Wallenberg Laboratory for Cardiovascular Research, Sahlgrenska Academy, Göteborg University, Göteborg.
Glycobiology. 2010 Jan;20(1):33-40. doi: 10.1093/glycob/cwp139. Epub 2009 Sep 11.
Macrophages are prominent in hypoxic areas of atherosclerotic lesions, and their secreted proteoglycans (PG), such as versican, can modulate the retention of lipoproteins and the activity of enzymes, cytokines, and growth factors involved in atherogenesis. In this study, we report the effects of hypoxia on PG secreted by human monocyte-derived macrophages (HMDM) and the potential regulation by the transcription factor hypoxia-inducible factor (HIF-1alpha and HIF-2alpha). We found that versican co-localized with HIF-1alpha in macrophage-rich areas in human advanced atherosclerotic lesions. Versican and perlecan mRNA expression increased after exposure to 0.5% O(2) (hypoxia) compared with 21% O(2) (control cells). Using precursors to GAG biosynthesis combined with immunoabsorption with a versican antibody an increased versican synthesis was detected at hypoxia. Furthermore, siRNA knockdown of HIF-1alpha and HIF-2alpha in THP-1 cells showed that the hypoxic induction of versican and perlecan mRNA expression involved HIF signaling. Versican expression was co-regulated by HIF-1alpha and HIF-2alpha but expression of perlecan was influenced only by HIF-1alpha and not by HIF-2alpha knockdown. The results show that oxygen concentration is an important modulator of PG expression in macrophages. This may be a novel component of the complex role of macrophages in atherosclerosis.
巨噬细胞在动脉粥样硬化病变的缺氧区域中很突出，其分泌的蛋白聚糖（PG），如 versican，可以调节脂蛋白的保留和参与动脉粥样硬化形成的酶、细胞因子和生长因子的活性。在这项研究中，我们报告了缺氧对人单核细胞衍生的巨噬细胞（HMDM）分泌的 PG 的影响，以及转录因子缺氧诱导因子（HIF-1alpha 和 HIF-2alpha）的潜在调节作用。我们发现 versican 与人动脉粥样硬化晚期病变中富含巨噬细胞的区域中的 HIF-1alpha 共定位。与 21% O2（对照细胞）相比，暴露于 0.5% O2（缺氧）后 versican 和 perlecan mRNA 表达增加。使用 GAG 生物合成前体并结合 versican 抗体免疫吸收，在缺氧时检测到 versican 合成增加。此外，THP-1 细胞中 HIF-1alpha 和 HIF-2alpha 的 siRNA 敲低表明，versican 和 perlecan mRNA 表达的缺氧诱导涉及 HIF 信号。Versican 的表达受 HIF-1alpha 和 HIF-2alpha 共同调节，但 perlecan 的表达仅受 HIF-1alpha 调节，不受 HIF-2alpha 敲低的影响。结果表明，氧浓度是巨噬细胞 PG 表达的重要调节剂。这可能是巨噬细胞在动脉粥样硬化中复杂作用的一个新组成部分。
