Hypoxic Pulmonary Hypertension in Mice with Constitutively Active Platelet‐Derived Growth Factor Receptor‐β

Pulmonary Circulation - Tập 1 Số 2 - Trang 259-268 - 2011
Bhola K. Dahal1, Rainer Heuchel2,3, Soni Savai Pullamsetti4,1, Jochen Wilhelm1, Hossein A. Ghofrani1, Norbert Weißmann1, Werner Seeger4,1, Friedrich Grimminger1, Ralph T. Schermuly4,1
1University of Giessen Lung Centre (UGLC), Giessen, Germany
2CLINTEC, Karolinska University Hospital Huddinge, Stockholm, Sweden
3Ludwig Institute for Cancer Research, Uppsala, Sweden
4Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany

Tóm tắt

Platelet‐derived growth factor (PDGF) has been implicated in the pathobiology of vascular remodeling. The multikinase inhibitor imatinib that targets PDGF receptor (PDGFR), c‐kit and Abl kinases, shows therapeutic efficacy against experimental pulmonary hypertension (PH); however, the role of PDGFR‐β in experimental PH has not been examined by genetic approach. We investigated the chronic hypoxia‐induced PH in mice carrying an activating point mutation of PDGFR‐β (D849N) and evaluated the therapeutic efficacy of imatinib. In addition, we studied pulmonary global gene expression and confirmed the expression of identified genes by immunohistochemistry. Chronically hypoxic D849N mice developed PH and strong pulmonary vascular remodeling that was improved by imatinib (100 mg/kg/day) as evident from the significantly reduced right ventricular systolic pressure, right ventricular hypertrophy and muscularization of peripheral pulmonary arteries. Global gene expression analysis revealed that stromal cell derived factor SDF)‐1αwas significantly upregulated, which was confirmed by immunohistochemistry. Moreover, an enhanced immunoreactivity for SDF‐1α, PDGFR‐β and CXCR4, the receptor for SDF‐1α was localized to the α‐smooth muscle cell (SMC) actin positive pulmonary vascular cells in hypoxic mice and patients with idiopathic pulmonary arterial hypertension (IPAH). In conclusion, our findings substantiate the major role of PDGFR activation in pulmonary vascular remodeling by a genetic approach. Immunohistochemistry findings suggest a role for SDF‐1α/CXCR4 axis in pulmonary vascular remodeling and point to a potential interaction between the chemokine SDF‐1 and the growth factor PDGF signaling. Future studies designed to elucidate an interaction between the chemokine SDF‐1 and the PDGF system may uncover novel therapeutic targets.

Từ khóa


Tài liệu tham khảo

10.1016/j.jacc.2004.02.029

10.1146/annurev.pathol.2.010506.092033

10.1038/nrd3297

10.1016/j.jacc.2009.04.006

10.1161/01.HYP.29.1.334

10.1016/S0304-419X(98)00015-8

10.1152/physrev.1999.79.4.1283

10.3109/08977199909002130

10.1101/gad.1653708

10.1126/science.1079666

10.1152/ajplung.00199.2002

10.1164/rccm.200707-1037OC

10.1172/JCI24838

Barbero S, 2003, Stromal cell‐derived factor 1alpha stimulates human glioblastoma cell growth through the activation of both extracellular signal‐regulated kinases 1/2 and Akt, Cancer Res, 63, 1969

Koshiba T, 2000, Expression of stromal cell‐derived factor 1 and CXCR4 ligand receptor system in pancreatic cancer: A possible role for tumor progression, Clin Cancer Res, 6, 3530

Scotton CJ, 2002, Multiple actions of the chemokine CXCL12 on epithelial tumor cells in human ovarian cancer, Cancer Res, 62, 5930

10.1016/j.yexcr.2005.04.024

10.1038/sj.onc.1209497

10.1093/cvr/cvn244

10.1161/01.CIR.0000099508.76665.9A

10.1161/01.ATV.0000250606.70669.14

10.1161/01.RES.0000162100.52009.38

10.1074/jbc.M406051200

Dahal BK, 2008, Platelet derived growth factor receptor‐β contributes to hypoxia‐induced pulmonary vascular remodeling [abstract], Am J Respir Crit Care Med, 177, A532

10.1164/rccm.200811-1682OC

10.1161/CIRCULATIONAHA.106.676809

Development R, Core Team. R: A language and environment for statistical computing

10.1007/0-387-29362-0_23

10.1186/gb-2004-5-10-r80

10.1093/bioinformatics/btg083

10.1016/S1046-2023(03)00155-5

10.2202/1544-6115.1027

10.1091/mbc.E06-04-0306

10.1016/j.cytogfr.2004.03.005

10.1161/ATVBAHA.107.154211

10.1016/S0006-291X(02)00331-5

10.1152/ajpheart.01077.2005

10.1038/labinvest.2008.81

10.1186/1471-2407-7-224

10.1073/pnas.90.16.7908d

10.1023/A:1026506801659

10.1074/jbc.M208332200

10.1183/09031936.00052210

10.1186/1465-9921-12-60

10.1160/TH07-02-0085

10.1158/1078-0432.CCR-09-2329

10.4049/jimmunol.178.12.8148

10.1172/JCI200420997

10.1161/01.ATV.0000254669.12675.70

10.1038/nm1075

10.1161/ATVBAHA.107.151050

10.1183/09031936.00045710

10.1161/CIRCRESAHA.107.169896

10.1164/rccm.200810-1662OC

Thông tin
Thông tin xuất bản

Pulmonary Circulation

Tập 1 Số 2

259-268

Thông tin tác giả