Receptor-independent fluid-phase macropinocytosis promotes arterial foam cell formation and atherosclerosis.
Receptor-independent fluid-phase macropinocytosis promotes arterial foam cell formation and atherosclerosis.
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DOI：
10.1126/scitranslmed.add2376
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发表时间：
2022-09-21
影响因子：
17.1
通讯作者：
Csanyi, Gabor
中科院分区：
文献类型：
--
作者：
Lin, Hui-Ping;Singla, Bhupesh;Ahn, WonMo;Ghoshal, Pushpankur;Blahove, Maria;Cherian-Shaw, Mary;Chen, Alex;Haller, April;Hui, David Y.;Dong, Kunzhe;Zhou, Jiliang;White, Joseph;Stranahan, Alexis M.;Jasztal, Agnieszka;Lucas, Rudolf;Stansfield, Brian K.;Fulton, David;Chlopicki, Stefan;Csanyi, Gabor
载脂泡沫细胞在动脉壁中的积聚在动脉粥样硬化病变的发展、斑块的进展和动脉粥样硬化的晚期并发症中起着中心作用。然而，我们对动脉粥样硬化动脉中泡沫细胞形成的潜在机制的认识仍然存在根本性的空白。本研究的目的是探讨受体非依赖性巨胞饮在动脉脂质积聚和动脉粥样硬化发病机制中的作用。在这里，我们发现，在骨髓细胞（LysMCre+ NHE 1fl/fl）中的液相巨胞饮的遗传抑制和FDA批准的抑制巨噬细胞巨胞饮的药物的再利用，大大减少了LDL受体缺陷和ApoE−/−小鼠中动脉粥样硬化病变的发展。使用遗传（H-RASG 12 V）和生理相关方法刺激巨胞饮作用可促进野生型和清道夫受体（SR）敲除（CD 36 −/−/SR-A−/−）巨噬细胞中未修饰天然（nLDL）和修饰（oxLDL和acLDL）脂蛋白的内化。高胆固醇血症野生型和CD 36 −/−/SR-A−/−小鼠中巨胞饮的药理学抑制确定了巨胞饮在体内病变巨噬细胞摄取LDL和动脉粥样硬化发展中的重要作用。此外，连续切片高分辨率成像，低密度脂蛋白免疫标记和3D重建的内皮下泡沫细胞提供了第一个直观的证据，脂质巨胞饮在人类和小鼠动脉粥样硬化动脉。总之，我们的研究结果补充了动脉粥样硬化的SR范式，并确定了一种全新的治疗策略，以对抗动脉粥样硬化的发展，降低心血管疾病患者的发病率和死亡率。巨噬细胞巨胞饮作用：动脉粥样硬化的重要参与者和关键治疗靶点。
Accumulation of lipid-laden foam cells in the arterial wall plays a central role in atherosclerotic lesion development, plaque progression and late-stage complications of atherosclerosis. Yet, there are still fundamental gaps in our knowledge of the underlying mechanisms leading to foam cell formation in atherosclerotic arteries. The goal of this study was to investigate the role of receptor-independent macropinocytosis in arterial lipid accumulation and pathogenesis of atherosclerosis. Here, we showed that genetic inhibition of fluid-phase macropinocytosis in myeloid cells (LysMCre+ NHE1fl/fl) and repurposing of an FDA-approved drug that inhibits macrophage macropinocytosis, substantially decrease atherosclerotic lesion development in LDL receptor-deficient and ApoE−/− mice. Stimulation of macropinocytosis using genetic (H-RASG12V) and physiologically relevant approaches promotes internalization of unmodified native (nLDL) and modified (oxLDL and acLDL) lipoproteins in both wild-type and scavenger receptor (SR) knockout (CD36−/−/SR-A−/−) macrophages. Pharmacological inhibition of macropinocytosis in hypercholesterolemic wild-type and CD36−/−/SR-A−/− mice identifies an important role of macropinocytosis in LDL uptake by lesional macrophages in vivo and development of atherosclerosis. Furthermore, serial section high-resolution imaging, LDL immunolabeling and 3D reconstruction of subendothelial foam cells provide the first visual evidence of lipid macropinocytosis in both human and murine atherosclerotic arteries. In summary, our findings complement the SR paradigm of atherosclerosis and identify an entirely new therapeutic strategy to counter the development of atherosclerosis and reduce morbidity and mortality in patients with cardiovascular disease. Macrophage macropinocytosis: an important player and key therapeutic target in atherosclerosis.
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影响因子：
64.8
作者：
Kojima Y;Volkmer JP;McKenna K;Civelek M;Lusis AJ;Miller CL;Direnzo D;Nanda V;Ye J;Connolly AJ;Schadt EE;Quertermous T;Betancur P;Maegdefessel L;Matic LP;Hedin U;Weissman IL;Leeper NJ
通讯作者：
Leeper NJ
影响因子：
6.2
作者：
Begum G;Song S;Wang S;Zhao H;Bhuiyan MIH;Li E;Nepomuceno R;Ye Q;Sun M;Calderon MJ;Stolz DB;St Croix C;Watkins SC;Chen Y;He P;Shull GE;Sun D
通讯作者：
Sun D
影响因子：
2.3
作者：
Gajda M;Jasztal A;Banasik T;Jasek-Gajda E;Chlopicki S
通讯作者：
Chlopicki S
影响因子：
6.6
作者：
Ghoshal, Pushpankur;Singla, Bhupesh;Csanyi, Gabor
通讯作者：
Csanyi, Gabor
影响因子：
15.9
作者：
Febbraio, M;Podrez, EA;Silverstein, RL
通讯作者：
Silverstein, RL