2. Academic Validation
  3. BMAL1-Downregulation Aggravates Porphyromonas Gingivalis-Induced Atherosclerosis by Encouraging Oxidative Stress

BMAL1-Downregulation Aggravates Porphyromonas Gingivalis-Induced Atherosclerosis by Encouraging Oxidative Stress

  • Circ Res. 2020 Mar 13;126(6):e15-e29. doi: 10.1161/CIRCRESAHA.119.315502.
Mengru Xie 1 2,  Qingming Tang 1 2,  Jiaming Nie 1 2,  Chao Zhang 3,  Xin Zhou 1 2,  Shaoling Yu 1 2,  Jiwei Sun 1 2,  Xiang Cheng 4,  Nianguo Dong 3,  Yu Hu 5,  Lili Chen 1 2
Affiliations

Affiliations

  • 1 From the Department of Stomatology (M.X., Q.T., J.N., X.Z., S.Y., J.S., L.C.), Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 2 Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, China (M.X., Q.T., J.N., X.Z., S.Y., J.S., L.C.).
  • 3 Department of Cardiovascular Surgery (C.Z., N.D.), Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 4 Department of Cardiology (X.C.), Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 5 Institute of Hematology (Y.H.), Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
PMID: 32078488 DOI: 10.1161/CIRCRESAHA.119.315502
Abstract

Rationale: Atherosclerotic cardiovascular diseases are the leading cause of mortality worldwide. Atherosclerotic cardiovascular diseases 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 atherosclerotic cardiovascular diseases.

Methods and results: Bmal1-/- (brain and muscle Arnt-like protein 1) 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. Pgingivalis 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 atherosclerotic cardiovascular diseases.

Conclusions: P gingivalis accelerates atherosclerosis via the NF-κB-BMAL1-NF-κB signaling loop. Melatonin and metronidazole are promising auxiliary medications toward atherosclerotic cardiovascular diseases.

Keywords

NF-kappa B signaling; Porphyromonas gingivalis; atherosclerosis; circadian rhythm; oxidative stress.

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