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A4623 - Role of Secreted Protein Acidic and Rich in Cysteine in Pulmonary Vascular Remodeling in Pulmonary Hypertension
Author Block: I. Vartürk-Özcan, O. Pak, F. C. Weisel, S. Kraut, K. Quanz, J. Wilhelm, K. Schäfer, E. Morbitzer, F. Veit, W. Seeger, N. Weissmann, C. Veith; Universities of Giessen and Marburg Lung Center (UGMLC), member of the German Center for Lung Research (DZL), Excellence Cluster Cardio-Pulmonary System (ECCPS), Giessen, Germany, Giessen, Germany.
Rationale Pulmonary hypertension (PH) is a life-threatening disease, characterized by excessive pulmonary vascular remodeling, leading to elevated pulmonary arterial pressure and right heart hypertrophy. PH is caused among others by chronic hypoxia, vasoconstrictor/vasodilator and/or growth factor imbalance, leading to pulmonary arterial smooth muscle cell (PASMC) dysregulation. Upon re-exposure to normoxia, hypoxia-induced PH in mice is reversible. Until now, research in the field of PH concentrates mostly on the onset and development of PH. In this study, we focus on the mechanisms underlying the reversal of PH. By using the microarray technique, we aim to identify potential candidate genes contributing to reverse remodeling, specifically in the pulmonary vasculature. Methods Reverse remodeling was investigated in adult mice (C57BL/6J) either exposed to normoxia (21% O2), chronic hypoxia (10% O2), or chronic hypoxia with subsequent re-exposure to normoxia for 1, 3, 7, 14 days. Pulmonary vessels were laser-microdissected followed by RNA isolation and microarray analysis. Regulation of potential candidate genes was assessed by quantitative real-time PCR. In addition, the functional impact was confirmed in vitro in human primary PASMC and in vivo in respective knockout mice. Results In laser-microdissected murine pulmonary vessels, we identified secreted protein acidic and rich in cysteine (SPARC) as one gene down-regulated in all re-oxygenation time points investigated. Hypoxia-dependent SPARC regulation was confirmed in primary human PASMC and in chronic hypoxic mice. SPARC knock-down in PASMC led to diminished proliferation and Akt activation. Molecular analysis revealed HIF-2α-dependent SPARC expression following hypoxic stimulation. Elevated SPARC expression in murine PH was confirmed in human idiopathic pulmonary arterial hypertension patients. In addition, role of SPARC in hypoxia-induced PH in mice was assessed in vivo in SPARC-/- mice. Conclusions In conclusion, we suggest SPARC as a novel potential contributor for pulmonary vascular remodeling. This is however the first report revealing the association of SPARC with PH.