Masakuni Kido, MD, Lingling Du, MD, Christopher C

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Presentation transcript:

Gene transfer of a TIE2 receptor antagonist prevents pulmonary hypertension in rodents Masakuni Kido, MD, Lingling Du, MD, Christopher C. Sullivan, MS, Reena Deutsch, PhD, Stuart W. Jamieson, MB, FRCS, Patricia A. Thistlethwaite, MD, PhD The Journal of Thoracic and Cardiovascular Surgery Volume 129, Issue 2, Pages 268-276 (February 2005) DOI: 10.1016/j.jtcvs.2004.09.013 Copyright © 2005 The American Association for Thoracic Surgery Terms and Conditions

Figure 1 TIE2 receptor with a unique extracellular ligand–binding domain comprised of immunoglobulin (IG) domains, epithelial growth factor (EGF) repeats, and fibronectin-like 3 (FN3) repeats is a transmembrane protein with intracellular tyrosine kinase domain. Soluble TIE2 (sTIE2), a competitive inhibitor of TIE2 activation, is composed of the extracellular ligand–binding domain only. The Journal of Thoracic and Cardiovascular Surgery 2005 129, 268-276DOI: (10.1016/j.jtcvs.2004.09.013) Copyright © 2005 The American Association for Thoracic Surgery Terms and Conditions

Figure 2 Flow sheet of treatment strategies. AAV, Adeno-associated virus; sTIE2, soluble TIE2; Fio2, fraction of inspired oxygen; SC, subcutaneous. The Journal of Thoracic and Cardiovascular Surgery 2005 129, 268-276DOI: (10.1016/j.jtcvs.2004.09.013) Copyright © 2005 The American Association for Thoracic Surgery Terms and Conditions

Figure 3 A, Photomicrographs of hematoxylin and eosin–stained rat pulmonary arterioles from 3 animal models of PH and respective control animals. The top panel compares monocrotaline-induced pathology to control injection of PBS. The middle panel compares hypoxia-induced pathology with normoxic lung. The bottom panel demonstrates AAV–Ang-1–induced pathology compared with that seen in lungs injected with AAV-lacZ or PBS- carrier. The scale bar represents 40 μm. B, Northern blot demonstrating constitutive Ang-1 expression in the lungs of animals with 3 types of PH. Transcript lengths are shown on the right. SC, Subcutaneous injection; Fio2, fraction of inspired oxygen. The Journal of Thoracic and Cardiovascular Surgery 2005 129, 268-276DOI: (10.1016/j.jtcvs.2004.09.013) Copyright © 2005 The American Association for Thoracic Surgery Terms and Conditions

Figure 4 A, Lung specimens 4 and 7 weeks after injection with AAV-sTIE2, AAV-lacZ, or PBS carrier tested for sTIE2 expression by means of RT-PCR. The transgene sTIE2 was constitutively expressed in the lungs of animals injected with AAV-sTIE2 only. B, Pathologic changes in lung specimens (hematoxylin and eosin stain). Injection of AAV-sTIE2 prevented pulmonary arteriolar smooth muscle hyperplasia in monocrotaline- and Ang-1–induced models of PH but had no effect on hypoxia-induced PH. The scale bar represents 50 μm. The Journal of Thoracic and Cardiovascular Surgery 2005 129, 268-276DOI: (10.1016/j.jtcvs.2004.09.013) Copyright © 2005 The American Association for Thoracic Surgery Terms and Conditions

Figure 5 Pulmonary angiograms using the Microfil cast technique of rodent lungs with PH induced by either monocrotaline (A), constitutive Ang-1 expression (B), or hypoxia (C) treated or untreated with AAV-sTIE2. Note the absence of peripheral vessel staining in the lungs of all 3 models of PH, which is indicative of small-vessel occlusion and normal pulmonary vascular tree in lungs of animals treated with sTIE2. The scale bar represents 25 mm. The Journal of Thoracic and Cardiovascular Surgery 2005 129, 268-276DOI: (10.1016/j.jtcvs.2004.09.013) Copyright © 2005 The American Association for Thoracic Surgery Terms and Conditions