Interventional hepatic apoC-III knockdown improves atherosclerotic plaque stability and remodeling by triglyceride lowering.
Interventional hepatic apoC-III knockdown improves atherosclerotic plaque stability and remodeling by triglyceride lowering.
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DOI：
10.1172/jci.insight.158414
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发表时间：
2022-07-08
期刊：
影响因子：
8
通讯作者：
Witztum, Joseph L.
中科院分区：
文献类型：
--
作者：
Ramms, Bastian;Patel, Sohan;Sun, Xiaoli;Pessentheiner, Ariane R.;Ducasa, G. Michelle;Mullick, Adam E.;Lee, Richard G.;Crooke, Rosanne M.;Tsimikas, Sotirios;Witztum, Joseph L.;Gordts, Philip L. S. M.;Witztum, Joseph L.
载脂蛋白 C-III (apoC-III) 是甘油三酯代谢的关键调节因子，与高甘油三酯血症和心血管疾病 (CVD) 呈正相关。目前尚不清楚治疗性降低 apoC-III 是否会降低 CVD 风险，以及 CVD 相关性是否取决于降脂或抗炎特性。我们使用 apoC-III 反义寡核苷酸 (ASO) 在 2 个高甘油三酯血症小鼠模型和第三个脂质难治性模型中确定了介入性 apoC-III 降低对动脉粥样硬化形成的影响，其中干预措施降低了血浆甘油三酯。在高胆固醇西方饮食中，apoC-III ASO 治疗没有改变动脉粥样硬化病变的大小，但确实减弱了甘油三酯反应性小鼠模型中晚期和不稳定斑块的发展。在脂质难治性小鼠中，apoC-III ASO 未观察到病变大小或成分改善。为了避免持续高胆固醇喂养的混杂效应，我们测试了在西方饮食 12 周后转为低胆固醇饮食时干预性 apoC-III 降低的影响。在这种饮食转换方案中，apoC-III ASO 治疗显着降低了脂质反应性小鼠的血浆甘油三酯、动脉粥样硬化病变进展和坏死核心面积，并增加了纤维帽厚度。同样，在饮食转换后，apoC-III ASO 治疗并没有改变脂质难治性小鼠的甘油三酯水平、病变发展和病变组成。我们的研究结果表明，介入性apoC-III降低可能是在实现降脂后减少动脉粥样硬化病变大小并改善斑块稳定性的有效策略。
Apolipoprotein C-III (apoC-III) is a critical regulator of triglyceride metabolism and correlates positively with hypertriglyceridemia and cardiovascular disease (CVD). It remains unclear if therapeutic apoC-III lowering reduces CVD risk and if the CVD correlation depends on the lipid-lowering or antiinflammatory properties. We determined the impact of interventional apoC-III lowering on atherogenesis using an apoC-III antisense oligonucleotide (ASO) in 2 hypertriglyceridemic mouse models where the intervention lowers plasma triglycerides and in a third lipid-refractory model. On a high-cholesterol Western diet apoC-III ASO treatment did not alter atherosclerotic lesion size but did attenuate advanced and unstable plaque development in the triglyceride-responsive mouse models. No lesion size or composition improvement was observed with apoC-III ASO in the lipid-refractory mice. To circumvent confounding effects of continuous high-cholesterol feeding, we tested the impact of interventional apoC-III lowering when switching to a cholesterol-poor diet after 12 weeks of Western diet. In this diet switch regimen, apoC-III ASO treatment significantly reduced plasma triglycerides, atherosclerotic lesion progression, and necrotic core area and increased fibrous cap thickness in lipid-responsive mice. Again, apoC-III ASO treatment did not alter triglyceride levels, lesion development, and lesion composition in lipid-refractory mice after the diet switch. Our findings suggest that interventional apoC-III lowering might be an effective strategy to reduce atherosclerosis lesion size and improve plaque stability when lipid lowering is achieved.
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影响因子：
39.3
作者：
Chapman MJ;Ginsberg HN;Amarenco P;Andreotti F;Borén J;Catapano AL;Descamps OS;Fisher E;Kovanen PT;Kuivenhoven JA;Lesnik P;Masana L;Nordestgaard BG;Ray KK;Reiner Z;Taskinen MR;Tokgözoglu L;Tybjærg-Hansen A;Watts GF;European Atherosclerosis Society Consensus Panel
通讯作者：
European Atherosclerosis Society Consensus Panel
DOI：
10.1161/atvbaha.113.301637
发表时间：
2013-09
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
--
作者：
Foley EM;Gordts PLSM;Stanford KI;Gonzales JC;Lawrence R;Stoddard N;Esko JD
通讯作者：
Esko JD
影响因子：
4.8
作者：
Larsson, Mikael;Vorrsjo, Evelina;Olivecrona, Gunilla
通讯作者：
Olivecrona, Gunilla
影响因子：
20.1
作者：
Gimbrone MA Jr;García-Cardeña G
通讯作者：
García-Cardeña G
DOI：
10.1007/978-1-4939-2929-0_1
发表时间：
2015-01-01
期刊：
METHODS IN MOUSE ATHEROSCLEROSIS
影响因子：
--
作者：
Getz, Godfrey S.;Reardon, Catherine A.
通讯作者：
Reardon, Catherine A.