NYU School of Medicine, Departments of Medicine (Cardiology) and Cell Biology, Marc and Ruti Bell Program in Vascular Biology, New York, NY 10016, USA.
Circ Res. 2011 Oct 28;109(10):1141-52. doi: 10.1161/CIRCRESAHA.111.246363. Epub 2011 Sep 15.
Human atherosclerotic plaques contain large numbers of cells deprived of O(2). In murine atherosclerosis, because the plaques are small, it is controversial whether hypoxia can occur.
To examine if murine plaques contain hypoxic cells, and whether hypoxia regulates changes in cellular lipid metabolism and gene expression in macrophages.
Aortic plaques from apolipoprotein-E-deficient mice were immunopositive for hypoxia-inducible transcription factor (HIF-1α) and some of its downstream targets. Murine J774 macrophages rendered hypoxic demonstrated significant increases in cellular sterol and triglycerides. The increase in sterol content in hypoxic macrophages correlated with elevated 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase activity and mRNA levels. In addition, when macrophages were incubated with cholesterol complexes, hypoxic cells accumulated 120% more cholesterol, predominately in the free form. Cholesterol-efflux assays showed that hypoxia significantly decreased efflux mediated by ATP-binding cassette subfamily A member 1 (ABCA1), whose sub cellular localization was altered in both J774 and primary macrophages. Furthermore, in vivo expression patterns of selected genes from cells in hypoxic regions of murine plaques were similar to those from J774 and primary macrophages incubated in hypoxia. The hypoxia-induced accumulation of sterol and decreased cholesterol efflux was substantially reversed in vitro by reducing the expression of the hypoxia-inducible transcription factor, HIF-1α.
Hypoxic regions are present in murine plaques. Hypoxic macrophages have increased sterol content due to the induction of sterol synthesis and the suppression of cholesterol efflux, effects that are in part mediated by HIF-1α.
人类动脉粥样硬化斑块中含有大量处于缺氧状态的细胞。在小鼠动脉粥样硬化中，由于斑块较小，是否存在缺氧仍存在争议。
研究小鼠斑块中是否存在缺氧细胞，以及缺氧是否调节巨噬细胞中细胞脂质代谢和基因表达的变化。
载脂蛋白 E 缺陷小鼠的主动脉斑块免疫组化染色呈缺氧诱导转录因子（HIF-1α）及其部分下游靶基因阳性。使 J774 巨噬细胞缺氧，细胞固醇和甘油三酯含量明显增加。缺氧巨噬细胞固醇含量增加与 3-羟-3-甲基戊二酰辅酶 A（HMG-CoA）还原酶活性和 mRNA 水平升高相关。此外，当巨噬细胞与胆固醇复合物孵育时，缺氧细胞积累的胆固醇增加 120%，主要以游离形式存在。胆固醇流出测定表明，缺氧显著降低了 ABCA1 介导的流出，而 ABCA1 是 ATP 结合盒子家族 A 成员 1 的亚细胞定位在 J774 和原代巨噬细胞中均发生改变。此外，在体内，来自缺氧区域的细胞的特定基因的表达模式与在缺氧环境下孵育的 J774 和原代巨噬细胞中的表达模式相似。在体外，通过降低缺氧诱导转录因子 HIF-1α 的表达，可显著逆转固醇的积累和胆固醇流出的减少。
在小鼠斑块中存在缺氧区域。缺氧巨噬细胞固醇含量增加，原因是固醇合成诱导和胆固醇流出抑制，这些作用部分由 HIF-1α 介导。
