Telmisartan Prevents Alveolar Bone Loss by Decreasing the Expression of Osteoclasts Markers in Hypertensive Rats With Periodontal Disease.

Victor Gustavo Balera Brito,Mariana Sousa Patrocinio,Vanessa Lara,Carlos Ferreira Santos,Maria Carolina Linjardi,Ayná Emanuelli Alves Barreto,Sabrina Ct Frasnelli,Sandra Helena Penha Oliveira

doi:10.3389/fphar.2020.579926

Victor Gustavo Balera Brito, Mariana Sousa Patrocinio + Show 6 more

Open Access

https://doi.org/10.3389/fphar.2020.579926

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Abstract

Periodontal disease (PD) is a prevalent inflammatory disease with the most severe consequence being the loss of the alveolar bone and teeth. We therefore aimed to evaluate the effects of telmisartan (TELM), an angiotensin II type 1 receptor (Agtr1) antagonist, on the PD-induced alveolar bone loss, in Wistar (W) and Spontaneous Hypertensive Rats (SHRs). PD was induced by ligating the lower first molars with silk, and 10 mg/kg TELM was concomitantly administered for 15 days. The hemimandibles were subjected to microtomography, ELISA was used for detecting tumor necrosis factor (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), CXCL3, and CCL2, while qRT-PCR was used for analyzing expression of components of renin-angiotensin system (RAS) (Agt, Ace, Agt1r, Agt2r, Ace2, and Masr), and bone markers (Runx2, Osx, Catnb, Alp, Col1a1, Opn, Ocn, Bsp, Bmp2, Trap, Rank, Rankl, CtsK, Mmp-2, Mmp-9, and osteoclast-associated receptor (Oscar)). The SHR + PD group showed greater alveolar bone loss than the W + PD group, what was significantly inhibited by treatment with TELM, especially in the SHR group. Additionally, TELM reduced the production of TNF-α, IL-1β, and CXCL3 in the SHR group. The expression of Agt increased in the groups with PD, while Agtr2 reduced, and TELM reduced the expression of Agtr1 and increased the expression of Agtr2, in W and SHRs. PD did not induce major changes in the expression of bone formation markers, except for the expression of Alp, which decreased in the PD groups. The bone resorption markers expression, Mmp9, Ctsk, and Vtn, was higher in the SHR + PD group, compared to the respective control and W + PD group. However, TELM attenuated these changes and increased the expression of Runx2 and Alp. Our study suggested that TELM has a protective effect on the progression of PD, especially in hypertensive animals, as evaluated by the resorption of the lower alveolar bone. This can be partly explained by the modulation in the expression of Angiotensin II receptors (AT1R and AT2R), reduced production of inflammatory mediators, the reduced expression of resorption markers, and the increased expression of the bone formation markers.

Highlights

Periodontal disease (PD) is the most prevalent inflammatory disease worldwide, affecting the structures that support the teeth, including the gingiva, periodontal ligament, and alveolar bone (Pihlstrom et al, 2005)
The present study results demonstrated that the AT1R blocker, TELM, had a protective effect on PD-induced inflammation and alveolar bone loss in hypertensive animals by decreasing the production of cytokines and reducing the expression of osteoclast markers in hypertensive animals
The Spontaneous Hypertensive Rats (SHRs) strain is known to present alterations in the systemic renin-angiotensin system (RAS) (Schiffrin et al, 1984; Ohta et al, 1996; Gouldsborough et al, 2003) as well as intrinsic bone impairment associated with the hypertensive genotype and phenotype (Manrique et al, 2012; Landim de Barros et al, 2016; Tiyasatkulkovit et al, 2019)

Summary

Introduction

Periodontal disease (PD) is the most prevalent inflammatory disease worldwide, affecting the structures that support the teeth, including the gingiva, periodontal ligament, and alveolar bone (Pihlstrom et al, 2005). The progression of PD depends on microbial virulence, and on the inflammatory response of the host, which plays a major role in tissue disruption. Comorbidities, such as hypertension, can significantly affect disease severity by increasing the inflammatory burden of the host, inducing alterations such as increased oxidative stress, causing endothelial dysfunction, and activating the renin-angiotensin system (RAS) (Paizan and Vilela-Martin, 2014). The major effects of Ang II, including vasoconstriction, oxidative stress, increased blood pressure, and increased inflammation, are mediated via the type 1 receptor (At1r) (Paul et al, 2006; Capettini et al, 2012). They have opposing effects on At1r signaling, which are mediated via counterregulatory mechanisms (Simões e Silva et al, 2013)

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