Soluble receptor for advanced glycation end products (sRAGE) attenuates haemodynamic changes to chronic hypoxia in the mouse

• Published in: Pulmonary pharmacology & therapeutics 2014-10, Vol.29 (1), p.7-14
• Main Authors: Farmer, David G.S, Ewart, Marie-Ann, Mair, Kirsty M, Kennedy, Simon
• Format: Article
• Language: English
• Subjects: Animals; Cell Line; Cell Proliferation - physiology; Cricetinae; Cricetulus; Disease Models, Animal; Fibroblasts; Fibroblasts - metabolism; Hemodynamics; Hypertension, Pulmonary - physiopathology; Hypoxia; Hypoxia - complications; Male; Medical Education; Mice; Mice, Inbred C57BL; MTS1/S100A4; Muscle Contraction - physiology; Pulmonary Artery - metabolism; Pulmonary hypertension; Pulmonary/Respiratory; RAGE; Receptor for Advanced Glycation End Products - administration & dosage; Receptor for Advanced Glycation End Products - metabolism; Serotonin - administration & dosage; Serotonin - metabolism; Vascular Remodeling - physiology
• ISSN: 1094-5539; 1522-9629
• DOI: 10.1016/j.pupt.2014.01.002

Abstract The calgranulin-like protein MTS1/S100A4 and the receptor for advanced glycation end-products (RAGE) have recently been implicated in mediating pulmonary arterial smooth muscle cell proliferation and vascular remodelling in experimental pulmonary arterial hypertension (PH). Here, the effects of RAGE antagonism upon 2 weeks of hypobaric hypoxia (10% O2 )-induced PH in mice were assessed. Treatment with sRAGE was protective against hypobaric hypoxia-induced increases in right ventricular pressure but distal pulmonary vascular remodelling was unaffected. Intralobar pulmonary arteries from hypobaric hypoxic mice treated with sRAGE showed protection against a hypoxia-induced reduction in compliance. However, a combination of sRAGE and hypoxia also dramatically increased the force of contractions to KCl and 5-HT observed in these vessels. The acute addition of sRAGE to the organ bath produced a small, sustained contraction in intralobar pulmonary vessels and produced a synergistic enhancement of the maximal force of contraction in subsequent concentration–response curves to 5-HT. sRAGE had no effect on 5-HT-induced proliferation of Chinese hamster lung fibroblasts (CCL39), used since they have a similar pharmacological profile to mouse pulmonary fibroblasts but, surprisingly, produced a marked increase in hypoxia-induced proliferation. These data implicate RAGE as a modulator of both vasoreactivity and of proliferative processes in the response of the pulmonary circulation to chronic-hypoxia.