高脂血症和 IFNgamma/TNFalpha 协同作用与内皮细胞中胆固醇晶体的形成有关，部分是通过调节溶酶体 pH 和胆固醇稳态。
Hyperlipidaemia and IFNgamma/TNFalpha Synergism are associated with cholesterol crystal formation in Endothelial cells partly through modulation of Lysosomal pH and Cholesterol homeostasis.
机构信息
Section of Inflammation and Cardiometabolic Diseases, National Heart, Lung and Blood Institute, 10 Center Drive, Bethesda, MD 20892, USA; Social Determinants of Obesity and Cardiovascular Risk Laboratory, National Heart, Lung and Blood Institute, 10 Center Drive, Bethesda, MD 20892, USA.
Section of Inflammation and Cardiometabolic Diseases, National Heart, Lung and Blood Institute, 10 Center Drive, Bethesda, MD 20892, USA.
出版信息
EBioMedicine. 2020 Sep;59:102876. doi: 10.1016/j.ebiom.2020.102876. Epub 2020 Jul 6.
BACKGROUND
Inflammation plays an important role in the development of cardiovascular disease (CVD). Patients with chronic inflammation diseases have high levels of inflammation and early fatal myocardial infarction due to early, unstable coronary plaques. Cholesterol crystals (CC) play a key role in atherogenesis. However, the underlying mechanisms of endothelial cell (EC)-derived CC formation are not well understood in chronic inflammation.
METHODS
We utilized a combination of a mouse psoriasis model (K14-Rac1V12 mouse model) and human psoriasis patients to study the effect of inflammatory cytokines on CC formation in ECs. Lysosomal pH, alterations in lipid load and inflammatory proteins were evaluated as potential mechanisms linking inflammatory cytokines to CC formation. Coronary CT angiography was performed (n = 224) to characterize potential IFNγ and TNFα synergism on vascular diseases in vivo.
FINDINGS
We detected CC presence in the aorta of K14-Rac1V12 mice on chow diet. IFNγ and TNFα were found to synergistically increase LDL-induced CC formation by almost 2-fold. There was an increase in lysosomal pH accompanied by a 28% loss in pH-dependent lysosomal signal and altered vATPaseV1E1 expression patterns. In parallel, we found that LDL+IFNγ/TNFα treatments increased free cholesterol content within EC and led to a decrease in SOAT-1 expression, an enzyme critically involved cholesterol homeostasis. Finally, the product of IFNγ and TNFα positively associated with early non-calcified coronary burden in patients with psoriasis (n = 224; β = 0.28, p < 0.001).
INTERPRETATION
Our results provide evidence that IFNγ and TNFα accelerate CC formation in endothelial cells in part by altering lysosomal pH and free cholesterol load. These changes promote early atherogenesis and contribute to understanding the burden of CVD in psoriasis.
FUNDING
Funding was provided by the Intramural Research Program at NIH (NNM) and the National Psoriasis Foundation (NNM and YB).
背景
炎症在心血管疾病（CVD）的发展中起着重要作用。患有慢性炎症性疾病的患者由于早期不稳定的冠状动脉斑块，炎症水平较高，且早期发生致命性心肌梗死。胆固醇晶体（CC）在动脉粥样硬化形成中起关键作用。然而，在慢性炎症中，内皮细胞（EC）衍生的 CC 形成的潜在机制尚不清楚。
方法
我们利用小鼠银屑病模型（K14-Rac1V12 小鼠模型）和人类银屑病患者的组合来研究炎症细胞因子对 EC 中 CC 形成的影响。评估溶酶体 pH、脂质负荷和炎症蛋白的改变，作为将炎症细胞因子与 CC 形成联系起来的潜在机制。进行了冠状动脉 CT 血管造影（n=224），以体内研究 IFNγ 和 TNFα 对血管疾病的潜在协同作用。
发现
我们在喂食正常饮食的 K14-Rac1V12 小鼠的主动脉中检测到 CC 的存在。IFNγ 和 TNFα 协同作用可使 LDL 诱导的 CC 形成增加近 2 倍。溶酶体 pH 升高，伴有 pH 依赖性溶酶体信号丧失 28%和 vATPaseV1E1 表达模式改变。与此同时，我们发现 LDL+IFNγ/TNFα 处理增加了 EC 中的游离胆固醇含量，并导致 SOAT-1 表达降低，SOAT-1 是参与胆固醇稳态的关键酶。最后，IFNγ 和 TNFα 的产物与银屑病患者的早期非钙化冠状动脉负担呈正相关（n=224；β=0.28，p<0.001）。
解释
我们的研究结果提供了证据，表明 IFNγ 和 TNFα 通过改变溶酶体 pH 和游离胆固醇负荷来加速内皮细胞中 CC 的形成。这些变化促进了早期动脉粥样硬化的发生，并有助于理解银屑病患者 CVD 的负担。
资助
本研究由 NIH 内部研究计划（NNM）和国家银屑病基金会（NNM 和 YB）提供资金支持。
Zotero 插件