Rationale: Atherosclerotic cardiovascular diseases (ACVDs) are the leading cause of mortality worldwide. ACVDs are considered as chronic inflammation processes. In addition to risk factors associated with the cardiovascular system itself, pathogenic bacteria such as the periodontitis-associated Porphyromonas gingivalis (P. gingivalis) are also closely correlated with the development of atherosclerosis, but the underlying mechanisms are still elusive. Objective: To elucidate the mechanisms of P. gingivalis-accelerated atherosclerosis and explore novel therapeutic strategies of ACVDs. Methods and Results: Bmal1-/- mice, ApoE-/- mice, Bmal1-/-ApoE-/- mice, conditional endothelial cell Bmal1 knockout mice (Bmal1fl/fl; Tek-Cre mice), and the corresponding jet-legged mouse model were used. P. gingivalis accelerates atherosclerosis progression by triggering arterial oxidative stress and inflammatory responses in ApoE-/- mice, accompanied by the perturbed circadian clock. Circadian clock disruption boosts P. gingivalis-induced atherosclerosis progression. The mechanistic dissection shows that P. gingivalis infection activates the TLRs-NF-κB signaling axis, which subsequently recruits DNMT-1 to methylate the BMAL1 promoter and thus suppresses BMAL1 transcription. The downregulation of BMAL1 releases CLOCK, which phosphorylates p65 and further enhances NF-κB signaling, elevating oxidative stress and inflammatory response in human aortic endothelial cells. Besides, the mouse model exhibits that joint administration of metronidazole and melatonin serves as an effective strategy for treating ACVDs. Conclusions: P. gingivalis accelerates atherosclerosis via the NF-κB-BMAL1-NF-κB signaling loop. Melatonin and metronidazole are promising auxiliary medications toward ACVDs.

中文翻译：

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BMAL1下调通过鼓励氧化应激加剧了牙龈卟啉单胞菌引起的动脉粥样硬化。

理由：动脉粥样硬化性心血管疾病（ACVD）是全球死亡的主要原因。ACVD被认为是慢性炎症过程。除了与心血管系统本身相关的危险因素外，诸如牙周炎相关的牙龈卟啉单胞菌（P. gingivalis）等致病细菌也与动脉粥样硬化的发展密切相关，但其潜在机制仍难以捉摸。目的：阐明牙龈卟啉单胞菌加速动脉粥样硬化的机制，并探索新的ACVD治疗策略。方法和结果：Bmal1-/-小鼠，ApoE-/-小鼠，Bmal1-/-ApoE-/-小鼠，条件性内皮细胞Bmal1敲除小鼠（Bmal1fl / fl； Tek-Cre小鼠）和相应的有腿小腿小鼠模型。P. 牙龈炎通过触发ApoE-/-小鼠的动脉氧化应激和炎症反应，并伴随着昼夜节律的紊乱，从而加速了动脉粥样硬化的发展。昼夜节律紊乱促进了牙龈卟啉单胞菌引起的动脉粥样硬化进展。机械解剖显示牙龈卟啉单胞菌感染激活TLRs-NF-κB信号转导轴，随后募集DNMT-1使BMAL1启动子甲基化，从而抑制BMAL1转录。BMAL1的下调释放了CLOCK，CLOCK磷酸化了p65，并进一步增强了NF-κB信号传导，从而提高了人主动脉内皮细胞的氧化应激和炎症反应。此外，小鼠模型显示甲硝唑和褪黑激素的联合给药是治疗ACVD的有效策略。结论：P．牙龈炎通过NF-κB-BMAL1-NF-κB信号传导回路促进动脉粥样硬化。褪黑激素和甲硝唑有望成为ACVD的辅助药物。