Soluble receptor for advanced glycation end products (sRAGE) attenuates haemodynamic changes to chronic hypoxia in the mouse
Introduction
Pulmonary hypertension (PH) is a rare, progressive disease of the small pulmonary arteries characterised by pulmonary vascular remodelling, vasoconstriction and thrombosis [34]. Pulmonary vascular remodelling is associated with smooth muscle proliferation, muscularisation of peripheral pulmonary arteries and medial thickening in larger pulmonary arteries. Muscularisation is associated with fibroelastosis, ablated responses to vasodilators and formation of obliterative plexiform lesions. Sustained elevation of pulmonary vascular pressure increases afterload in the right ventricle, ultimately leading to right heart failure [14], [15], [34].
Recent studies have suggested a role for the receptor for advanced glycation end-products (RAGE) in experimental models of PH [11], [18], [24], [37]. In systemic vascular disease, RAGE activation is associated with the generation of reactive oxygen species, activation of inflammatory transcription factors (e.g. NF-κB), increased vascular permeability, adhesion molecule expression and increased expression of RAGE itself. RAGE is therefore implicated in both the induction and amplification of inflammation [1], [31], [36]. RAGE is basally expressed in small arteries and arteriolar capillaries of the lung [2], [26]. The calcium-binding, calgranulin-like protein MTS1/S100A4, a RAGE ligand, is expressed in remodelled pulmonary vessels and advanced occlusive vascular lesions in PH patients [11]. Thus RAGE ligands by their interaction with RAGE may modulate vascular remodelling in PH. In vitro, MTS1/S100A4 produces proliferation in human pulmonary arterial smooth muscle cells (PASMC) via an action at RAGE. Additionally, expression and secretion of MTS1/S100A4 is part of a downstream pathway producing proliferation in response to 5-HT; an established mitogen which is implicated in PH [7], [18], [21]. In vivo, overexpression of MTS1/S100A4 in transgenic mice is associated with spontaneous formation of obliterative, plexiform-like lesions in a subset (∼5%) of animals [11]. All MTS1/S100A4 mice show impaired recovery from a chronic hypoxic challenge, reduced pulmonary vascular lumen diameter and increased elastin deposition occurring downstream of RAGE activation [24].
Much work to date has focussed on the role of RAGE in PASMC proliferation. In the hypoxic lung in vivo however, adventitial fibroblasts demonstrate a more immediate and dramatic proliferation before migrating to the media and secreting substances which are mitogenic to PASMCs [33], [38]. The role of RAGE in pulmonary fibroblast proliferation is unknown but HMGB-1, a RAGE ligand, was shown to induce proliferation and migration of mouse 3T3 fibroblasts which were prevented by a RAGE antibody [32]. In contrast, RAGE blockade increased proliferation in cultured human pulmonary fibroblasts [30].
RAGE activation may be prevented experimentally using soluble RAGE (sRAGE). sRAGE possesses the RAGE ligand binding domains but lacks the cytoplasmic and transmembrane domains. sRAGE will therefore compete for ligands which bind to cell-bound RAGE [35]. Additionally, sRAGE can prevent RAGE signal transduction directly by preventing the homodimerisation of RAGE on the cell surface [46]. In this study we tested the hypothesis that treatment with sRAGE would attenuate the effect of chronic hypoxia in mice. Additionally, we attempted to characterise the proliferative response of pulmonary fibroblasts to mitogenic stimuli in the presence of sRAGE in vitro.
Section snippets
In vivo experiments
All animal care and experimental procedures were in accordance with the UK Animals (Scientific Procedures) Act 1986 and conformed to institutional regulations at the University of Glasgow. All mice used in the study were bred in the University of Glasgow, kept on a 12 h light/dark cycle and fed ad libitum.
Exposure to hypoxia
In humans, idiopathic and familial PH occurs with a greater frequency in females than males. However, in experimental animals, males are more prone than females to hypoxia-induced PH [44]. For
Effects of hypoxia
2 weeks chronic hypoxia markedly elevated the concentration of RAGE detected by ELISA in the plasma (3.21 ± 0.77 ng ml−1 in control mice vs. 11.97 ± 1.67 ng ml−1 in hypoxic mice; n = 5 p < 0.05 vs. control).
Systemic arterial pressure was not significantly altered by chronic hypoxia or by daily sRAGE injection in either normoxic or hypoxic animals (data not shown). Two weeks of hypobaric hypoxia produced significant increases in sRVP (Normoxia: 22.65 ± 1.01 mmHg; Hypoxia: 31.02 ± 1.51 mmHg; p
Discussion
The aim of the current study was to characterise the effects of sRAGE in two novel settings: as an intervention to hypoxia-induced pulmonary hypertension in vivo, and as an influence on proliferation in pulmonary fibroblasts. Since the RAGE agonist MTS1/S100A4 appears to mediate proliferation in PASMCs through RAGE and can alter structural and functional parameters which may affect pulmonary vascular resistance (i.e. remodelling, vasoreactivity) and influence the pulmonary blood pressure [18],
Conclusions
Although sRAGE-treatment caused a significant, beneficial effect on sRVP after chronic hypoxia, the mechanism does not appear to be via effects on small vessel remodelling or on vascular reactivity in the lung as these were both enhanced.
We speculate that sRAGE may, by acting directly upon PAMSCs or indirectly through enhancing proliferation of fibroblasts in hypoxia, produce enhanced sensitivity of the vasculature to contractile stimuli whilst simultaneously protecting against hypoxia-induced
Conflict of interest
None of the authors has any conflict of interest to declare.
Acknowledgements
This study was supported by the Integrative Mammalian Biology Initiative – jointly funded by the BBSRC and MRC.
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