Thrombosis and Atherosclerosis Research Institute, Department of Biochemistry and Biomedical Sciences, McMaster University, and Hamilton Health Sciences, Ontario, Canada.
Arterioscler Thromb Vasc Biol. 2023 Jan;43(1):45-63. doi: 10.1161/ATVBAHA.122.318062. Epub 2022 Nov 10.
Atherosclerosis is a chronic disease affecting artery wall and a major contributor to cardiovascular diseases. Large necrotic cores increase risk of plaque rupture leading to thrombus formation. Necrotic cores are rich in debris from dead macrophages. Programmed necrosis (necroptosis) contributes to necrotic core formation. HDL (high-density lipoprotein) exerts direct atheroprotective effects on different cells within atherosclerotic plaques. Some of these depend on the SR-B1 (scavenger receptor class B type I) and the adapter protein PDZK1 (postsynaptic density protein/Drosophila disc-large protein/Zonula occludens protein containing 1). However, a role for HDL in protecting against necroptosis and necrotic core formation in atherosclerosis is not completely understood.
Low-density lipoprotein receptor-deficient mice engineered to express different amounts of ApoA1 (apolipoprotein A1), or to lack PDZK1 were fed a high fat diet for 10 weeks. Atherosclerotic plaque areas, necrotic cores, and key necroptosis mediators, RIPK3 (receptor interacting protein kinase 3), and MLKL (mixed lineage kinase domain-like protein) were characterized. Cultured macrophages were treated with HDL to determine its effects, as well as the roles of SR-B1, PDZK1, and the PI3K (phosphoinositide 3-kinase) signaling pathway on necroptotic cell death.
Genetic overexpression reduced, and ApoA1 knockout increased necrotic core formation and RIPK3 and MLKL within atherosclerotic plaques. Macrophages were protected against necroptosis by HDL and this protection required SR-B1, PDZK1, and PI3K/Akt pathway. PDZK1 knockout increased atherosclerosis in LDLR mice, increasing necrotic cores and phospho-MLKL; both of which were reversed by restoring PDZK1 in BM-derived cells.
Our findings demonstrate that HDL in vitro and ApoA1, in vivo, protect against necroptosis in macrophages and necrotic core formation in atherosclerosis, suggesting a pathway that could be a target for the treatment of atherosclerosis.
动脉粥样硬化是一种影响动脉壁的慢性疾病，也是心血管疾病的主要诱因。大的坏死核增加了斑块破裂导致血栓形成的风险。坏死核富含来自死亡巨噬细胞的碎片。程序性细胞坏死（坏死性凋亡）有助于坏死核的形成。高密度脂蛋白（HDL）对动脉粥样硬化斑块内的不同细胞具有直接的抗动脉粥样硬化作用。其中一些作用依赖于 SR-B1（清道夫受体 B 类 I 型）和衔接蛋白 PDZK1（突触后密度蛋白/果蝇盘状大蛋白/含 1 个 Zonula occludens 蛋白）。然而，HDL 在保护动脉粥样硬化中的坏死性凋亡和坏死核形成方面的作用尚不完全清楚。
构建了表达不同量载脂蛋白 A1（ApoA1）或缺乏 PDZK1 的载脂蛋白 A1 缺乏的低密度脂蛋白受体缺陷型小鼠，并用高脂肪饮食喂养 10 周。对动脉粥样硬化斑块面积、坏死核和关键坏死性凋亡介质 RIPK3（受体相互作用蛋白激酶 3）和 MLKL（混合谱系激酶结构域样蛋白）进行了特征描述。用 HDL 处理培养的巨噬细胞，以确定其作用，以及 SR-B1、PDZK1 和 PI3K（磷酸肌醇 3-激酶）信号通路对坏死性细胞死亡的作用。
遗传过表达减少，而 ApoA1 敲除增加了动脉粥样硬化斑块内的坏死核形成和 RIPK3 和 MLKL。HDL 可保护巨噬细胞免受坏死性凋亡，这种保护作用需要 SR-B1、PDZK1 和 PI3K/Akt 通路。PDZK1 敲除增加了 LDLR 小鼠的动脉粥样硬化，增加了坏死核和磷酸化 MLKL；这两者都可以通过在 BM 来源的细胞中恢复 PDZK1 来逆转。
我们的研究结果表明，HDL 在体外和 ApoA1 在体内均能保护巨噬细胞免受坏死性凋亡，并减少动脉粥样硬化中的坏死核形成，这提示了一种可能成为动脉粥样硬化治疗靶点的途径。
