Department of Cardiovascular Sciences, University of Leicester, Leicester, UK; NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, University of Leicester, Leicester, UK.
Department of Cardiovascular Sciences, University of Leicester, Leicester, UK; Department of Chemical Pathology, University Hospitals of Leicester NHS Trust, Leicester, UK.
Lancet. 2015 Feb 26;385 Suppl 1:S21. doi: 10.1016/S0140-6736(15)60336-1.
The benefit of statins in the prevention of cardiovascular disease is well founded, derived from their lipid lowering and pleiotropic effects. The concept of lipoproteins as lipid transporters has evolved to encompass functions in coagulation, inflammation, and redox reactions due to their unique protein cargo. The aim of this study was to determine the effect of statin therapy on lipoproteins and their protein cargo by use of an unbiased bottom-up proteomics approach in people with hypercholesterolaemia.
11 people fulfilling the inclusion criteria were recruited into this UK-based single centre prospective observational study. They were started on statins for primary prevention. Blood was withdrawn at baseline and after a minimum of 2 months of statin therapy. Plasma was co-incubated with a lipoaffinity resin. Isolated proteins were digested and analysed with label-free two-dimensional liquid chromatography coupled to electrospray high-definition ion mobility tandem mass spectrometry.
218 proteins were identified with Progenesis QI software, with 33 proteins demonstrating significant differential expression between the pre-statin and the on-statin samples (each p<0·05). 17 proteins were upregulated by statin therapy, including proteins concerned with cytoskeletal organisation (vinculin p<0·0001, tropomyosin α4 p=0·0108), antioxidative (peroxiredoxin 2 p=0·0092), and anti-inflammatory effects (transgelin-2 p=0·0071). Apolipoprotein B100 was downregulated by statin therapy, consistent with it mechanism of action (p=0·0006). Statin therapy downregulated novel proteins concerned with the modulation of pancreatic β-cell function (adipsin p=0·0056) and haemopoietic precursor proliferation (stem cell growth factor p<0·0001).
Our findings show that statins remodel the cytoskeletal architecture and mediate various anti-inflammatory, antioxidant, and antiproliferative effects that might limit endothelial dysfunction. The downregulation of adipsin, a novel adipokine that stimulates insulin secretion, could explain the controversial link between statin use and the development of diabetes. This study extends our understanding of the beneficial and harmful pleiotropic effects of statin therapy.
British Heart Foundation.
他汀类药物在预防心血管疾病方面的益处是有充分依据的，这源于它们的降脂作用和多效性。由于脂蛋白具有独特的蛋白质载物，其作为脂质转运体的概念已经发展到包含在凝血、炎症和氧化还原反应中的功能。本研究旨在通过使用无偏倚的自下而上的蛋白质组学方法，确定他汀类药物治疗对高脂血症患者脂蛋白及其蛋白质载物的影响。
本研究纳入了 11 名符合纳入标准的英国单中心前瞻性观察性研究患者。他们因原发性预防而开始使用他汀类药物。在基线和至少 2 个月的他汀类药物治疗后采集血液。将血浆与脂亲和树脂共孵育。分离的蛋白质用无标记二维液相色谱与电喷雾高清晰度离子淌度串联质谱联用进行分析。
Progenesis QI 软件鉴定出 218 种蛋白质，其中 33 种蛋白质在他汀类药物治疗前后的样本中表达差异有统计学意义（p<0·05 ）。他汀类药物治疗后有 17 种蛋白质上调，包括与细胞骨架组织（连接蛋白 p<0·0001，原肌球蛋白α4 p=0·0108）、抗氧化（过氧化物酶 2 p=0·0092）和抗炎（转胶蛋白-2 p=0·0071）相关的蛋白质。载脂蛋白 B100 被他汀类药物下调，与它的作用机制一致（p=0·0006）。他汀类药物下调了与调节胰腺β细胞功能（脂联素 p=0·0056）和造血前体细胞增殖（干细胞生长因子 p<0·0001）有关的新型蛋白质。
我们的研究结果表明，他汀类药物重塑了细胞骨架结构，并介导了各种抗炎、抗氧化和抗增殖作用，可能限制了内皮功能障碍。脂联素是一种新型的脂肪因子，能刺激胰岛素分泌，其下调可能解释了他汀类药物使用与糖尿病发展之间存在争议的联系。本研究扩展了我们对他汀类药物治疗有益和有害多效性作用的理解。
英国心脏基金会。
