Inhibition of angiotensin II receptor I prevents inflammation and bone loss in periodontitis

Li, Jinle; Xiao, Xincai; Wei, Wei; Ding, Hong; Yue, Yuan; Tian, Ye; Nabar, Neel R.; Liu, Zhaohui; Zheng, Yang; Wang, Min

doi:10.1002/jper.17-0753

Cited by 10 publications

(14 citation statements)

References 52 publications

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“…Our previous and current results showed that Ang II increased in lesion area (Appendix Fig. 7A) and augmented the inflammatory response both in vivo and in vitro (Li et al 2019). We also analyzed the LPS receptor (TLR4) and Ang II receptor (AT1R) in vivo.…”

Section: Discussionsupporting

confidence: 57%

“…Four-week-old Nos3 -/- mice were acquired from the Model Animal Research Center of Nanjing University for mating and breeding; these mice showed spontaneous hypertension (de Jonge et al 2002; Li et al 2004) and upregulation of Ang II (Li et al 2019). Eight-week-old female mice were divided into 8 groups for the experiment:…”

Section: Methodsmentioning

confidence: 99%

“…In our previous study, we successfully established a Nos3 knockout ( Nos3 -/- )–related hypertension mouse model with periodontitis and showed that Nos3 -/- mice, which have higher blood pressure and Ang II expression as compared with wild-type mice, can greatly aggravate periodontal bone destruction (Li et al 2019). As hypertension is associated with immunity and inflammation (Agita and Alsagaff 2017) and Ang II plays an important role in the course of hypertension, we hypothesized that Ang II and its downstream STAT1 pathway may play an active role in periodontitis.…”

Section: Introductionmentioning

confidence: 99%

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Activation of the STAT1 Pathway Accelerates Periodontitis inNos3^-/-Mice

Wei

Xiao

et al. 2019

J Dent Res

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Early studies on the etiology and pathogenesis of hypertension have shown that it has a considerable association with inflammation and the immune response as well as periodontitis. Clinical studies have also shown that hypertension can promote the periodontal tissue destruction caused by periodontitis. However, the underlying mechanisms remain unclear. This study aimed to explore the possible mechanisms of how hypertension aggravates periodontitis. Treatment with or without the signal transducer and activator of transcription 1 (STAT1) inhibitor fludarabine was performed in an endothelial nitric oxide synthase gene knockout-related ( Nos3-/-) mouse model with the hypertension phenotype of periodontitis induced by bacteria. Micro–computed tomography, immunohistochemistry, Western blot, quantitative reverse transcription polymerase chain reaction, immunofluorescence, and ELISA were performed. We demonstrated that Nos3-/--related hypertension increases bone resorption and periodontal destruction in periodontitis lesion areas, which can be inhibited by the STAT1 inhibitor. Experimental data also showed that Nos3-/- significantly increased macrophage infiltration and proinflammatory cytokine expression in the periodontitis lesion area, which is dependent on the angiotensin II–induced STAT1 pathway. Inhibition of STAT1 in vivo can decrease the expression of proinflammatory cytokines and macrophage infiltration. Furthermore, data in this study showed that Nos3-/--related hypertension further downregulated the STAT3 anti-inflammatory function and its downstream chemokine expression in a STAT1-dependent manner. By applying RAW 264.7 and L929 cell lines and monocytes isolated from Nos3-/- mice, we confirmed that activation of the STAT1 pathway inhibits STAT3 and its downstream pathway and promotes inflammatory cytokine expression in vitro. Collectively, our current study demonstrated that STAT1 plays an indispensable role in the Nos3-/--related hypertension with aggravation of periodontitis, suggesting that STAT1 may be a key target for the treatment of periodontitis with hypertension.

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Section: Discussionsupporting

confidence: 57%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Activation of the STAT1 Pathway Accelerates Periodontitis inNos3^-/-Mice

Wei

Xiao

et al. 2019

J Dent Res

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“…Many of these metabolites are known to be increased in the circulation of tobacco smokers and also involved in periodontal disease development. 31,32 Further, pentosidine, a marker of advance glycation end products, was higher in the ENDS user group (3.19 fold) (Table 2). Advanced glycation end products are known to be involved in tobacco-induced inflammation and the development of periodontal disease.…”

Section: Resultsmentioning

confidence: 98%

Electronic nicotine delivery system-induced alterations in oral health via saliva assessment

Alqahtani

Cooper

Spears

et al. 2020

Exp Biol Med (Maywood)

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Use of electronic nicotine delivery systems (ENDS) is becoming increasingly prevalent. ENDS aerosols contain a variety of toxic components that may adversely impact health. Although exposure to traditional cigarette smoke is a risk factor for periodontal disease, the effects of ENDS on oral health have not been adequately examined. To evaluate potential oral health effects associated with ENDS use, a pilot study was performed with 14 current ENDS users and 16 never tobacco users. Participants completed questionnaires about their ENDS use and overall health. Saliva samples were assessed for differential biomarkers of inflammation, toxicity, and disease development. This included evaluation of specific inflammatory cytokines and the global assessment of alterations in metabolites. ENDS users were determined to have elevated saliva levels of interleukin-1β and tumor necrosis factor-α indicative of inflammation. Metabolite profiling determined 368 metabolites were differentially expressed in the saliva of ENDS users versus never tobacco users. Cotinine, the primary metabolite of nicotine, was the most significantly altered metabolite between the groups. Increased levels of prostaglandins and leukotrienes indicated that ENDS users exhibited increased arachidonic acid metabolism compared to never tobacco users. Additionally, a variety of other metabolites known to be involved in immune signaling such as gangliosides, ceramides, angiotensin, and others were also different between groups. Overall, our pilot study demonstrates differential saliva component profiles in current ENDS users, which may contribute to periodontal disease development. These alterations suggest specific pathways of oral disease induced by ENDS use and could be utilized as potential future biomarkers. Impact statement The use of traditional tobacco products is a known risk factor for the development of diseases including periodontal disease. To date, the potential oral health effects related to electronic nicotine delivery systems (ENDS) use is unknown. This study collected saliva from ENDS users and never tobacco users to examine differences in the oral cavity of inflammatory cytokines and metabolites. The identification and measurement of these ENDS-related changes provide insight into disease pathways potentially associated with ENDS use. The utilization of saliva samples collected from human participates enhances the application of the findings compared to the majority of studies using cell culture and animal models. In addition, these foundational findings can inform future studies to examining specific pathways identified, interventional approaches, and application of translatable biomarkers of ENDS use.

