Regulation of Vein Graft Hyperplasia by Survivin, an Inhibitor of Apoptosis Protein

• Published in: Arteriosclerosis, thrombosis, and vascular biology Vol. 25; no. 10; pp. 2081 - 2087
• Main Authors: Wang, Grace J, Sui, Xin Xin, Simosa, Hector F, Jain, Mukesh K, Altieri, Dario C, Conte, Michael S
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Heart Association, Inc 01.10.2005; Hagerstown, MD Lippincott
• Subjects: Adenoviridae - genetics; Animals; Apoptosis - physiology; Atherosclerosis (general aspects, experimental research); Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Carotid Arteries - pathology; Carotid Arteries - surgery; