|Year : 2016 | Volume
| Issue : 3 | Page : 323-333
|Role of endothelin-1 in periodontal diseases: A structured review
Waleed Khalid, Sheeja S Vargheese, Reema Lakshmanan, M Sankari, ND Jayakumar
Department of Periodontics, Saveetha Dental College and Hospitals, Chennai, Tamil Nadu, India
Click here for correspondence address and email
|Date of Submission||20-Feb-2014|
|Date of Decision||18-Oct-2014|
|Date of Acceptance||27-May-2016|
|Date of Web Publication||13-Jul-2016|
| Abstract|| |
Background and Objective: Endothelin-1 (ET-1) is a 21-amino acid peptide and is a potent vasoconstrictor produced by endothelial cells. It plays a role in the development of diseases such as hypertension and atherosclerosis. Previous studies have identified ET-1 in gingival tissues obtained from patients affected by chronic periodontitis or gingival overgrowth. Thus, there is a need to appraise the role of ET-1 in periodontal disease.
Materials and Methods: The electronic search strategy included the databases such as PubMed, PubMed Central, LILACS, MEDLINE, ScienceDirect, MeSH, Cochrane database of systematic reviews, and EMBASE databases. Hand search of relevant journals was also carried out until September 2013. The included studies were both cross-sectional and longitudinal performed in vivo/in vitro, which measures the expression of ET-1 from various cells of the periodontium and in periodontal disease. Further, studies assessing the factors which influence ET-1 expression were included in the study.
Results: A total of 15 articles were found relevant and fulfilled the inclusion criteria posed in this review. Ten studies discussed the concentration of ET-1 in periodontal disease, whereas eight studies investigated the cells expressing ET-1. Nine studies assessed the factors influencing ET-1 expression and two studies evaluated the influence of ET-1 on inflammatory mediators and other cytokines. The results suggested that ET-1 is elevated in periodontal diseases and is influenced by inflammatory cytokines and periodontal pathogens.
Conclusion: ET-1 was found to have a role in periodontal disease, but further research will be required to substantiate its use as a biomarker.
Keywords: Chronic periodontitis, cytokines, gingival overgrowth, endothelin
|How to cite this article:|
Khalid W, Vargheese SS, Lakshmanan R, Sankari M, Jayakumar N D. Role of endothelin-1 in periodontal diseases: A structured review. Indian J Dent Res 2016;27:323-33
|How to cite this URL:|
Khalid W, Vargheese SS, Lakshmanan R, Sankari M, Jayakumar N D. Role of endothelin-1 in periodontal diseases: A structured review. Indian J Dent Res [serial online] 2016 [cited 2022 Jan 17];27:323-33. Available from: https://www.ijdr.in/text.asp?2016/27/3/323/186247
Endothelins were originally identified by Yangisawa in 1988. It is of three different subtypes which include endothelin-1 (ET-1), ET-2, and ET-3. ET-1 is the most common type seen in humans. It is composed of 21 amino acid residues and is a potent vasoconstrictor. It is mostly secreted by endothelial cells, epithelial cells, macrophages, smooth muscle cells, and fibroblasts. It is involved in a wide array of disease states such as atherosclerosis, hypertension, and inflammatory and sclerotic diseases.
Chronic periodontitis is a host-mediated inflammatory disease which is provoked by pathogenic microorganisms, and it is characterized by elevated levels of various cytokines and inflammatory mediators. Drug-induced gingival overgrowth can be encountered as a side effect in patients under long-term usage of drugs such as cyclosporine, phenytoin, and nifedipine., Studies have reported an expression of ET-1 in these periodontal conditions. Thus, there is a strong need to probe into the role of ET-1 in various periodontal diseases.
This structured review aims to evaluate the role of ET-1 in periodontal disease by addressing the following questions:
- What are the cells which express ET-1 in the periodontium?
- What is the influence of ET-1 on other cytokines and other inflammatory mediators in periodontal tissues?
- What are the levels of ET-1 in periodontal health and disease? With increasing severity of the disease, is there a concomitant increase in ET-1 levels?
- What are the factors influencing ET-1 expression in periodontal disease?
| Materials and Methods|| |
A comprehensive literature search for the structured question was performed using the keywords and MeSH terms provided in [Table 1] and [Table 2] in the following electronic databases until September 2013. No limits and language restriction were applied during the electronic search to obtain all the relevant articles pertaining to the review topic. In addition, a manual hand search for articles was carried out. The entire search strategy has been represented in Flowchart 1.
