Abstract
The accumulation of oxidized ApoB-100-containing lipoproteins in the vascular intima and its subsequent recognition by macrophages results in foam cell formation and inflammation, key events during atherosclerosis development. Agents targeting this process are considered potentially atheroprotective. Since natural biflavonoids exert antioxidant and anti-inflammatory effects, we evaluated the atheroprotective effect of biflavonoids obtained from the tropical fruit tree Garcinia madruno. To this end, the pure biflavonoid aglycones morelloflavone (Mo) and volkensiflavone (Vo), as well as the morelloflavone’s glycoside fukugiside (Fu) were tested in vitro in primary macrophages, whereas a biflavonoid fraction with defined composition (85% Mo, 10% Vo, and 5% Amentoflavone) was tested in vitro and in vivo. All biflavonoid preparations were potent reactive oxygen species (ROS) scavengers in the oxygen radical absorbance capacity assay, and most importantly, protected low-density lipoprotein particle from both lipid and protein oxidation. In biflavonoid-treated macrophages, the surface expression of the oxidized LDL (oxLDL) receptor CD36 was significantly lower than in vehicle-treated macrophages. Uptake of fluorescently labeled oxLDL and cholesterol accumulation were also attenuated in biflavonoid-treated macrophages and followed a pattern that paralleled that of CD36 surface expression. Fu and Vo inhibited oxLDL-induced ROS production and interleukin (IL)-6 secretion, respectively, whereas all aglycones, but not the glucoside Fu, inhibited the secretion of one or more of the cytokines IL-1β, IL-12p70, and monocyte chemotactic protein-1 (MCP-1) in lipopolysaccharide (LPS)-stimulated macrophages. Interestingly, in macrophages primed with low-dose LPS and stimulated with cholesterol crystals, IL-1β secretion was significantly and comparably inhibited by all biflavonoid preparations. Intraperitoneal administration of the defined biflavonoid fraction into ApoE−/− mice was atheroprotective, as evidenced by the reduction of the atheromatous lesion size and the density of T cells and macrophages infiltrating the aortic root; moreover, this treatment also lowered the circulating levels of cholesterol and the lipid peroxidation product malondialdehyde. These results reveal the potent atheroprotective effects exerted by biflavonoids on key events of the oxLDL–macrophage interphase: (i) atheroligand formation, (ii) atheroreceptor expression, (iii) foam cell transformation, and (iv) prooxidant/proinflammatory macrophage response. Furthermore, our results also evidence the antioxidant, anti-inflammatory, hypolipemiant, and atheroprotective effects of Garcinia madruno’s biflavonoids in vivo.
Highlights
Atherosclerotic cardiovascular diseases (CVD) are the current major human killers worldwide
Treatment of low-density lipoprotein (LDL) with low biflavonoid concentrations (1.5 μM) demonstrated a less pronounced effect for Vo (Figure 2E). These results show that biflavonoids prevent LDL modification at lipid and protein levels and, reduce the formation of this key atherogenic ligand
(35), leading to complex chemical processes that result in the formation of oxidatively modified LDL particles, or oxidized LDL (oxLDL). oxLDLs are highly heterogeneous and contain an array of lipid peroxidation products in the lipidic component that are responsible of many down stream damaging effects on vascular cells, such as cell death, proliferation, migration, and inflammatory response [33, 34]
Summary
Atherosclerotic cardiovascular diseases (CVD) are the current major human killers worldwide. Key events in the atherosclerotic pathophysiology are [1] dyslipidemia-associated lipoprotein retention in the subintimal space of particular anatomical regions of the arterial tree, [2] physicochemical modifications of lipoproteins leading to endothelial dysfunction and activation, recruitment of leukocytes, and the subsequent triggering of inflammatory cascades governed by innate and adaptive immune systems, and [3] uncontrolled vicious circle of inflammation and lipoprotein accumulation/oxidation leading to lesion growth, inestabilization, and eventually to clinical events [2] Both non-hematopoietic and hematopoietic vascular cells participate in atherogenesis.
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