Anti-atherosclerotic potential of gossypetin via inhibiting LDL oxidation and foam cell formation
Graphical abstract
Introduction
Flavonoids are polyphenolic compounds found in fruits and vegetables and plant-derived products like red wine and tea, and can be divided into different subclasses such as anthocyanidins, flavonols, and flavones. The intake of dietary flavonoids has been related to a reduced risk for several diseases, such as cardiovascular and chronic inflammatory diseases (Geraets et al., 2007, Nijveldt et al., 2001). These positive health effects associated with the intake of flavonoids have been ascribed to their well-known antioxidant properties and to inhibiting effects on a wide range of enzymes (Middleton and Kandaswami, 1993, Rice-Evans et al., 1996). The presence of 3-hydroxyl group of flavonoids is important to their radical-scavenging capabilities higher than ascorbic acid (Wang et al., 2005). Gossypetin (3,5,7,8,3′,4′-hexahydroxy flavone) originally isolated from the flowers of Hibiscus species, has been shown to be quite effective in suppressing N-methyl-N′-nitro-N′-nitrosoguanidine (MNNG) mutagenicity, exhibiting as much as 70% inhibition (Francis et al., 1989). Previous studies also showed that gossypetin possessed antimicrobial activity (Jeong et al., 2009, Miceli et al., 2009) and prevented allergic reaction (Yoshikawa et al., 1995, Yoshikawa et al., 1996). Hibiscus sabdariffa is rich in two important flavonoids, quercetin and gossypetin, as well as anthocyanins. Consuming foods such as H. sabdariffa has been shown to help neutralize cancer-causing agents, decrease oxidative stress and atherosclerosis (Lin et al., 2011a).
Atherosclerosis is a complicated vascular disorder, and low-density lipoprotein (LDL) is implicated as a major risk factor for the progression of this disease (Ross, 1999). Oxidized LDL (ox-LDL) is also well-known as a key factor in the development of atherosclerosis stimulating macrophage foam cell formation in the aorta. It is associated with the accumulation of cholesterol in macrophages by imbalance of cholesterol influx and efflux (Ross, 1999). Recent data support the importance of macrophage surface proteins CD36 and class A scavenge receptors (SR-As), which can specially bind ox-LDL in the atherosclerosis (Yang et al., 2011). Furthermore, CD36 expression participates in cholesterol efflux and is controlled by regulating the transcription factor regulator peroxisome proliferator-activated receptors (PPARs), liver X receptor (LXR), and ATP-binding cassette transporter A1 (ABCA1) (Chawla et al., 2001, Chinetti et al., 2001). It has been demonstrated that SR-A and CD36 are the target genes for PPARγ (Tontonoz et al., 1998). All of these seemed to suggest that controlling the balance of cholesterol transport is strongly associated with regulation of atherosclerosis. To date, synthetic compounds such as PPAR agonists and LXR agonists have been demonstrated to have the effect of delaying atherosclerosis by stimulating cholesterol removal from macrophages (Larrede et al., 2009). Thus, seeking natural compounds for modulation of macrophage functions presents an attractive strategy for the prevention and treatment of atherosclerosis.
Many studies have demonstrated that flavonoids in medical and edible plants have various pharmacological activities, such as antioxidant, anti-inflammatory, anti-carcinogenic, and anti-atherogenic activities (de Whalley et al., 1990, Gaziano et al., 1992). Here, we aimed to investigate the putative effect of gossypetin, a hexahydroxylated flavonoid, on atherosclerosis. Whether the compound could influence LDL oxidation, foam cell formation, and protein expression of the cholesterol regulatory-related signals still needs to be clarified.
Section snippets
1,1-Diphenyl-2-picrylhydrazyl (DPPH) radical-scavenging activity
The effect of gossypetin (purity > 99.0%) (ChromaDex Inc., St. Santa Ana, CA, USA) on the DPPH radical was estimated according to the method of Yang et al. (2011). A reaction mixture containing methanol (3 mL), DPPH (1 mM) and gossypetin (1–1000 μM) was allowed to stand at room temperature for 30 min before mixing with redistilled water (1 mL) and toluene (3 mL). The solution was then centrifuged, and the absorbance of the upper phase was measured at 517 nm. The DPPH mixture without sample solution was
Gossypetin inhibited the protein oxidation and lipid peroxidation of LDL
In order to explore the capacity of free radical scavenging of gossypetin, the spectrophotometric measurement of DPPH consumption in the presence of gossypetin was performed. As can be observed in Fig. 1A, gossypetin at concentrations of > 50 μM scavenged over 50% of free radicals. Therefore, gossypetin may exhibit the antioxidant ability on the DPPH blocking in a dose-dependent manner.
