pharmacol Exp Ther 2003;307:175-81. [CrossRef]
17. 17. Matsuda N, Hayashi Y, Takahashi Y, Hattori Y. Phosphorylation of endothelial nitric oxide synthase is diminished in mesenteric arteries from septic rabbits depending on the altered phosphatidylinositol 3-kinase/Akt pathway: Reversal effect of fluvastatin therapy. J Pharmacol Exp Ther 2006;319:1348-54. [CrossRef]
18. 18. Fleming I, Busse R. Molecular mechanisms involved in the regulation of the endothelial nitric oxide synthase. Am J Physiol Regul Integr Comp Physiol 2003;284:R1-12. [CrossRef]
19. 19. Fulton D, Gratton JP, McCabe TJ, Fontana J, Fujio Y, Walsh K, et al. Regulation of endothelium-derived nitric oxide production by the protein kinase Akt. Nature 1999;399:597-601. [CrossRef]
20. 20. Zarzuelo MJ, López-Sepúlveda R, Sánchez M, Romero M, Gómez-Guzmán M, Ungvary Z, et al. SIRT1 inhibits NADPH oxidase activation and protects endothelial function in the rat aorta: implications for vascular aging. Biochem Pharmacol 2013;85:1288-96. [CrossRef]
21. 21. de Boer VC, de Goffau MC, Arts IC, Hollman PC, Keijer J. SIRT1 stimulation by polyphenols is affected by their stability and metabolism. Mech Ageing Dev 2006;127:618-27. [CrossRef]
22. 22. Kaeberlein M, McDonagh T, Heltweg B, Hixon J, Westman EA, Caldwell SD, et al. Substrate-specific activation of sirtuins by resveratrol. J Biol Chem 2005;280:17038-45. [CrossRef]
23. 23. Borra MT, Smith BC, Denu JM. Mechanism of human SIRT1 activation by resveratrol. J Biol Chem 2005;280:17187-95. [CrossRef]
24. 24. Xia N, Strand S, Schlufter F, Siuda D, Reifenberg G, Kleinert H, et al. Role of SIRT1 and FOXO factors in eNOS transcriptional activation by resveratrol. Nitric Oxide 2013;32:29-35. [CrossRef]