- PubMed Central
Cross-sectional and longitudinal studies which associated ET-1 and different types of periodontal diseases or disease severity were included in the study.
Clinical trials which correlate the levels of ET-1 before and after periodontal therapy were included in the study.
In vitro and in vivo studies (both human and animal) which evaluated or estimated the ET-1 expression in periodontal cells and periodontal disease were included in the study.
Studies which evaluated only endothelin-converting enzyme or endothelin receptor expression without measuring ET-1 levels were excluded from the study. Further, case reports were not included in this review.
The systematic search narrowed down to 25 articles from all the electronic databases based on the relevance of the title and abstract to the topic of interest. After assessing the full text, a total of 15 articles relevant to this review and satisfying the inclusion criteria were subjected to data extraction.
Data extraction was performed by two independent review authors. If there was disagreement on the inclusion of certain articles, a discussion was held to resolve it. In cases where a study did not report raw data but included precise graphical representations, the data were extracted. The articles were classified based on the levels of evidence given by the center of evidence-based medicine (available online at http://www.cebm.net/oxford-centre-evidence-based -medicine-levels-evidence-march-2009/).
| Results|| |
A total of 15 articles were selected based on the inclusion and exclusion criteria. The general information regarding the articles is given in [Table 3].
The level of evidence of the articles is given in [Table 4].
The excluded articles are given in [Table 5].
Cells which express endothelin-1 in the periodontium
Eight histochemistry-based studies evaluated the constituent cells of the periodontium for ET-1 expression. The ET-1 expression from fibroblasts was the most observed, with six studies ,,,,, showing expression by gingival and periodontal fibroblasts. Other cell types which express ET-1 include periodontal ligament cells,, epithelial cells,, vascular endothelial cells, and human gingival keratinocytes. Human gingival keratinocytes showed the strongest expression for ET-1 compared to fibroblasts and periodontal ligament cells.
Influence of endothelin-1 on inflammatory mediators and other cytokines
Two studies have evaluated the influence of ET-1 on inflammatory mediators and other cytokines. Onein vitro study has evaluated the relationship between ET-1 expression and proinflammatory cytokines such as interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and IL-6, where ET-1 increases the expression of the above-mentioned cytokines. Another PCR-based study has shown that ET-1 expression can upregulate the Il-1β mRNA and protein expression.
Endothelin-1 levels in periodontal disease
The concentration of ET-1 has been estimated in both human and animal studies. A total of ten studies have evaluated the levels of ET-1 in chronic periodontitis and drug-induced gingival overgrowth. Out of these, six human studies had shown increased levels of ET-1 in chronic periodontitis. Two studies showed increased ET-1 protein expression,, and four studies showed increased protein as well as mRNA expression.,,,
Studies by Yamamoto et al. and Ansai et al. assessed RNA and protein expression in the gingival samples of chronic periodontitis and healthy controls and found the elevated expression in the former. Studies by Lester et al., Rikimaru et al., and Chen et al. showed that in gingival samples of severely diseased periodontitis patients, the ET-1 levels were significantly higher than the slightly diseased or healthy groups. A similar study was conducted by Fujioka et al. where ET-1 protein expression were assessed in the gingival crevicular fluid (GCF) and arrived at similar results.
In one animal study, ligature-induced periodontitis model was found to show increased levels of ET-1 mRNA expression. The study in a ligature-induced periodontitis rat model by Ekuni et al. revealed a 2.2-fold increase in levels of endothelin-1 mRNA expression compared to healthy control groups in descending aorta samples.
One human study  and one animal study  showed that ET-1 protein and mRNA expression was upregulated in subjects with drug-induced gingival overgrowth. Tamilselvan et al. found that ET-1 mRNA expression was significantly higher in gingival samples of patients with cyclosporine-induced gingival overgrowth than in patients with periodontitis and healthy controls, whereas Chin et al. also arrived at similar results in established edentulous ridges of rats treated with cyclosporine than in controls.
One study reported that ET-1 was not detected in GCF samples in chronic periodontitis patients when compared with healthy controls.
Factors which may influence endothelin-1 expression in periodontal disease
A total of nine studies have studied about various factors that influence the ET-1 expression in periodontal disease condition. Porphyromonas gingivalis stimulates the production of ET-1 levels as seen in twoin vitro studies., Two human studies , and one animal study  reveal increased ET-1 mRNA concentration in cyclosporine-induced gingival overgrowth. One animal study reveals that ET-1 is upregulated in response to phenytoin and nifedipine.