Next, the effects of various concentrations of gossypetin on Cu2 +-mediated oxidation of LDL were determined by
Discussion
In recent years, attention has been focused on the antioxidant properties of pure components for an application in chemoprevention of disease. Previous studies have shown that consumption of flavonoid compounds mitigates the risk of cardiovascular diseases including atherosclerosis (Nicholson et al., 2008). The average daily human intake of these compounds in the UK and USA has been estimated to be 1 g or more (Pierpoint, 1986). Flavonoids have many properties including scavenging free radicals (
Conflict of interest statement
The authors declare that there are no conflicts of interest.
Acknowledgments
This work was supported by the grant from the National Science Council (NSC99-2632-B-040-001-MY3), Taiwan.
References (44)
- et al.
Chelating and free radical scavenging mechanisms of inhibitory actions of rutin and quercetin in lipid peroxidation
Biochem. Pharmacol.
(1989) - et al.
Hibiscus anthocyanins-rich extract inhibited LDL oxidation and oxLDL-mediated macrophages apoptosis
Food Chem. Toxicol.
(2006) - et al.
A PPAR gamma-LXR-ABCA1 pathway in macrophages is involved in cholesterol efflux and atherogenesis
Mol. Cell
(2001) - et al.
Flavonoids inhibit the oxidative modification of low density lipoproteins by macrophages
Biochem. Pharmacol.
(1990) - et al.
Induction of CD36 expression by oxidized LDL and IL-4 by a common signaling pathway dependent on protein kinase C and PPAR-gamma
J. Lipid Res.
(2000) - et al.
Dietary flavones and flavonoles are inhibitors of poly(ADP-ribose)polymerase-1 in pulmonary epithelial cells
J. Nutr.
(2007) - et al.
Neuraminidase inhibitory activities of flavonols isolated from Rhodiola rosea roots and their in vitro anti-influenza viral activities
Bioorg. Med. Chem.
(2009) - et al.
Fisetin, morin and myricetin attenuate CD36 expression and oxLDL uptake in U937-derived macrophages
Biochim. Biophys. Acta
(2008) - et al.
Chemopreventive properties of Hibiscus sabdariffa L. on human gastric carcinoma cells through apoptosis induction and JNK/p38 MAPK signaling activation
Chem. Biol. Interact.
(2007) - et al.
Andrographolide down-regulates hypoxia-inducible factor-1α in human non-small cell lung cancer A549 cells
Toxicol. Appl. Pharmacol.
(2011)
Curcumin inhibits oxLDL-induced CD36 expression and foam cell formation through the inhibition of p38 MAPK phosphorylation
Food Chem. Toxicol.
Flavonoids: a review of probable mechanisms of action and potential applications
Am. J. Clin. Nutr.
Structure–antioxidant activity relationships of flavonoids and phenolic acids
Free Radic. Biol. Med.
Dual promoter structure of mouse and human fatty acid translocase/CD36 genes and unique transcriptional activation by peroxisome proliferator-activated receptor alpha and gamma ligands
J. Biol. Chem.
Resveratrol regulates the expression of LXR-alpha in human macrophages
Biochem. Biophys. Res. Commun.
PPARgamma promotes monocyte/macrophage differentiation and uptake of oxidized LDL
Cell
Antioxidant phenolic constituents from Fagopyrum dibotrys
J. Ethnopharmacol.
Effects of hypolaetin-8-glucoside and related flavonoids on soybean lipoxygenase and snake venom phospholipase A2
Arch. Int. Pharmacodyn. Ther.
Radical scavenging by flavonoid antioxidants
Free Radic. Res. Commun.
PPAR-alpha and PPAR-gamma activators induce cholesterol removal from human macrophage foam cells through stimulation of the ABCA1 pathway
Nat. Med.
Dietary compound quercitrin dampens VEGF induction and PPARgamma activation in oxidized LDL-exposed murine macrophages: association with scavenger receptor CD36
J. Agric. Food Chem.
Effects of (+)-catechin in vitro and in vivo on disturbances produced in rat liver endoplasmic reticulum by carbon tetrachloride
Biochem. Soc. Trans.
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