Development of atherosclerosis involves chronic and sustained inflammation and oxidative stress. Recent studies have linked atherosclerosis to the innate immune system. Genetic deficiency in myeloid differentiation primary-response protein 88 (MyD88) protects against the development and progression of atherosclerosis. However, it is unknown if pharmacological inhibition of MyD88 is able to be a therapeutic strategy for this disease. In this study, we evaluated the effect of a newly synthesized small-molecule inhibitor of MyD88, LM9, in an ApoE^−/− mouse model of atherosclerosis. Our results showed that the major source of MyD88 in atherosclerotic lesions is infiltrated macrophage. Treatment of HFD-fed ApoE^−/− mice with LM9 significantly attenuated the pathogenesis of atherosclerosis, accompanied with reduced vascular inflammatory responses and oxidative stress. These effects were achieved without changes to serum lipid levels. We further showed that LM9 inhibited oxidized-lipoprotein induced foam cell formation through suppression of MyD88 and inflammatory pathway in macrophages. Additionally, either LM9 treatment or MyD88 knockdown prevented ox-LDL-induced oxidative stress in macrophages. This study highlights the translational role of MyD88 as a therapeutic target and identifies the MyD88 inhibitor LM9 as a new candidate for the treatment of atherosclerosis.

动脉粥样硬化的发展涉及慢性和持续性炎症和氧化应激。最近的研究已将动脉粥样硬化与先天免疫系统联系起来。髓样分化初级应答蛋白88（MyD88）的遗传缺陷可防止动脉粥样硬化的发生和发展。但是，尚不清楚MyD88的药理学抑制作用是否能够成为该疾病的治疗策略。在这项研究中，我们评估了一种新合成的MyD88小分子抑制剂LM9在动脉粥样硬化的ApoE ^-/-小鼠模型中的作用。我们的结果表明，动脉粥样硬化病变中MyD88的主要来源是浸润的巨噬细胞。HFD喂养的ApoE的治疗^-/-LM9小鼠明显减轻了动脉粥样硬化的发病机理，并伴有血管炎性反应和氧化应激的降低。在不改变血清脂质水平的情况下实现了这些效果。我们进一步表明，LM9通过抑制MyD88和巨噬细胞的炎症途径来抑制氧化脂蛋白诱导的泡沫细胞形成。此外，LM9处理或MyD88抑制均可防止巨噬细胞中ox-LDL诱导的氧化应激。这项研究突出了MyD88作为治疗靶点的翻译作用，并将MyD88抑制剂LM9鉴定为治疗动脉粥样硬化的新候选者。