Dual anti-oxidative effects of fraxetin isolated from Fraxinus rhinchophylla.
Atherosclerosis is main cause of arteriosclerosis. The pivotal role of low-density lipoprotein (LDL) oxidation in atherogenesis suggests antioxidants may help prevent cardiovascular disease. Fraxinus rhynchophylla DENCE (Oleaceae) is a traditional medicinal plant from East Asia. During the course of characterizing potential drug candidates from natural products, we isolated two major coumarins, esculetin and fraxetin and found that fraxetin has dual-antioxidative functions. Low concentrations (1-5 microM) of fraxetin potently inhibited LDL oxidation induced by metal and free radicals. Moreover, treatment of vascular smooth muscle cells (VSMCs) with higher concentrations (above 30 microM) of fraxetin significantly increased the protein level of heme oxygenase-1 (HO-1), a key enzyme that inhibits vascular proliferation and atherosclerosis. Subcellular fractionation and reporter gene analysis using an antioxidant response element (ARE) construct revealed that fraxetin increased the level of nuclear factor (NF)-E2-related factor 2 (Nrf2) and reporter activity, and these were associated with the induction of antioxidant enzymes, such as HO-1 and glutathione S-transferase-alpha. In conclusion, fraxetin has direct protective properties against LDL oxidation at lower concentrations, and higher concentrations of fraxetin induce antioxidant enzymes via Nrf2/ARE activation. These effects suggest potential anti-atherosclerosis effects of Fraxinus rhynchophylla D.
Thuong
Phuong Thien
PT
Chosun University, Gwangju, Republic of Korea.
Pokharel
Yuba Raj
YR
Lee
Moo Yeol
MY
Kim
Sang Kyum
SK
Bae
KiHwan
K
Su
Nguyen Duy
ND
Oh
Won Keun
WK
Kang
Keon Wook
KW
D000818:Animals; D000975:Antioxidants / Q000302:isolation & purification* / Q000502:physiology*; D050197:Atherosclerosis / Q000201:enzymology / Q000378:metabolism / Q000517:prevention & control; D002478:Cells, Cultured; D003374:Coumarins / Q000302:isolation & purification* / Q000494:pharmacology*; D031661:Fraxinus; D051547:Heme Oxygenase-1 / Q000096:biosynthesis / Q000502:physiology; D006801:Humans; D008077:Lipoproteins, LDL / Q000037:antagonists & inhibitors / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism / Q000502:physiology; D008517:Phytotherapy; D024301:Plant Bark; D010936:Plant Extracts / Q000302:isolation & purification / Q000494:pharmacology; D051381:Rats
D000975:Antioxidants; D003374:Coumarins; D008077:Lipoproteins, LDL; D051267:NF-E2-Related Factor 2; D010936:Plant Extracts; C105671:fraxetin; D051547:Heme Oxygenase-1