European Respiratory Society Annual Congress 2013 Abstract Number: 1891 Publication Number: P494 Abstract Group: 4.3. Pulmonary Circulation and Pulmonary Vascular Disease Keyword 1: Pulmonary hypertension Keyword 2: Hypoxia Keyword 3: Animal models
Title: Siah2 in pulmonary hypertension and right ventricular hypertrophy
Daniela 12847 Haag [email protected]giessen.de 1, Dr. Dorothea M. 12848 Peters [email protected] 1, Dr. Bakytbek 12849 Kojonazarov [email protected] MD 1, Simone 12850 Kraut [email protected] 1, Prof. Dr Hossein A. 12851 Ghofrani [email protected] MD 1, Prof. Dr Ralph T. 12867 Schermuly [email protected] 1, Prof. Dr Werner 14728 Seeger [email protected] MD 1, Prof. Dr Friedrich 14730 Grimminger [email protected] MD 1, Dr. Andreas 14737 Möller [email protected] 3, Prof. Dr M. Lienhard 14745 Schmitz [email protected] 2 and Prof. Dr Norbert 14775 Weissmann [email protected] 1. 1 Excellence Cluster Cardio Pulmonary System ECCPS, Universities of Giessen and Marburg Lung Center UGMLC, Member of the Deutsches Zentrum Für Lungenforschung DZL, Justus-Liebig University Giessen, Giessen, Hesse, Germany, 35390 ; 2 Institute of Biochemistry, Justus-Liebig University Giessen, Giessen, Hesse, Germany, 35390 and 3 Head Tumour Microenvironment Laboratory, Queensland Institute of Medical Research, Herston, Brisbane, Queensland, Australia, 4006 .
Body: Pulmonary hypertension (PH) is a disease of multifactorial etiology, which has a poor prognosis. It results in right heart hypertrophy which can culminate in decompensation and death. This study investigated the role of seven in absentia homologue 2 (Siah2) ubiquitin ligase in the pathogenesis of pulmonary vascular and right ventricular (RV) remodelling. Siah2 regulates Hypoxia-inducible factor-1α (HIF-1α) which plays a pivotal role in the pathogenesis of PH and RV hypertrophy by influencing cell metabolism, proliferation, survival and tissue vascularisation. Siah2 knockout (ko) mice and wildtype (wt) controls were examined in a model of hypoxia-induced PH and in pulmonary artery banding (PAB) which induces RV pressure overload independently of pulmonary vascular changes. Hypoxia-treated mice were kept in 10% O2 for 4 weeks. PAB-operated mice received a clip on the pulmonary artery and were examined after 3 weeks. Hypoxic Siah2 ko mice showed reduced RV hypertrophy and improved RV function (determined by echocardiography) compared to wt mice; however, both showed similarly increased pulmonary vascular remodelling. Siah2 ko PAB mice showed less RV hypertrophy and a partially conserved RV function. Fibrosis in the RV, determined by quantification of collagen, was significantly reduced in PAB Siah2 ko mice compared to wt mice. However, Siah2 mRNA expression was not altered in hypoxic lungs and RVs as well as in PAB-RVs of wt mice. Protein- and mRNA-expression of vegfa, a target gene of HIF1α important for neoangiogenesis, did not show any regulation in both models. In conclusion, even though Siah2 crucially influences cardiac function, it does not seem to play a role in the pulmonary pathology of PH.