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

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 ( Bmal1 fl/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 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.

Porphyromonas gingivalis and Its Systemic Impact: Current Status

“…Periodontal treatment has been shown to improve the endothelial function and reduce the biomarkers (such as CRP, IL-6, TNF-α, fibrinogen, triglycerides) of atherosclerotic disease, particularly in individuals already suffering from CVDs [ 29 ]. Trials in humans have found P. gingivalis in clinical samples at a detection rate of 82.61% by fluorescent in situ hybridization assay [ 30 ]. Subsequently, in vivo experiments confirmed the promoting effect of P. gingivalis on AS.…”

“…Subsequently, in vivo experiments confirmed the promoting effect of P. gingivalis on AS. Infection with P. gingivalis exacerbated atherogenesis in apolipoprotein E (ApoE)-deficient mice [ 2 , 30 ], and the proximal aortic lesion size in P. gingivalis -inoculated mice was 2-fold larger than that in control mice [ 2 ]. These results strongly suggest that P. gingivalis may enter the lesion area and promote the development of AS.…”

“…This is an essential step in the pathogenesis of endothelial dysfunction. In recently published research, it was revealed that P. gingivalis enhanced oxidative stress and the inflammatory response in aortic endothelial cells via the NF-κB-BMAL1-NF-κB signaling loop, leading to the aggravation of AS [ 30 ]. Furthermore, P. gingivalis can induce procoagulant effects in endothelial cells, and this prothrombotic response may be associated with plaque progression and instability [ 34 ].…”

Circadian rhythm and atherosclerosis (Review)

“…The levels of immune inflammatory immunoreactive cells and pro-inflammatory cytokines have an obvious daily rhythm ( 80 ) and functionality of the immune system has been linked to the circadian clock ( 81 ). A recent study reported that circadian disruption by sleep fragmentation accelerates atherosclerosis development by increasing the number of circulating monocytes ( 82 ).…”

A Novel Insight at Atherogenesis: The Role of Microbiome

“…Rhythmic oscillations of gut microbiota were observed in diabetic mice as well as analysis of circulating metabolites showed changes in the daily concentration of metabolites of the histidine pathway and the metabolism of betaine, methionine, cysteine, followed by an increase in TMAO production ( Beli et al, 2019 ). Moreover, in the study of atherosclerosis, associated with infection of P orphyromonas gingivalis that causes periodontitis, circadian clock disruption enhanced atherosclerosis progression in Bmal1−/− ApoE−/− mice ( Xie et al, 2020 ). Despite of a number of studies on the influence of circadian rhythms on atherogenesis and the composition of gut microbiome and its metabolites, the mechanism of the influence of diurnal variations in the microbiome on the development of atherosclerosis is still an actual topic for research in the near future.…”