The Lipopolysaccharide-Induced Up-Regulation of Bradykinin B2-Receptor in the Mouse Heart Is Mediated by Tumor Necrosis Factor-.ALPHA. and Angiotensin II

Abstract

Lipopolysaccharide (LPS) is one of the most potent and widely studied signal molecules involved in the initiation of septic shock. LPS activates multiple cells to release cytokines (such as tumor necrosis factor (TNF)-a, interleukin (IL)-1b, IL-6, interferon-g), nitric oxide (NO), metabolites of arachidonic acid, platelet-activating factor, and kinins. 1,2) These mediators contribute to the subsequent cellular responses, including increased vascular permeability, the generation of toxic oxygen metabolites, the generation of microthrombi, systemic hypotension, and organ failure.3)The presence and functional relevance of the kallikreinkinin system in the heart are firmly established. 4) Kinins, liberated by kallikrein from substrate kininogen, stimulate the release of NO and prostacyclin through the activation of bradykinin B 2 -receptor. This action opposes angiotensin II (Ang II)-induced vasoconstriction and exerts anti-ischemic, antiproliferative and antiatherosclerotic effects, preserving myocardial stores of energy-rich phosphates and glycogen. 5)Furthermore, stimulation of Ang II type 2 (AT 2 -) receptor present in myocardium attenuates the AT 1 -medicated cardiac hypertrophy and interstitial fibrosis through the B 2 -receptordependent mechanisms.6) The activation of B 2 -receptor in cardiac myocytes involves the cardioprotective effect of angiotensin-converting enzyme inhibitors and AT 1 -receptor antagonists in heart failure. 7)The presence of two subtypes of bradykinin receptors, B 1 -and B 2 -receptors, has been identified in the myocardium, 8) although B 1 -receptors are detectable after the induction of inflammation. LPS induces B 1 -receptors in the rat heart. 9)However, B 1 -receptor blockade does not attenuate the LPSinduced mortality.10) In contrast, it has been demonstrated that the administration of B 2 -receptor antagonists shows beneficial effects, i.e., increased survival rates and improved hemodynamic parameters in a model of endotoxin shock. [11][12][13][14] However, whether the expression of the B 2 -receptor in the heart is altered during sepsis is unknown. Therefore, the present study has been undertaken in mice to elucidate 1) whether the cardiac expression of B 2 -receptor mRNA is altered by LPS, and 2) which mediators are involved in the LPSinduced changes in cardiac B 2 -receptor mRNA expression. MATERIALS AND METHODS MaterialsThe following chemicals were obtained from commercial sources: LPS (Staphylococcus typhosa 0901) from Difco (Detroit, MI, U.S.A.); Ang II from Peptide Institute (Osaka, Japan); TNF-a, IL-1b and IL-6 from Sigma (St Louis, MO, U.S.A.), endothelin-1 (Nacalai Tesque); losartan (AT 1 -receptor antagonist; Funakoshi, Osaka, Japan), PD123319 (AT 2 -receptor antagonist; Wako Chemicals, Kyoto, Japan).Animal Treatment All animal experiments were performed according to the guidelines of the Kobe Gakuin University Experimental Animal Care and Use Committee. Male ddY mice, aged 6-8 weeks, 28-32 g (Japan SLC, Hamamatsu, Japan) were used in this study. Mice were injected with ...

Activation of Toll-like receptor 2 induces B1 and B2 kinin receptors in human gingival fibroblasts and in mouse gingiva

“…Although TNF-α expressing neutrophils are present in the inflamed gingiva during periodontitis 37 , the up-regulation of BDKRB1 in gingival fibroblasts, independently of IL-1β and TNF-α, may be of importance for the actions of kinins in the periodontium in chronic inflammation. As regards the BDKRB2 up-regulation, it has previously been shown that the up-regulation of this receptor by cardiac myocytes challenged with LPS was partially dependent on TNF-α production 38 , in agreement with our data. Nevertheless, it is interesting to note that the BDKRB2 up-regulation by P. gingivalis LPS was not completely inhibited by TNF-α neutralizing antibody in the gingival fibroblasts, which means that other TNF-α-independent pathways may also be involved in the regulation of the expression of this receptor.…”

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