背景：银屑病（Psoriasis）是一种常见的、慢性、非传染性疾病。全球患病人数超过1.25亿人。近年来的研究表明，银屑病不仅局限于皮肤，更是一种全身性炎症性疾病，能够影响多个器官系统，尤其是心血管系统。大量临床研究证据显示，银屑病的严重程度与心血管疾病的发生风险显著相关，并且改善银屑病皮损可在一定程度上减少冠状动脉粥样斑块的形成。然而，银屑病在动脉粥样硬化发生和进展中的确切的分子机制仍未完全阐明，其潜在的炎症通路和免疫机制有待进一步深入研究。

目的：本研究旨在探讨血小板碱性蛋白（Pro-platelet basic protein, PPBP）对银屑病动脉粥样硬化共病的影响并深入挖掘PPBP介导动脉粥样硬化的分子机制，为预防和治疗银屑病心血管共病提供依据。

方法：

1.PPBP的表达：转录组测序及qRT-PCR验证PPBP在银屑病患者脂肪组织中表达情况。ELISA检测PPBP在外周血表达。在咪喹莫特 (imiquimod, IMQ) 诱导的银屑病样炎症小鼠模型中进一步验证。

2.PPBP在银屑病中的作用：用IMQ在WT及Ppbp敲除小鼠背部皮肤诱导炎症以评估PPBP在银屑病样炎症因子网络中的定位，PASI评分、H&E染色、免疫荧光评估严重程度。

3.银屑病样炎症与动脉粥样硬化：在ApoE⁻/⁻小鼠中诱导银屑病样炎症，通过qRT-PCR、透射电镜、油红O、H&E、Masson、免疫荧光染色等评估对动脉粥样硬化斑块的影响。

4.PPBP与动脉粥样硬化：在ApoE⁻/⁻小鼠中注射PPBP蛋白，构建ApoE^-/-Ppbp^-/-和ApoE^-/-小鼠，IMQ诱导银屑病样炎症，评估各因素对动脉粥样硬化斑块的影响（方法同3）。

5.PPBP致动脉粥样硬化的机制：PPBP蛋白处理人冠状动脉内皮细胞，通过ROS检测试剂盒检测ROS表达，联合mito-Tracker、流式细胞仪、WB、OCR、ECAR、透射电镜等探索ROS的来源。通过转录组学方法筛选PPBP致主动脉内皮细胞损伤的分子，并验证其生物学机制。

6.拮抗PPBP或调控ROS的干预效果：通过系统使用PPBP中和抗体以及氧化应激调节剂mito-TEMPO，探究这些干预措施对银屑病炎症相关动脉粥样硬化的疗效（方法同3）。

结果：

1.PPBP的表达及对银屑病的作用：银屑病患者皮损区的脂肪组织中PPBP表达显著上调且高表达于CD68⁺CD14⁺巨噬细胞中。PPBP在银屑病患者外周血中表达升高。银屑病皮损中GM-CSF通过GM-CSF/P38 MAPK信号通路诱导PPBP合成。Ppbp缺失缓解小鼠银屑病样炎症。

2.PPBP与动脉粥样硬化：ApoE⁻/⁻小鼠中，IMQ诱导或Ppbp注射均加重动脉粥样硬化，表现为斑块及坏死核心面积增大，巨噬细胞浸润增加，敲除Ppbp可以逆转上述表型。

3.PPBP诱导人冠状动脉内皮细胞损伤：PPBP通过抑制ZNG1F表达，导致线粒体电子传递链复合物成分表达下调， ROS释放，线粒体膜电位下调，氧化磷酸化及糖酵解功能被抑制，引起线粒体氧化应激，线粒体棘断裂及线粒体肿胀，最终导致主动脉内皮细胞氧化应激相关功能障碍。

4.拮抗PPBP或调节氧化应激缓解动脉粥样硬化：PPBP中和抗体、氧化应激调节剂mito-TEMPO均能显著缓解银屑病样炎症相关动脉粥样硬化。

结论：PPBP通过诱导动脉内皮细胞线粒体氧化应激损伤，推动银屑病动脉粥样硬化共病的发展，可能成为预测银屑病动脉粥样硬化共病风险的潜在生物标志物，本研究为银屑病合并动脉粥样硬化的靶向治疗提供了新的研究方向。

Background: Psoriasis is a common, chronic, non-infectious disease affecting more than 125 million people worldwide. Recent studies have shown that psoriasis is not merely a skin disorder but a systemic inflammatory disease that can affect multiple organ systems, particularly the cardiovascular system. Substantial clinical evidence suggests a significant correlation between the severity of psoriasis and the risk of cardiovascular disease. Moreover, improving psoriatic lesions may reduce the formation of coronary atherosclerotic plaques to some extent. However, the exact molecular mechanisms by which psoriasis contributes to the onset and progression of atherosclerosis remain unclear, and the underlying inflammatory pathways and immune mechanisms require further investigation.

