Macrophage proliferation, the engine of plaque progression

巨噬细胞是动脉粥样硬化病变中最丰富的细胞类型。它们摄取脂蛋白，产生炎症介质和金属蛋白酶，刺激斑块生长和不稳定。这导致心绞痛，并最终在斑块破裂和冠状动脉闭塞后发生心肌梗死。巨噬细胞在动脉粥样硬化的发病机制中起关键作用，如实验研究所证明的，其中单核细胞耗竭和单核细胞募集（病变巨噬细胞的祖细胞）的抑制减少斑块形成。这确立了斑块生长和病变巨噬细胞积聚依赖于持续的单核细胞募集和分化的流行概念。然而，申请人在最近的一项研究中挑战了这种范式，他在波士顿的博士后奖学金。它表明，随着疾病的进展，斑块巨噬细胞积累变得越来越直接依赖于局部巨噬细胞增殖，而不是单核细胞募集。这一新发现提出了许多关于斑块进展的有趣和重要的问题。所有的病变巨噬细胞都同样增殖吗？增殖的巨噬细胞对斑块炎症的特殊贡献是什么？控制病变巨噬细胞增殖的因素是什么？直接或间接抑制巨噬细胞增殖是否会减缓甚至逆转斑块的发展？巨噬细胞增殖在其他心血管疾病中的作用是什么？下面的研究方案整合了小鼠模型和人类样本分析来解决这些问题。揭示心血管疾病中巨噬细胞增殖的病理机制对于开发世界头号死亡原因急需的新治疗策略至关重要。

Macrophages are the most abundant cell type in atherosclerotic lesions. They ingest lipoproteins and produce inflammatory mediators and metalloproteinases that stimulate plaque growth and destabilization. This leads to angina pectoris and ultimately myocardial infarction after plaque rupture and coronary artery occlusion. Macrophages play a key role in the pathogenesis of atherosclerosis as evidenced by experimental studies in which monocyte depletion and inhibition of monocyte recruitment, the progenitor cells of lesional macrophages, reduced plaque formation. This established the prevailing concept that plaque growth and lesional macrophage accumulation depend on continuous monocyte recruitment and differentiation. The applicant challenged, however, this paradigm in a recent study from his postdoctoral fellowship in Boston. It shows that with disease progression plaque macrophage accumulation becomes increasingly and directly dependent on local macrophage proliferation rather then monocyte recruitment. This novel finding raises many interesting and important questions regarding plaque progression. Do all lesional macrophages proliferate equally? What is the particular contribution of proliferating macrophages to plaque inflammation? What are the factors that control lesional macrophage proliferation? Will direct or indirect inhibition of macrophage proliferation slow or even revert plaque development? What is the role of macrophage proliferation in other cardiovascular diseases? The following research proposal integrates mouse models and human sample analyses to address these questions. Uncovering the pathomechanisms of macrophage proliferation in cardiovascular disease is crucial for developing much needed novel therapeutic strategies for the number one cause of death in the world.