Binding to heparin triggers deleterious structural and biochemical changes in human low-density lipoprotein, which are amplified in hyperglycemia.,Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids

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Binding to heparin triggers deleterious structural and biochemical changes in human low-density lipoprotein, which are amplified in hyperglycemia.
Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids ( IF 3.9 ) Pub Date : 2020-04-11 , DOI: 10.1016/j.bbalip.2020.158712
Shobini Jayaraman ₁ , Olivia R Chavez ₁ , Antonio Pérez ₂ , Inka Miñambres ₃ , Jose Luis Sánchez-Quesada ₄ , Olga Gursky ₅

Affiliation

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.

中文翻译：

与肝素结合会触发人类低密度脂蛋白的有害结构和生化变化，而这些变化会在高血糖症中放大。

低密度脂蛋白 (LDL) 与动脉蛋白多糖结合，启动动脉壁中的 LDL 保留和修饰，引发动脉粥样硬化。这种结合的细节、它的效应子和它的后果尚不完全清楚。我们将肝素亲和色谱与生化、光谱和电子显微镜技术相结合，以表明与肝素的短暂结合会引发人 LDL 的不可逆促动脉粥样硬化重塑。这涉及降低 LDL 的结构稳定性和增加对水解、氧化和融合的敏感性。此外，在体外 LDL 的磷脂水解、轻度氧化和/或糖基化增加了 apoB 的蛋白水解敏感性及其肝素结合亲和力，这可能是通过揭示额外的肝素结合位点来实现的。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 apoB 断裂和 LDL 融合。然而，对于治疗后血糖控制恢复的类似患者，LDL-肝素结合亲和力得到纠正，LDL结构稳定性部分恢复。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会产生一种特别促动脉粥样硬化的电负性 LDL 亚类。总之，与肝素结合会改变 apoB 构象，可能是通过将其从脂质上部分剥离，并触发促动脉粥样硬化的 LDL 修饰，包括水解、氧化和不稳定。此外，在体外 LDL 的磷脂脂解、轻度氧化和糖化增强了其与肝素的结合，这有助于解释在高血糖 LDL 中观察到的更强的结合。高血糖症和肝素结合的联合作用尤其有害，但在糖尿病治疗后可在很大程度上得到纠正。这些发现有助于建立糖尿病和动脉粥样硬化之间的机制联系。

更新日期：2020-04-11

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