OBJECTIVE Intraplaque neovascularization is an important feature of unstable human atherosclerotic plaques. However, its impact on plaque formation and stability is poorly studied. Because proliferating endothelial cells generate up to 85% of their ATP from glycolysis, we investigated whether pharmacological inhibition of glycolytic flux by the small-molecule 3PO (3-[3-pyridinyl]-1-[4-pyridinyl]-2-propen-1-one) could have beneficial effects on plaque formation and composition. Approach and Results: ApoE-/- (apolipoprotein E deficient) mice treated with 3PO (50 µg/g, ip; 4×/wk, 4 weeks) showed a metabolic switch toward ketone body formation. Treatment of ApoE-/-Fbn1C1039G+/- mice with 3PO (50 µg/g, ip) either after 4 (preventive, twice/wk, 10 weeks) or 16 weeks of Western diet (curative, 4×/wk, 4 weeks) inhibited intraplaque neovascularization by 50% and 38%, respectively. Plaque formation was significantly reduced in all 3PO-treated animals. This effect was independent of intraplaque neovascularization. In vitro experiments showed that 3PO favors an anti-inflammatory M2 macrophage subtype and suppresses an M1 proinflammatory phenotype. Moreover, 3PO induced autophagy, which in turn impaired NF-κB (nuclear factor-kappa B) signaling and inhibited TNF-α (tumor necrosis factor-alpha)-mediated VCAM-1 (vascular cell adhesion molecule-1) and ICAM-1 (intercellular adhesion molecule-1) upregulation. Consistently, a preventive 3PO regimen reduced endothelial VCAM-1 expression in vivo. Furthermore, 3PO improved cardiac function in ApoE-/-Fbn1C1039G+/- mice after 10 weeks of treatment. CONCLUSIONS Partial inhibition of glycolysis restrained intraplaque angiogenesis without affecting plaque composition. However, less plaques were formed, which was accompanied by downregulation of endothelial adhesion molecules-an event that depends on autophagy induction. Inhibition of coronary plaque formation by 3PO resulted in an overall improved cardiac function.

中文翻译：

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部分抑制糖酵解可减少小鼠动脉粥样硬化，与斑块内新血管形成无关。

目的 斑块内新生血管形成是不稳定的人类动脉粥样硬化斑块的一个重要特征。然而，其对牙菌斑形成和稳定性的影响却鲜有研究。由于增殖的内皮细胞通过糖酵解产生高达 85% 的 ATP，因此我们研究了小分子 3PO (3-[3-吡啶基]-1-[4-吡啶基]-2-丙烯- 1-一）可能对牙菌斑的形成和组成产生有益的影响。方法和结果：用 3PO（50 µg/g，腹腔注射；4 次/周，4 周）治疗的 ApoE-/-（载脂蛋白 E 缺陷）小鼠显示出向酮体形成的代谢转变。在西方饮食 4 周（预防性，每周两次，10 周）或 16 周（治疗性，4 次/周，4 周）后，用 3PO（50 µg/g，腹腔注射）治疗 ApoE-/-Fbn1C1039G+/- 小鼠分别抑制斑块内新血管形成 50% 和 38%。所有 3PO 处理的动物中斑块形成均显着减少。该效应与斑块内新血管形成无关。体外实验表明，3PO 有利于抗炎 M2 巨噬细胞亚型并抑制 M1 促炎表型。此外，3PO 诱导自噬，进而损害 NF-κB（核因子-κ B）信号传导并抑制 TNF-α（肿瘤坏死因子-α）介导的 VCAM-1（血管细胞粘附分子-1）和 ICAM-1 （细胞间粘附分子-1）上调。一致地，预防性 3PO 方案减少了体内内皮 VCAM-1 的表达。此外，治疗 10 周后，3PO 改善了 ApoE-/-Fbn1C1039G+/- 小鼠的心脏功能。结论 部分抑制糖酵解可抑制斑块内血管生成，而不影响斑块组成。然而，形成的斑块较少，并伴随着内皮粘附分子的下调——这一事件取决于自噬诱导。3PO 对冠状动脉斑块形成的抑制导致心脏功能的整体改善。