Objective: This study aims to investigate the role of pro-platelet basic protein (PPBP) in psoriasis-associated atherosclerosis and to explore the molecular mechanisms by which PPBP mediates the development of atherosclerosis, providing potential insights for the prevention and treatment of cardiovascular comorbidities in psoriasis.

Methods:

1. Expression of PPBP: Transcriptomic sequencing and qRT-PCR were used to determine PPBP expression in adipose tissues from psoriasis patients. ELISA was performed to measure PPBP levels in peripheral blood. An imiquimod (IMQ)-induced psoriasiform inflammation mouse model was used for further validation.

2. Role of PPBP in Psoriasis: IMQ was applied to the dorsal skin of wild-type and Ppbp⁻/⁻ mice to induce inflammation and assess the involvement of PPBP in the psoriatic inflammatory network. Disease severity was evaluated using PASI scoring, H&E staining, and immunofluorescence.

3. Psoriasiform Inflammation and Atherosclerosis: Psoriasiform inflammation was induced in ApoE⁻/⁻ mice. The effects on atherosclerotic plaque formation were assessed using qRT-PCR, transmission electron microscopy, Oil Red O staining, H&E, Masson staining, and immunofluorescence.

4. PPBP and Atherosclerosis: PPBP protein was injected into ApoE⁻/⁻ mice. ApoE⁻/⁻Ppbp⁻/⁻ mice were also used. IMQ was applied to induce psoriasiform inflammation, and the effects on atherosclerotic plaque development were evaluated as in method 3.

5. Mechanism of PPBP-Induced Atherosclerosis: Human coronary artery endothelial cells were treated with recombinant PPBP protein. ROS levels were measured using detection kits. Combined with MitoTracker staining, flow cytometry, Western blotting, oxygen consumption rate (OCR), extracellular acidification rate (ECAR), and transmission electron microscopy, the source of ROS and mitochondrial alterations were explored. Transcriptomic analysis was used to identify PPBP-induced molecular changes and verify related mechanisms of endothelial injury.

6. Intervention with PPBP Neutralization or ROS Modulation: The therapeutic effects of systemic administration of a PPBP-neutralizing antibody and the mitochondrial oxidative stress modulator mito-TEMPO were evaluated in the context of psoriasis-related atherosclerosis (methods as in 3).

Results:

1. PPBP Expression and Role in Psoriasis: PPBP expression was significantly upregulated in adipose tissues from psoriatic lesions, predominantly in CD68⁺CD14⁺ macrophages. PPBP levels were also elevated in the peripheral blood of psoriasis patients. GM-CSF in psoriatic lesions promoted PPBP expression via the GM-CSF/p38 MAPK signaling pathway. Genetic deletion of Ppbp alleviated psoriasiform inflammation in mice.

2. PPBP and Atherosclerosis: In ApoE⁻/⁻ mice, both IMQ-induced inflammation and exogenous PPBP administration exacerbated atherosclerosis, as evidenced by increased plaque and necrotic core areas and enhanced macrophage infiltration. These effects were reversed by Ppbp deletion.

3. PPBP-Induced Endothelial Injury: PPBP downregulated ZNG1F expression in human coronary artery endothelial cells, leading to decreased expression of mitochondrial electron transport chain components, increased ROS production, mitochondrial membrane potential loss, impaired oxidative phosphorylation and glycolysis, mitochondrial fragmentation, and swelling—ultimately causing ROS-dependent endothelial dysfunction.

4. Therapeutic Effects of PPBP Neutralization or ROS Regulation: Both the PPBP-neutralizing antibody and mito-TEMPO significantly mitigated psoriasis-related atherosclerosis.

Conclusion: PPBP promotes the comorbidity of psoriasis and atherosclerosis by inducing mitochondrial oxidative stress and endothelial injury. It may serve as a potential biomarker for predicting atherosclerotic risk in psoriasis and offers a novel target for therapeutic intervention in psoriasis-associated cardiovascular diseases.