From the Key Laboratory of Metabolism on Lipid and Glucose, Centre for Lipid Research, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China (Y.C., L.Z., Q.L., A.H., X.Z.R.); Division of Nephrology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan (L.C.L.); and John Moorhead Research Laboratory, Centre for Nephrology, University College London (UCL) Medical School, United Kingdom (H.K., D.C.W., Z.V., J.F.M., S.H.P., X.Z.R.).
Arterioscler Thromb Vasc Biol. 2014 Feb;34(2):365-76. doi: 10.1161/ATVBAHA.113.301301. Epub 2013 Nov 14.
The risk of cardiovascular disease is increased by up to 33 to 50× in chronic inflammatory states and convention doses of statins may not provide the same cardiovascular protection as in noninflamed patients. This study investigated whether the increase in 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCoA-R)-mediated cholesterol synthesis observed under inflammatory stress was resistant to the action of statins and if so, whether this was because of interference with the sterol regulatory element binding protein cleavage-activating protein pathway.
Inflammatory stress was induced by adding cytokines (interleukin-1β, tumor necrosis factor-α, and interleukin-6) and lipopolysaccharides to vascular smooth muscle cells in vitro and by subcutaneous casein injection in apolipoprotein E/scavenger receptors class A/CD36 triple knockout mice in vivo. Inflammatory stress exacerbated cholesterol ester accumulation and was accompanied in vitro and in vivo by increased HMGCoA-R mRNA and protein expression mediated via activation of the sterol regulatory element binding protein cleavage-activating protein/sterol regulatory element binding protein-2 pathway. Atorvastatin reduced HMGCoA-R enzymatic activity and intracellular cholesterol synthesis in vitro. However, inflammatory stress weakened these suppressive effects. Atorvastatin at concentrations of 16 μmol/L inhibited HMGCoA-R activity by 50% in vascular smooth muscle cells, but the same concentration resulted in only 30% of HMGCoA-R activity in vascular smooth muscle cells in the presence of interleukin-1β. Knocking down sterol regulatory element binding protein cleavage-activating protein prevented statin resistance induced by interleukin-1β, and overexpression of sterol regulatory element binding protein cleavage-activating protein induced statin resistance even without inflammatory stress. In vivo, the amount of atorvastatin required to lower serum cholesterol and decrease aortic lipid accumulation rose from 2 to 10 mg/kg per day in the presence of inflammatory stress.
Increased cholesterol synthesis mediated by HMGCoA-R under inflammatory stress may be one of the mechanisms for intracellular lipid accumulation and statin resistance.
在慢性炎症状态下，心血管疾病的风险增加了 33 至 50 倍，而常规剂量的他汀类药物可能无法为非炎症患者提供相同的心血管保护。本研究旨在探讨炎症应激下观察到的 3-羟基-3-甲基戊二酰基辅酶 A 还原酶（HMGCoA-R）介导的胆固醇合成增加是否对他汀类药物的作用具有抗性，如果是，是否是因为干扰了固醇调节元件结合蛋白切割激活蛋白途径。
在体外通过添加细胞因子（白细胞介素-1β、肿瘤坏死因子-α和白细胞介素-6）和脂多糖以及在体内通过皮下酪蛋白注射载脂蛋白 E/清道夫受体 A/CD36 三重基因敲除小鼠来诱导炎症应激。炎症应激加剧了胆固醇酯的积累，并伴有 HMGCoA-R mRNA 和蛋白表达的增加，这是通过固醇调节元件结合蛋白切割激活蛋白/固醇调节元件结合蛋白-2 途径的激活介导的。阿托伐他汀在体外降低 HMGCoA-R 酶活性和细胞内胆固醇合成。然而，炎症应激削弱了这些抑制作用。阿托伐他汀在 16 μmol/L 的浓度下可抑制血管平滑肌细胞中的 HMGCoA-R 活性达 50%，但在存在白细胞介素-1β的情况下，相同浓度仅导致 HMGCoA-R 活性的 30%。敲低固醇调节元件结合蛋白切割激活蛋白可防止白细胞介素-1β诱导的他汀类药物耐药，即使没有炎症应激，固醇调节元件结合蛋白切割激活蛋白的过表达也会诱导他汀类药物耐药。在体内，在炎症应激存在的情况下，阿托伐他汀降低血清胆固醇和减少主动脉脂质积累所需的剂量从每天 2 毫克/千克增加到 10 毫克/千克。
炎症应激下 HMGCoA-R 介导的胆固醇合成增加可能是细胞内脂质积累和他汀类药物耐药的机制之一。
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