Department of Physiology & Biophysics, Boston University School of Medicine, Boston, MA 02118, USA.
Department of Physiology & Biophysics, Boston University School of Medicine, Boston, MA 02118, USA.
Biochim Biophys Acta Mol Cell Biol Lipids. 2020 Aug;1865(8):158712. doi: 10.1016/j.bbalip.2020.158712. Epub 2020 Apr 11.
Low-density lipoprotein (LDL) binding to arterial proteoglycans initiates LDL retention and modification in the arterial wall, triggering atherosclerosis. The details of this binding, its effectors, and its ramifications are incompletely understood. We combined heparin affinity chromatography with biochemical, spectroscopic and electron microscopic techniques to show that brief binding to heparin initiates irreversible pro-atherogenic remodeling of human LDL. This involved decreased structural stability of LDL and increased susceptibility to hydrolysis, oxidation and fusion. Furthermore, phospholipid hydrolysis, mild oxidation and/or glycation of LDL in vitro increase the proteolytic susceptibility of apoB and its heparin binding affinity, perhaps by unmasking additional heparin-binding sites. For LDL from hyperglycemic type-2 diabetic patients, heparin binding was particularly destabilizing and caused apoB fragmentation and LDL fusion. However, for similar patients whose glycemic control was restored upon therapy, LDL-heparin binding affinity was rectified and LDL structural stability was partially restored. These results complement previous studies of LDL binding to arterial proteoglycans and suggest that such interactions may produce a particularly pro-atherogenic subclass of electronegative LDL. In summary, binding to heparin alters apoB conformation, perhaps by partially peeling it off the lipid, and triggers pro-atherogenic LDL modifications including hydrolysis, oxidation, and destabilization. Furthermore, phospholipid lipolysis, mild oxidation and glycation of LDL in vitro strengthen its binding to heparin, which helps explain stronger binding observed in hyperglycemic LDL. Combined effects of hyperglycemia and heparin binding are especially deleterious but are largely rectified upon diabetes therapy. These findings help establish a mechanistic link between diabetes and atherosclerosis.
低密度脂蛋白（LDL）与动脉蛋白聚糖的结合起始 LDL 在动脉壁中的滞留和修饰，引发动脉粥样硬化。这种结合的细节、其效应物及其后果尚不完全清楚。我们结合肝素亲和层析以及生化、光谱和电子显微镜技术，证明了与肝素的短暂结合会引发人 LDL 的不可逆转的促动脉粥样硬化重塑。这涉及 LDL 结构稳定性降低和水解、氧化和融合的易感性增加。此外，体外 LDL 的磷脂水解、轻度氧化和/或糖基化会增加载脂蛋白 B 的蛋白水解易感性及其肝素结合亲和力，这可能是通过暴露出更多的肝素结合位点。对于来自高血糖 2 型糖尿病患者的 LDL，肝素结合特别不稳定，并导致载脂蛋白 B 的片段化和 LDL 的融合。然而，对于类似的患者，其血糖控制在治疗后得到恢复，LDL-肝素结合亲和力得到纠正，并且 LDL 结构稳定性得到部分恢复。这些结果补充了之前关于 LDL 与动脉蛋白聚糖结合的研究，并表明这种相互作用可能产生一种特别促动脉粥样硬化的带负电荷的 LDL 亚类。总之，与肝素的结合改变了载脂蛋白 B 的构象，可能是通过部分将其从脂质上剥离下来，并引发包括水解、氧化和失稳在内的促动脉粥样硬化的 LDL 修饰。此外，体外 LDL 的磷脂水解、轻度氧化和糖基化会增强其与肝素的结合，这有助于解释在高血糖 LDL 中观察到的更强结合。高血糖和肝素结合的综合作用特别有害，但在糖尿病治疗后大部分得到纠正。这些发现有助于在糖尿病和动脉粥样硬化之间建立一种机制联系。
