BACKGROUND:Atherosclerosis, a leading cause of cardiovascular disease, involves the pathological activation of various cell types, including immunocytes (eg, macrophages and T cells), smooth muscle cells (SMCs), and endothelial cells. Accumulating evidence suggests that transition of SMCs to other cell types, known as phenotypic switching, plays a central role in atherosclerosis development and complications. However, the characteristics of SMC-derived cells and the underlying mechanisms of SMC transition in disease pathogenesis remain poorly understood. Our objective is to characterize tumor cell–like behaviors of SMC-derived cells in atherosclerosis, with the ultimate goal of developing interventions targeting SMC transition for the prevention and treatment of atherosclerosis.METHODS:We used SMC lineage tracing mice and human tissues and applied a range of methods, including molecular, cellular, histological, computational, human genetics, and pharmacological approaches, to investigate the features of SMC-derived cells in atherosclerosis.RESULTS:SMC-derived cells in mouse and human atherosclerosis exhibit multiple tumor cell–like characteristics, including genomic instability, evasion of senescence, hyperproliferation, resistance to cell death, invasiveness, and activation of comprehensive cancer-associated gene regulatory networks. Specific expression of the oncogenic mutant Kras^G12D in SMCs accelerates phenotypic switching and exacerbates atherosclerosis. Furthermore, we provide proof of concept that niraparib, an anticancer drug targeting DNA damage repair, attenuates atherosclerosis progression and induces regression of lesions in advanced disease in mouse models.CONCLUSIONS:Our findings demonstrate that atherosclerosis is an SMC-driven tumor-like disease, advancing our understanding of its pathogenesis and opening prospects for innovative precision molecular strategies aimed at preventing and treating atherosclerotic cardiovascular disease.

中文翻译：

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动脉粥样硬化是一种平滑肌细胞驱动的肿瘤样疾病

背景：动脉粥样硬化是心血管疾病的主要原因，涉及多种细胞类型的病理激活，包括免疫细胞（例如巨噬细胞和T细胞）、平滑肌细胞（SMC）和内皮细胞。越来越多的证据表明，平滑肌细胞向其他细胞类型的转变（称为表型转换）在动脉粥样硬化的发展和并发症中发挥着核心作用。然而，人们对 SMC 衍生细胞的特征以及 SMC 转变在疾病发病机制中的潜在机制仍知之甚少。我们的目标是表征动脉粥样硬化中 SMC 衍生细胞的肿瘤细胞样行为，最终目标是开发针对 SMC 转变的干预措施，以预防和治疗动脉粥样硬化。 方法：我们使用 SMC 谱系追踪小鼠和人体组织，并应用一系列方法，包括分子、细胞、组织学、计算、人类遗传学和药理学方法，研究动脉粥样硬化中 SMC 衍生细胞的特征。 结果：小鼠和人类动脉粥样硬化中的 SMC 衍生细胞表现出多种肿瘤细胞样特征，包括基因组不稳定性、逃避衰老、过度增殖、抵抗细胞死亡、侵袭性以及与癌症相关的综合基因调控网络的激活。 SMC 中致癌突变体Kras ^G12D的特异性表达会加速表型转换并加剧动脉粥样硬化。此外，我们还提供了概念证明，即尼拉帕尼（一种靶向 DNA 损伤修复的抗癌药物）可以在小鼠模型中减缓动脉粥样硬化进展并诱导晚期疾病病变消退。结论：我们的研究结果表明，动脉粥样硬化是一种 SMC 驱动的肿瘤样疾病，增进我们对其发病机制的理解，并为旨在预防和治疗动脉粥样硬化性心血管疾病的创新精准分子策略开辟前景。