Wang Chaonan, Feng Yuyao, Liu Xiaoyan, Sun Haidan, Guo Zhengguang, Shao Jiang, Li Kang, Chen Junye, Shu Keqiang, Kong Deqiang, Wang Jiaxian, Li Yiran, Lei Xiangling, Li Chen, Liu Bao, Sun Wei, Lai Zhichao
Department of Hemangiomas & Vascular Malformations, Plastic Surgery Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
Department of Vascular Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Shuaifuyuan 1, Dongcheng District, Beijing, 100730, China.
BMC Med. 2025 May 1;23(1):254. doi: 10.1186/s12916-025-04058-2.
Atherosclerosis is a major contributor to cardiovascular diseases worldwide. Despite advancements in understanding its pathology, significant gaps remain in the molecular characterization of atherosclerotic plaques. This study addresses this gap by extensively profiling the proteomic landscape of carotid atherosclerotic plaques, classified under the American Heart Association (AHA) types IV to VI, to identify potential biomarkers and therapeutic targets.
The study employed an integrated approach using data-independent acquisition (DIA) proteomics, single-cell RNA sequencing, and Mendelian randomization (MR). A total of 87 human carotid plaques were analyzed to identify and quantify protein expression. These proteins were then mapped to specific regions within the plaques, such as the fibrous cap and lipid core, and further validated in independent samples and single-cell datasets. Furthermore, Mendelian randomization techniques were employed to assess causal relationships between identified proteins levels and ischemic stroke.
The proteomic analysis of the 87 carotid plaques revealed 6143 proteins, highlighting diverse expression profiles across different plaque stages. Notably, proteins like CD44 and GAL-1 were predominantly expressed in the fibrous cap, suggesting a role in plaque stability, while TREM2, SMAD3, and IL-6R showed higher expression in the lipid core, indicating involvement in inflammatory processes. These findings were further corroborated by single-cell RNA sequencing, revealing cell-specific expression patterns that align with the observed proteomic data. Additionally, MR analysis indicated the causal role of IL6R, CD44, and SMAD3 in ischemic stroke.
This study provides valuable insights into the progression of atherosclerotic plaques, identifying key proteins that could serve as potential biomarkers and therapeutic targets. It enhances our molecular understanding of atherosclerosis and opens up new avenues for treatment. Additionally, our study demonstrates the accuracy and robustness of proteomics in prioritizing genes associated with plaque-related traits.
动脉粥样硬化是全球心血管疾病的主要成因。尽管在理解其病理方面取得了进展，但在动脉粥样硬化斑块的分子特征方面仍存在重大差距。本研究通过广泛分析美国心脏协会（AHA）IV至VI型颈动脉粥样硬化斑块的蛋白质组图谱，以识别潜在的生物标志物和治疗靶点，从而填补这一差距。
该研究采用了一种综合方法，结合数据非依赖采集（DIA）蛋白质组学、单细胞RNA测序和孟德尔随机化（MR）。共分析了87个人类颈动脉斑块，以识别和量化蛋白质表达。然后将这些蛋白质定位到斑块内的特定区域，如纤维帽和脂质核心，并在独立样本和单细胞数据集中进一步验证。此外，采用孟德尔随机化技术评估已识别蛋白质水平与缺血性中风之间的因果关系。
对87个颈动脉斑块的蛋白质组分析揭示了6143种蛋白质，突出了不同斑块阶段的多样表达谱。值得注意的是，CD44和GAL-1等蛋白质主要在纤维帽中表达，表明其在斑块稳定性中发挥作用，而TREM2、SMAD3和IL-6R在脂质核心中表达较高，表明其参与炎症过程。单细胞RNA测序进一步证实了这些发现，揭示了与观察到的蛋白质组数据一致的细胞特异性表达模式。此外，MR分析表明IL6R、CD44和SMAD3在缺血性中风中具有因果作用。
本研究为动脉粥样硬化斑块的进展提供了有价值的见解，识别出可作为潜在生物标志物和治疗靶点的关键蛋白质。它增强了我们对动脉粥样硬化的分子理解，并开辟了新的治疗途径。此外，我们的研究证明了蛋白质组学在确定与斑块相关特征的基因优先级方面的准确性和稳健性。
