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2018-12-11 - Colloque/Présentation - poster - Anglais - page(s)

Pierard Mélany, Tassin Alexandra , Zouaoui Boudjeltia Karim , Legrand Alexandre , "Effect of hypoxia on adiponectin pathway in murine and cellular models: which involvement in COPD-associated cardiovascular risk ?" in Europhysiology, London, United-Kingdom, 2018

  • Codes CREF : Sciences biomédicales (DI3200)
  • Unités de recherche UMONS : Physiologie et réadaptation respiratoire (M117)
  • Instituts UMONS : Institut des Sciences et Technologies de la Santé (Santé)
Texte intégral :

Abstract(s) :

(Anglais) Introduction: Modulation of adiponectin plasmatic level (Adpl) was previously found to vary differently in COPD (Chronic Obstructive Pulmonary Disease) patients, probably due to the heterogeneity of the disease 1,2. Hypoxaemia is a component of respiratory diseases frequently observed in severe COPD. It initiates compensatory mechanisms mainly mediated by a family of transcription factors (Hypoxia Inducible Factors HIFs) 3. Hypoxaemia was suggested to modulate Ad pathway but mechanisms are unclear 4,5. Due to its anti-diabetic, anti-inflammatory and anti-atherosclerotic properties 4, we postulate that alteration of Ad pathway could participate to metabolic troubles and cardiovascular co-morbidities in COPD patients. Methods and Results: To better understand the specific impact of hypoxaemia on Ad pathway, we used a mouse model of chronic hypoxaemia (CH) (n=13, FiO2 = 10%, 8h/day). Exposure to hypoxaemia for 35 days resulted in (i) an increased level of high MW multimers (CH : 12,879 + 0.881 % vs control : 10,202 + 0.586 % ; Mean + SEM, p<0.05, T-Test) without change in Ad plasmatic level (CH : 8694 + 470ng/ml vs control : 8520 + 528 ng/ml ; Mean + SEM, NS, T-Test) (ii) a tissue-specific reduction of AdipoR protein level without change in mRNA expression. Given the role of macrophages in the atherogenic risk, we also evaluated AdipoR abundance in RAW murine macrophages exposed to low oxygen level (CH, n=4, PO2 = 2% Patm, 24h). Exposure to hypoxia in vitro reduced AdipoR1/2 level (AdipoR1: fold change = 0.47; AdipoR2: fold change = 0.36, p<0.05, T-Test) as well as the abundance of p-AMPK, a metabolic sensor involved in Ad signalling pathway (fold change = 0.41, p<0.05, Mann-Whitney Rank Sum Test) . To investigate the contribution of HIF-1α in the effect of hypoxia on AdipoR2 abundance, macrophages were exposed to the chemical HIF-1α inducer CoCl2 (n=6, 5μM, 24h). As expected, macrophages exposed to CoCl2 increased HIF-1α abundance (fold change = 3.75 ; p<0.001, T-Test), and decreased AdipoR2 level (fold change = 0.68 ; p<0.05, T-Test). Investigations of the effect of shRNA-mediated HIF-1α gene silencing on AdipoR2 abundance are ongoing. Conclusion: Chronic hypoxaemia, per se, modifies Ad oligomerisation state and AdipoR protein level in vivo and in macrophages in vitro. These effects could be partly linked to HIF-1α activation during adaptive response to hypoxia and could influence the cardiovascular risk in hypoxamic COPD patients. Acknowledgement We acknowledge V. Jenart and B. Blairon for technical assistance. Molecular analyses were funded by the FRMH (Fonds pour la Recherche Médicale dans le Hainaut). The ISPPC (Intercommunale de Santé Publique du Pays de Charleroi) provides funding for the conception of device inducing intermittent hypoxia. MP and SC held PhD fellowships from the University of Mons 1 Minas M, Kostikas K, Papaioannou AI, Mystridou P, Karetsi E, Georgoulias P et al. The association of metabolic syndrome with adipose tissue hormones and insulin resistance in patients with COPD without co-morbidities. COPD 2011; 8: 414–420. 2 Carolan BJ, Kim Y, Williams AA, Kechris K, Lutz S, Reisdorph N et al. The association of adiponectin with computed tomography phenotypes in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2013; 188: 561–566. 3 Kent BD, Mitchell PD, McNicholas WT. Hypoxemia in patients with COPD: cause, effects, and disease progression. Int J Chron Obstruct Pulmon Dis 2011; 6: 199–208. 4 Natarajan R, Salloum FN, Fisher BJ, Kukreja RC, Fowler AA. Hypoxia inducible factor-1 upregulates adiponectin in diabetic mouse hearts and attenuates post-ischemic injury. J Cardiovasc Pharmacol 2008; 51: 178–187. 5 Jiang C, Qu A, Matsubara T, Chanturiya T, Jou W, Gavrilova O et al. Disruption of hypoxia-inducible factor 1 in adipocytes improves insulin sensitivity and decreases adiposity in high-fat diet-fed mice. Diabetes 2011; 60: 2484–2495.