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“…Moreover, recent studies have shown that RAS blockers are able to reduce the inflammation and, therefore, decrease the expression of matrix metalloproteinases (MMPs) in RANK/RANKL axis and cathepsin K in a rat model of PD (Araújo et al, 2013). Furthermore, our knowledge about this concept is growing due to increase in the number of studies that have described treatment of mice with ACE inhibitor preventing bone loss Gonçalves-Zillo et al (2013), the protective effect of ACE inhibitors in PD-induced and arthritis-associated alveolar bone loss (Queiroz-Junior et al, 2015), and the mechanism by which AT1R inhibitor prevents inflammation and alveolar bone loss in periodontitis (Li et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Aliskiren Attenuates the Inflammatory Response and Wound Healing Process in Diabetic Mice With Periodontal Disease

et al. 2019

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The aim of this study was to characterize the role of local RAS (renin–angiotensin system) in the inflammatory response of normal (N) and diabetic (D) mice with periodontal disease (PD). Diabetes Mellitus (DM) was induced by peritoneal injection of streptozotocin in Balb/c mice. PD was induced by ligature around the first molar in both N and D, irrespective of whether they were treated with aliskiren (50 mg/kg, Alisk). Mandibles were harvested for histomorphometric analyses, and gingival tissue (GT) was collected to evaluate gene expression and extracellular matrix components (ECM). Immunohistochemical (IHC) analyses were used to localize RAS in GT. The production of C-reactive protein (CRP), IL-1β, CXCL2, and CCL8 was evaluated by enzyme-linked immunosorbent assay (ELISA). Renin was found to exacerbate the inflammation and periodontal bone loss at 14 days after PD, and Alisk inhibited this process in GT of N and D. PD increased CRP, CXCL2, CCL8, and IL-1β production in both animals. Alisk could inhibit CRP, CXCL2, and CCL8 primarily in D animals. However, only CCL8 was decreased in N animals after Alisk pretreatment. PD enhanced expression and production of AGT, ACE, AT1R, and AT2R in both N and D. AT1R expression was higher in D with PD, and AT2R expression was higher in N with PD. ACE2 and receptor Mas (MasR) expression and production was elevated in the control group of both animals. PD inhibited ACE2 in N but not in D. MasR expression was unaffected in both N and D with PD. Alisk reduced expression and production of all RAS components in GT of both animals, except for ACE2 in N. RAS staining was observed in all layers of epithelium, basal cell layer, and lamina propria and was higher in N with PD. Col1a1, Col1a2, Col3a1, and fibronectin (Fn1) were increased in both animals with PD. Alisk inhibited Col1a1 and Fn in both animals, Col1a2 was decreased only in D, while levels of Col3a1 remained unchanged in all animal groups. In conclusion, these data demonstrated the presence and functional role of local RAS in GT, exacerbating the inflammatory response, periodontal bone loss, and wound healing processes in both N and D animal groups. In addition, Alisk was able to significantly reduce gingival inflammation, excessive wound healing processes, and periodontal bone loss.

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Inhibition of angiotensin II receptor I prevents inflammation and bone loss in periodontitis

Abstract: Our studies show a central role for Ang II as a pro-inflammatory Toll-like receptor mediator in the pathogenesis of PH-exacerbated periodontitis, indicating that Ang II may be a reasonable target in patients with PH and periodontitis comorbidity.

Cited by 10 publications

References 52 publications

Activation of the STAT1 Pathway Accelerates Periodontitis inNos3^-/-Mice

Activation of the STAT1 Pathway Accelerates Periodontitis inNos3^-/-Mice

Electronic nicotine delivery system-induced alterations in oral health via saliva assessment

Aliskiren Attenuates the Inflammatory Response and Wound Healing Process in Diabetic Mice With Periodontal Disease

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Inhibition of angiotensin II receptor I prevents inflammation and bone loss in periodontitis

Abstract: Our studies show a central role for Ang II as a pro-inflammatory Toll-like receptor mediator in the pathogenesis of PH-exacerbated periodontitis, indicating that Ang II may be a reasonable target in patients with PH and periodontitis comorbidity.

Cited by 10 publications

References 52 publications

Activation of the STAT1 Pathway Accelerates Periodontitis inNos3-/-Mice

Activation of the STAT1 Pathway Accelerates Periodontitis inNos3-/-Mice

Electronic nicotine delivery system-induced alterations in oral health via saliva assessment

Aliskiren Attenuates the Inflammatory Response and Wound Healing Process in Diabetic Mice With Periodontal Disease

Contact Info

Product

Resources

About

Activation of the STAT1 Pathway Accelerates Periodontitis inNos3^-/-Mice

Activation of the STAT1 Pathway Accelerates Periodontitis inNos3^-/-Mice