Onein vitro study  has evaluated the effect of proinflammatory cytokines on ET-1 production which shows that IL-1β increases expression of ET-1 mRNA up to twice the control group in human gingival keratinocytes. TNF-α increases level of ET-1 mRNA expression at 1 h. Both cytokines increased ET-1 production in a time-dependent manner. The effect of mechanical stress on gingival fibroblasts proliferation has been evaluated in one human study  which shows increased ET-1 production from gingival fibroblasts in response to mechanical stress. The effect of nonsurgical treatment has also been evaluated in one human study. This study shows that ET-1 gene is downregulated in response to nonsurgical periodontal therapy.
| Discussion|| |
Endothelin-1 in periodontal health and disease
Increased ET-1 levels play a pivotal role in the pathogenesis of various diseases. It contributes to the development of vascular diseases such as hypertension  and atherosclerosis  through the activation of ETA receptors.
The concentration of ET-1 has been found to be elevated in both human and animal studies. The reasons for the elevated ET levels in diseased groups than the healthy groups can be attributed to various factors.
One among these factors could be due to P. gingivalis, a key pathogen causing chronic periodontitis. In the study by Awano et al., it has been found that a novel endopeptidase gene from P. gingivalis called as PgPepO was similar in structure and function with endothelin-converting enzyme-1 (ECE-1). The endothelin precursors or preproendothelins are cleaved by endopeptidases to form the biologically inactive intermediates termed as big ETs. ECE-1 is responsible for conversion of big ET-1, -2, and-3 to ET-1, -2, and -3, respectively. Similarly, anin vitro study by Ansai et al. showed upregulated mRNA expression of ET-1 on exposure to P. gingivalis strains. Cross-sectional studies by Yamamoto et al., Ansai et al., and Fujioka et al. also revealed an elevated ET-1 expression in diseased condition compared to healthy controls.
Elevated expression of proinflammatory cytokines in periodontitis may play a role in the expression of ET-1. Fujioka et al. found that the exposure of the cell lines with IL-1β and TNF-α enhanced the expression of ET-1 and its receptors. The results were concurrent with the study by Rikimaru et al., where a positive correlation existed between the concentrations of ET-1 and IL-1β in gingival tissues. The findings by Lester et al. also revealed a positive correlation between ET-1 and IL-6, IL-1β, TNF-α. Another study by Endo et al. found an upregulation of ET-1 as a result of IL-1, -6, and -8 in cultured porcine respiratory epithelial cells.
It has also been reported that certain anti-inflammatory cytokines play a role in the inhibition of ET-1 expression. The study by Lester et al. revealed a negative correlation of angiopoietin-1 (Ang-1) with ET-1 and gingival inflammation. A study by McCarter et al. suggested that the anti-inflammatory action of Ang-1 was key to the inhibition of ET-1 secretion, which dampened the proinflammatory cytokine synthesis.
Another anti-inflammatory cytokine which can play a role in the expression of ET-1 is nitric oxide (NO). In blood dynamics, the balance between NO and ET system is an important factor. NO has biologic function to inhibit ET levels. During periodontitis, it is seen that NO is relevantly increased; however, due to development of reiterative infection, the levels are much lower than ET levels and this leads to pathological changes. In the study by Chen et al., it was found that the expression of ET-1 was increased significantly in the gingiva of chronic periodontitis compared with healthy gingiva. This could be due to continuous relapsing inflammation which could stimulate endothelial cells to synthesize and release ET, causing a vessel constriction and injuring endothelial cells, causing a further increase in release of ET. This suggests the role ET plays in amplifying inflammation in chronic periodontitis.
Another factor influences that the expression of ET-1 is mechanical strain. In the study by Guo et al., mechanical strain was able to upregulate ET-1 expression in gingival fibroblasts which increased its proliferative capacity. They further assessed the synthesis of ET-1 between dermal and gingival fibroblasts. They concluded that the ET-1 synthesis was much lower in gingival compared to dermal fibroblasts, which explains the absence of scar formation in the oral cavity.
Out of all the studies included in this review, only one study showed no detection of ET-1 in GCF samples in healthy, gingivitis, and chronic periodontitis groups. The inability to detect ET-1 could be due to the rapid degradation by microbial- and host-derived proteases, short plasma half-life of 1.5 min, and a heterogeneous study population. Other reason was the absence of free form in the GCF due to the binding of ET-1 to its receptors in the gingival tissues.
