Molecular Regulation of Atherosclerosis

摘要 尽管有有效的降脂治疗和预防计划，但动脉粥样硬化仍然是导致 美国的死亡率。在突出的危险因素中，血管内皮细胞导致的动脉硬化 细胞活化和新生内膜增生在促进动脉粥样硬化中起重要作用。更重要的是， 在晚期动脉粥样硬化中，巨噬细胞功能障碍导致细胞过度死亡是斑块形成的原因。 破裂，继发性血栓形成，以及最终中风和心肌梗死。然而，由于缺乏 合适的分子靶点，人们普遍认为阻碍功能障碍的内皮和巨噬细胞 预防动脉粥样硬化仍然令人望而生畏。我们的长期目标是发现分子机制并确定 预防内皮和巨噬细胞功能障碍的新靶点，希望提供潜在的新的 治疗方法。为此，我们历史上的努力主要集中在研究内皮细胞的作用 内毒素在动脉粥样硬化形成中的作用在这个应用中，我们假设探索髓系特异性内啡肽在脑内的功能。 动脉粥样硬化是由于巨噬细胞在促进动脉粥样硬化方面做出的基本贡献。这个 我们前述原创研究的科学前提部分建立在一个耐人寻味的观察结果上 内毒素在病变巨噬细胞中上调。因此，了解巨噬细胞是否以及如何 在动脉粥样硬化的进展中起关键作用的内皮肽是迫切需要的。我们现在创作小说 髓系特异性内毒素缺陷小鼠模型的建立及发现髓系特异性内毒素缺陷 显著抑制西方饮食诱导的载脂蛋白E-/-小鼠动脉粥样硬化。此外，内毒素在巨噬细胞中的丢失 显著损害泡沫细胞的形成，阻碍受体介导的oxLDL摄取，并干扰肌动蛋白驱动的 非受体介导的内吞作用。同时，巨噬细胞内毒素的丢失会导致SR-B1升高，而 减少的SR-B1消除了动脉粥样硬化保护的自噬。因此，巨噬细胞内啡肽是否抑制 通过下调SR-B1来实现自噬是一个全新的问题。为了进行测试，我们建议确定分子 机制1)内皮肽调节泡沫细胞形成过程中的脂质摄取和2)潜在的内皮肽- 介导SR-BI在巨噬细胞中的降解和自噬减弱，并确定巨噬细胞来源 促分解脂类介体生物合成。我们预计，在成功完成拟议的 研究表明，获得的大量知识将推动这一领域的发展，包括内皮肽如何调控泡沫细胞的形成 通过控制非受体和受体介导的脂质摄取，以及SR-B1和epsins如何相反发挥作用 以调节巨噬细胞的动脉粥样硬化保护自噬。此外，鉴于对这一问题的了解极其有限 巨噬细胞衍生的促分解脂质介质参与动脉粥样硬化，在此提出的研究是 准备提供对可用于治疗动脉粥样硬化的新方法的见解。如果富有成效，我们的发现 将揭示巨噬细胞内毒素在动脉粥样硬化中的原始作用，提供一类新的治疗策略 通过靶向epins，并开启了与抗击心脏病高度相关的研究的范式转变。

ABSTRACT Despite effective lipid-lowering therapies and prevention programs, atherosclerosis is still the leading cause of mortality in the United States. Among prominent risk factors, hardening of arteries resulting from endothelial cell activation and neointima hyperplasia plays a causative role in promoting atherogenicity. More importantly, in advanced atheroma, macrophage dysfunction causing excessive cell death is responsible for plaque rupture, consequential thrombosis, and ultimate stroke and myocardial infarction. However, owing to scarcity of proper molecular targets, it is widely recognized that hindering dysfunctional endothelium and macrophages to prevent atherosclerosis remains daunting. Our long-term goal is to uncover molecular mechanisms and identify fresh targets that prevent endothelial and macrophage dysfunction in hopes of offering potential new therapeutic approaches. To this end, our historical efforts have centered on examining the role of endothelial epsins in atherogenesis. In this application, we posit to explore the function of myeloid specific epsins in atherosclerosis owing to the fundamental contribution lesion macrophages make to fuel atherogenicity. The scientific premise for our aforesaid original research is in part established from an intriguing observation that epsins are upregulated in lesion macrophages. Therefore, understanding whether and how macrophage epsins critically contribute to the progression of atherosclerosis is urgently necessitated. We now create novel myeloid-specific epsins deficient mouse models and discover that myeloid-specific deficiency of epsins markedly inhibits western diet induced atherosclerosis in ApoE-/- mice. Further, epsins loss in macrophages dramatically impairs foam cell formation, hinders receptor-mediated oxLDL uptake, and perturbs actin-driven non-receptor mediated endocytosis. In parallel, loss of macrophage epsins results in elevated SR-B1, while diminished SR-B1 abrogates atheroprotective autophagy. Therefore, whether macrophage epsins inhibit autophagy by downregulating SR-B1 is an entirely novel question. To test, we propose to determine molecular mechanisms 1) by which epsins regulate lipid uptake during foam cell formation and 2) underlying epsin- mediated SR-BI degradation and autophagy attenuation in macrophages, and determine macrophage-derived pro-resolving lipid mediator biosynthesis. We anticipate that upon successful completion of the proposed studies, vast knowledge gained will advance the field encompassing how epsins regulate foam cell formation by controlling non-receptor and receptor-mediated lipid uptake, and how SR-B1 and epsins function opposingly to modulate atheroprotective autophagy in macrophages. Moreover, given extremely limited knowledge of the macrophage-derived pro-resolving lipid mediator involved in atherosclerosis, the study proposed herein is poised to provide insights into new means that can be exploited to treat atherosclerosis. If fruitful, our findings will uncover original roles for macrophage epsins in atherosclerosis, offer a new class of therapeutic strategies by targeting epsins, and inaugurate a paradigm shift in research highly relevant to fighting heart disease.