Understanding the Link Between Copper and Atherosclerosis
Atherosclerosis (AS) is a chronic inflammatory condition characterized by the accumulation of lipids and immune cells within arterial walls, leading to plaque formation and an increased risk of cardiovascular diseases. While many factors contribute to AS, recent research has shed light on the role of copper, an essential trace element, in its development.
Copper is involved in numerous physiological processes, including mitochondrial respiration, oxidative stress regulation, and angiogenesis. However, excessive copper accumulation can lead to cellular toxicity, promoting oxidative damage and inflammation—both of which are critical factors in AS progression. A newly recognized form of cell death, termed cuproptosis, has emerged as a potential mechanism through which copper may contribute to AS.
What Is Cuproptosis?
Unlike apoptosis or necrosis, cuproptosis is a copper-dependent cell death mechanism. Intracellular copper binds to proteins involved in the tricarboxylic acid (TCA) cycle, causing protein aggregation. This leads to mitochondrial dysfunction and ultimately results in cell death. This process is distinct from other cell death pathways, such as ferroptosis or necroptosis, and highlights the importance of copper homeostasis in cellular health.
The identification of cuproptosis as a regulated form of cell death provides new insights into its biological significance. This discovery highlights how excessive copper levels might contribute to vascular damage and AS progression.
How Cuproptosis Contributes to Atherosclerosis
Several mechanisms may explain the role of cuproptosis in AS development:
- Oxidative Stress and Mitochondrial Dysfunction
Copper is a redox-active metal, meaning it can participate in oxidative reactions. When copper accumulates excessively, it generates reactive oxygen species (ROS) through the Fenton reaction, leading to oxidative damage to lipids, proteins, and DNA. This oxidative stress is a well-known contributor to AS, as it promotes endothelial dysfunction and plaque instability. - Inflammation and Immune Activation
Elevated copper levels have been shown to activate inflammatory pathways, such as the NF-κB signaling cascade, which triggers the release of pro-inflammatory cytokines. This can lead to increased recruitment of immune cells to the arterial walls, further promoting plaque formation. - Disruption of Lipid Metabolism
Research suggests that copper influences cholesterol metabolism, affecting low-density lipoprotein (LDL) oxidation and uptake by macrophages. The resulting foam cell formation accelerates plaque development, making it a key process in AS progression. - Endothelial and Smooth Muscle Cell Dysfunction
Endothelial cells, which form the inner lining of blood vessels, are particularly sensitive to oxidative stress. Excess copper can impair endothelial function, reduce nitric oxide (NO) availability, and promote vascular smooth muscle cell proliferation. These factors contribute to atherosclerosis (AS).
Given these multiple pathways, cuproptosis represents a promising target for novel therapeutic strategies aimed at preventing or slowing AS progression.
Potential Biomarkers and Therapeutic Targets
Identifying cuproptosis-related genes may provide new diagnostic and treatment approaches for AS. Recent studies have identified several key cuproptosis-related biomarkers:
- Ferredoxin 1 (FDX1): A key regulator of cuproptosis that mediates copper-induced cell death.
- Solute Carrier Family 31 Member 1 (SLC31A1): A copper transporter that contributes to intracellular copper uptake.
- Glutaminase (GLS): Involved in mitigating oxidative stress and protecting cells from copper toxicity.
By studying these biomarkers, researchers aim to develop early diagnostic tools for AS, enabling timely intervention before severe cardiovascular events occur.
Targeting Cuproptosis for Atherosclerosis Treatment
Several therapeutic approaches are being explored to regulate copper levels and mitigate the effects of cuproptosis in AS:
- Copper Chelation Therapy
Agents such as tetrathiomolybdate (TTM) have been shown to lower bioavailable copper and reduce vascular inflammation, making them promising candidates for AS treatment. - Copper Ionophores
These compounds selectively transport copper into cells, potentially reducing toxic effects. However, their clinical application requires further investigation to ensure safety and specificity. - Small-Molecule Inhibitors of Copper Chaperones
Targeting copper-binding proteins, such as antioxidant copper chaperone 1 (ATOX1), may help regulate intracellular copper levels while minimizing side effects. - Nanomedicine-Based Copper Homeostasis Regulators
Advances in nanotechnology have enabled the development of targeted copper-regulating therapies. For example, curcumin-based nanoparticles have been investigated for their ability to chelate excess copper and reduce oxidative stress.
Future Directions and Challenges
While cuproptosis presents a promising avenue for understanding and treating AS, several challenges remain:
- Lack of Specific Biomarkers: Further research is needed to validate cuproptosis-related biomarkers and establish their clinical relevance.
- Mechanistic Uncertainty: The precise molecular interactions between cuproptosis, oxidative stress, and lipid metabolism in AS require more in-depth exploration.
- Therapeutic Safety: Strategies targeting copper metabolism must ensure that essential copper-dependent biological functions are not disrupted.