Among the articles reviewed, two studies estimated the influence of ET-1 on inflammatory mediators and other cytokines. The study conducted by Rikimaru et al. demonstrated that the ET-1 in human periodontal ligament fibroblasts and human oral epithelial cell lines (KB cells) stimulated the IL-1β mRNA expression and protein release in a dose-dependent manner. Chronic periodontitis reflects an underlying constant inflammatory condition which is established by an ET-1-IL-1β inflammatory loop which is independent of the original stimulus. A similar model was suggested by Mullol et al. in nasal sinusitis, where an inflammatory loop was established, by interplay of ET-1 and IL-1 β. Another study by Li Liang et al. demonstrated that ET-1-induced proinflammatory cytokine such as TNF-α, IL-1β, and IL-6 expression acted via mitogen-activated protein kinase (MAPK) pathway signaling pathways. Extracellular signal-regulated protein kinase 1/2 inhibitor showed the pronounced reducing effects on TNF-α, IL-1β, and IL-6 expression, c-Jun N-terminal kinase inhibitor demonstrated the decreasing effect on TNF-α and IL-1β expression, whereas p38 inhibitor showed the reducing effects on IL-1 β and IL-6 expression. They collectively concluded that each cytokine acted via a specific variant of MAPK pathway.
In this structured review, one study assessed the influence of treatment on secretion of ET-1. Thomas Beiker et al. found that following periodontal therapy the proinflammatory cytokine profile fell within a normal healthy range, which led to a decreased expression of ET-1.
Endothelin-1 in drug-induced gingival overgrowth
Gingival overgrowth is observed in patients receiving cyclosporine, phenytoin, and nifedipine. It has been found that these drugs also play a role in elevating ET-1 levels during the pathogenesis of drug-induced gingival overgrowth. The structured review included four articles that showed elevated levels of ET-1 in drug-induced gingival overgrowth.
The effects of phenytoin and nifedipine have been studied in thein vitro study by Ohuchi et al. It has been found that above drugs can induce Ang-II and ET-1 secretion in cultured porcine gingival fibroblasts. Phenytoin and nifedipine prevent calcium accumulation in juxtaglomerular cells which in turn increase renin secretion. Renin mediates the conversion of angiotensinogen to Ang-I which in turn is converted to Ang-II by the action of angiotensin-converting enzyme. Ang-II acts as a potent hypertrophic agent and is known to stimulate ET-1 secretion from endothelial cells., This mechanism was substantiated by the results of latter part of Nozomi's study where they found an increased cell proliferation in fibroblast cultures when treated with Ang-II and ET-1. It has been shown by Yangisawa et al. that cyclosporine indirectly stimulated renin-angiotensin and thereby lead to an increase in ET-1 levels. It is also found that cyclosporine can indirectly induce the ET-1 stimulation by inducing the synthesis of Ang-II. This could be the direct mechanism by which ET-1 plays a role in the pathogenesis of drug-induced gingival overgrowth.
The second possible mechanism is through mast cell chymase as suggested by Toyoda et al. Mast cell chymase are elevated in drug-induced gingival overgrowth and tends to replace endothelin-converting enzyme which converts big ET to ET-1.
An indirect mechanism by which ET-1 is expressed in drug-induced gingival overgrowth is by the upregulation of proinflammatory cytokines as a result of P. gingivalis infection.
In the study by Chin et al., it was suggested that the mRNA expression of ET-1 presented a biphasic nature where increasing concentrations of cyclosporine, induced increased ET-1 expression up to a point after which it started to decrease. However, a clear reasoning for this effect has not been discussed.
Limitations and future implications
The major limitations posed in our structured review were that the unpublished research was not procured. Moreover, only published data from the articles were taken for analysis. Conversely, a more detailed understanding could have been possible had raw data been available. Finally, the search strategies did not extend to other databases which would have hampered the thoroughness of the review.
The available literature on ET-1 in periodontal disease is limited toin vitro and cross-sectional studies which are of lower levels of evidence. More number of long-term association and interventional studies is required to establish it as a diagnostic and prognostic marker for periodontal disease.
The present state and future implications of ET-1 in periodontal disease are given in [Table 6].
| Conclusion|| |
From this structured review, we can conclude that ET-1 plays a role in the pathogenesis of chronic periodontitis and drug-induced gingival overgrowth. However, further utilization of ET-1 as a marker requires additional interventional and longitudinal studies.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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Department of Periodontics, Saveetha Dental College and Hospitals, Chennai, Tamil Nadu
Source of Support: None, Conflict of Interest: None
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]
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