Cen Kuan, Huang YinFei, Xie Yu, Zhang Renwei, Cai Qi, Zou Li, Xiang Qiaoyuan, Yang Chunjiao, Liu YuMin
Department of Neurology, Zhongnan Hospital Affiliated to Wuhan University, Wuhan 430000, China.
Department of Neurology, Zhongnan Hospital Affiliated to Wuhan University, Wuhan 430000, China.
Phytomedicine. 2025 Jun 19;145:157014. doi: 10.1016/j.phymed.2025.157014.
The leakage of vasa vasorum (VV) and intraplaque hemorrhage (IPH) pose significant risk for the instability and rupture of atherosclerosis (AS) plaques. The development of novel herbal monomers for anti-AS therapy has emerged as an increasingly promising strategy in combating cardiovascular diseases and stroke, which are frequently triggered by the rupture of vulnerable plaques.
This study aimed to explore the protective effects of theaflavin-3,3'-digallate (TFDG) on plaque stability and its underlying mechanisms in preventing IPH through promoting VV maturation.
A carotid vulnerable plaque mouse model was established via tandem stenosis surgery. Non-targeted metabolomics and proteomics were integrated to identify the metabolic targets of TFDG. Molecular docking, co-immunoprecipitation, and western blotting were employed to elucidate the interactions within the HK2/TIGAR/MAPK pathway. Additionally, the expression levels of inflammatory cytokines and the energy metabolism status associated with metabolic reprogramming were evaluated.
TFDG significantly modulated key serum inflammatory cytokines (IL-6, IL-1β, MCP-1, IL-4, NO) and lipid profiles (LDL, TC, HDL, TG), while suppressing AS plaque formation in Apoe mice. Quantitative analysis revealed that TFDG treatment increased fibrous cap thickness by 9.78 µm (p = 0.0085) and reduced lipid core size by 21% (p = 0.0004). Furthermore, TFDG improved the organization of the vascular lumen, restored pericyte synaptic function, and increased pericyte coverage by 8.42% (p < 0.001), while concomitantly decreasing pericyte apoptosis. These effects collectively reduced the incidence of IPH from 56.25% to 26.67%, thereby enhancing plaque stability. At the molecular level, TFDG downregulated HK2 expression and rebalanced the dynamics between glycolysis and OXPHOS through the TIGAR/p38/JNK signaling axis, thereby shifting VV metabolism toward a low-energy state. This mechanism consequently inhibited excessive pathological vascular sprouting and promoted a 24% increase in pericyte quiescence and adhesion (p = 0.0037), ultimately stabilizing the microvascular network architecture within plaques. While focusing on male mice adheres to standard protocols for AS modeling, future investigations should explicitly address potential sex differences in disease progression.
This study demonstrates that TFDG effectively inhibits AS progression via the HK2/TIGAR/MAPK axis, specifically by promoting the maturation of VV within plaques to reduce the incidence of IPH. The findings suggest that TFDG exhibits substantial potential for preventing acute cardiovascular and cerebrovascular events. The results provide promising directions and preliminary experimental evidence for future research aimed at preventing vulnerable plaque rupture.
血管滋养血管（VV）渗漏和斑块内出血（IPH）对动脉粥样硬化（AS）斑块的不稳定和破裂构成重大风险。开发新型抗AS治疗的草药单体已成为对抗心血管疾病和中风的一种越来越有前景的策略，这些疾病常由易损斑块破裂引发。
本研究旨在探讨茶黄素-3,3'-双没食子酸酯（TFDG）对斑块稳定性的保护作用及其通过促进VV成熟预防IPH的潜在机制。
通过串联狭窄手术建立颈动脉易损斑块小鼠模型。整合非靶向代谢组学和蛋白质组学以鉴定TFDG的代谢靶点。采用分子对接、免疫共沉淀和蛋白质印迹法阐明HK2/TIGAR/MAPK途径内的相互作用。此外，评估与代谢重编程相关的炎性细胞因子表达水平和能量代谢状态。
TFDG显著调节关键血清炎性细胞因子（IL-6、IL-1β、MCP-1、IL-4、NO）和血脂谱（LDL、TC、HDL、TG），同时抑制Apoe小鼠的AS斑块形成。定量分析显示，TFDG治疗使纤维帽厚度增加9.78 µm（p = 0.0085），脂质核心大小减少21%（p = 0.0004）。此外，TFDG改善血管腔的组织结构，恢复周细胞突触功能，并使周细胞覆盖率增加8.42%（p < 0.001），同时减少周细胞凋亡。这些作用共同将IPH的发生率从56.25%降至26.67%，从而增强斑块稳定性。在分子水平上，TFDG下调HK2表达，并通过TIGAR/p38/JNK信号轴重新平衡糖酵解和氧化磷酸化之间的动态平衡，从而使VV代谢向低能量状态转变。该机制因此抑制过度的病理性血管芽生，并促进周细胞静止和黏附增加24%（p = 0.0037），最终稳定斑块内的微血管网络结构。虽然专注于雄性小鼠符合AS建模的标准方案，但未来的研究应明确解决疾病进展中潜在的性别差异。
本研究表明，TFDG通过HK2/TIGAR/MAPK轴有效抑制AS进展，特别是通过促进斑块内VV成熟以降低IPH的发生率。研究结果表明，TFDG在预防急性心脑血管事件方面具有巨大潜力。这些结果为未来旨在预防易损斑块破裂的研究提供了有希望的方向和初步实验证据。
