Th1‐type immune responses to Porphyromonas gingivalis antigens exacerbate angiotensin II‐dependent hypertension and vascular dysfunction

Abstract

Background and Purpose Emerging evidence indicates that hypertension is mediated by immune mechanisms. We hypothesized that exposure to Porphyromonas gingivalis antigens, commonly encountered in periodontal disease, can enhance immune activation in hypertension and exacerbate the elevation in BP, vascular inflammation and vascular dysfunction. Experimental Approach Th1 immune responses were elicited through immunizations using P. gingivalis lysate antigens (10 μg) conjugated with aluminium oxide (50 μg) and IL‐12 (1 μg). The hypertension and vascular endothelial dysfunction evoked by subpressor doses of angiotensin II (0.25 mg·kg−1·day−1) were studied, and vascular inflammation was quantified by flow cytometry and real‐time PCR. Key Results Systemic T‐cell activation, a characteristic of hypertension, was exacerbated by P. gingivalis antigen stimulation. This translated into increased aortic vascular inflammation with enhanced leukocyte, in particular, T‐cell and macrophage infiltration. The expression of the Th1 cytokines, IFN‐γ and TNF‐α, and the transcription factor, TBX21, was increased in aortas of P. gingivalis/IL‐12/aluminium oxide‐immunized mice, while IL‐4 and TGF‐β were unchanged. These immune changes in mice with induced T‐helper‐type 1 immune responses were associated with an enhanced elevation of BP and endothelial dysfunction compared with control mice in response to 2 week infusion of a subpressor dose of angiotensin II. Conclusions and Implications These results support the concept that Th1 immune responses induced by bacterial antigens such as P. gingivalis can increase sensitivity to subpressor pro‐hypertensive insults such as low‐dose angiotensin II, thus providing a mechanistic link between chronic infection, such as periodontitis, and hypertension. Linked Articles This article is part of a themed section on Immune Targets in Hypertension. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.12/issuetoc

Association between Periodontitis and High Blood Pressure: Results from the Study of Periodontal Health in Almada-Seixal (SoPHiAS)

“…Additionally, T and B lymphocytes, as well as monocytes/macrophages, are primed in an inflamed periodontium increasing the risk for vascular dysfunction, hypertension and atherosclerosis [63,64]. Furthermore, Porphyromonas gingivalis has been recently loomed to trigger an immune reaction, enhancing the sensitivity to pro-hypertensive factors such as low-dose angiotensin II [25]. Importantly, it has been proven that treating severe periodontitis reduces systemic inflammation levels and improves endothelial function [43,65,66].…”

“…Similarly, epidemiological and limited interventional studies worldwide have observed an association between periodontitis and hypertension [18,22]. Periodontitis-related low-grade systemic inflammation could be at the basis of this association as already linked to vascular stiffness and dysfunction, which could, in turn, contribute to an increased systemic vascular resistance leading to hypertension [23][24][25]. Recent evidence highlighted the role of periodontal bacteria in atherosclerosis and vascular dysfunction [26,27].…”

Porphyromonas gingivalis and Its Systemic Impact: Current Status

“…This evidence preliminarily confirms the role of periodontitis in hypertension. Furthermore, in vivo studies have shown that intraperitoneal injection of P. gingivalis exacerbated the hypertensive response to angiotensin II in mice [ 60 ], suggesting an adverse effect of P. gingivalis on hypertension.…”

“…It was shown that repeated exposure of live P. gingivalis or bacteria LPS induced the release of pro-inflammatory CKs and angiotensin II in human coronary artery endothelial cells, together with P. gingivalis -associated mediators of systemic inflammation (such as CRP, IL-6, TNF-α), contributing to both endothelial dysfunction and the development of arterial hypertension [ 61 ]. Recently, an animal study supported the hypothesis that the Th1 immune response induced by P. gingivalis antigens is response for elevated BP [ 60 ]. Moreover, P. gingivalis can induce high expression of endothelial cell adhesion molecules, platelet aggregation, and SMC proliferation, thus impairing vasomotor function [ 33 , 34 , 42 ].…”

Causal association between periodontitis and hypertension: evidence from Mendelian randomization and a randomized controlled trial of non-surgical periodontal therapy

“…Because of this, it is imperative to establish if periodontitis can cause hypertension. Our group has recently shown that immune activation induced by a keystone periodontal pathogen ( Porphyromonas gingivalis ) promotes the development of hypertension in mice 13 . Small interventional studies concluded that intensive periodontal therapy may lead to BP reduction, although sufficiently powered evidence in well-defined hypertensive cohorts is lacking 12 …”