The translation of the preceding English text in Chinese:
理解铜与动脉粥样硬化的关系
动脉粥样硬化（AS）是一种慢性炎症性疾病，其特征是脂质和免疫细胞在动脉壁内积聚，形成斑块，并增加心血管疾病的风险。虽然许多因素会影响 AS 的发生，但最新研究揭示了铜这种必需微量元素在 AS 发展中的作用。
铜参与多种生理过程，包括线粒体呼吸、氧化应激调节和血管生成。然而，铜的过度积累可能导致细胞毒性，促进氧化损伤和炎症，而这两者都是 AS 进展的关键因素。近期，研究发现了一种新的细胞死亡方式——铜死亡（cuproptosis），这可能是铜促进 AS 发展的重要机制。
什么是铜死亡（Cuproptosis）？
铜死亡不同于细胞凋亡（apoptosis）或坏死（necrosis），它是一种依赖铜的细胞死亡机制。当细胞内铜与三羧酸（TCA）循环相关蛋白结合时，会导致蛋白聚集、线粒体功能障碍，并最终导致细胞死亡。铜死亡的过程与铁死亡（ferroptosis）或程序性坏死（necroptosis）不同，突出了铜稳态在细胞健康中的重要性。
铜死亡被鉴定为一种受调控的细胞死亡形式，为铜水平过高如何导致血管损伤和 AS 进展提供了新的见解。
铜死亡如何促进动脉粥样硬化？
铜死亡可能通过以下几种机制影响 AS 发展：
-
氧化应激与线粒体功能障碍
铜是一种具有氧化还原活性的金属，能够参与氧化反应。当铜积累过多时，它可以通过 Fenton 反应生成活性氧（ROS），从而对脂质、蛋白质和 DNA 造成氧化损伤。氧化应激已被证明是 AS 的主要诱因之一，因为它会导致内皮功能障碍并降低斑块稳定性。 -
炎症与免疫激活
研究表明，铜水平升高会激活炎症信号通路，如 NF-κB 信号通路，进而促进促炎细胞因子的释放。这种炎症反应会增加免疫细胞在动脉壁的聚集，进一步加速斑块形成。 -
脂质代谢紊乱
研究显示，铜会影响胆固醇代谢，促进低密度脂蛋白（LDL）的氧化和巨噬细胞的吞噬作用。这种泡沫细胞的形成是 AS 进展的关键过程。 -
内皮细胞与血管平滑肌细胞功能障碍
血管内皮细胞对氧化应激非常敏感。铜过量可能损害内皮功能，减少一氧化氮（NO）的可用性，并促进血管平滑肌细胞的增殖，这些因素都会加重 AS。
鉴于这些机制，铜死亡可能成为防治 AS 的新型靶点。
可能的生物标志物与治疗靶点
鉴定铜死亡相关基因可能为 AS 的诊断和治疗提供新的策略。近期研究发现了一些关键的铜死亡相关生物标志物：
- 铁氧还蛋白 1（FDX1）：铜死亡的关键调控因子，参与铜诱导的细胞死亡。
- 溶质载体家族 31 成员 1（SLC31A1）：负责细胞内铜摄取的转运蛋白。
- 谷氨酰胺酶（GLS）：在缓解氧化应激和保护细胞免受铜毒性方面发挥作用。
通过研究这些生物标志物，科学家希望开发出 AS 早期诊断工具，以便在严重心血管事件发生前进行干预。
针对铜死亡的动脉粥样硬化治疗策略
目前，研究人员正在探索多种方法来调节铜水平并缓解 AS 相关的铜死亡：
-
铜螯合治疗
如四硫钼酸盐（TTM）等药物可降低生物可利用的铜水平，并减少血管炎症，是 AS 治疗的潜在候选药物。 -
铜离子载体（Copper Ionophores）
这些化合物能够选择性地将铜运输到细胞内，可能减少其毒性作用。然而，该类药物的临床应用仍需进一步研究，以确保安全性和特异性。 -
铜伴侣蛋白的小分子抑制剂
针对铜结合蛋白（如抗氧化铜伴侣 1，ATOX1）的抑制剂可能有助于调节细胞内铜水平，同时减少副作用。 -
基于纳米医学的铜稳态调节
纳米技术的进步使得靶向铜调节治疗成为可能。例如，基于姜黄素的纳米颗粒已被研究用于螯合过量铜并减少氧化应激。
未来方向与挑战
虽然铜死亡为理解和治疗 AS 提供了新的视角，但仍面临多个挑战：
- 缺乏特异性生物标志物：需要进一步研究来验证铜死亡相关生物标志物的临床意义。
- 机制尚不完全明确：铜死亡、氧化应激和脂质代谢之间的具体相互作用仍需深入探索。
- 治疗安全性问题：针对铜代谢的治疗策略必须确保不影响必需的铜依赖性生物过程。
随着对铜死亡及其在 AS 中作用的深入研究，未来有望开发出更加精准和有效的治疗方法，以改善动脉粥样硬化患者的预后。
Reference:
Jiankang Wang, Zhian Chen, Hang Shang, Jiajuan Guo
The molecular mechanisms of cuproptosis and its relevance to atherosclerosis
Biomol Biomed [Internet]. 2025 Jan. 15 [cited 2025 Feb. 21];
Available from: https://www.bjbms.org/ojs/index.php/bjbms/article/view/11826
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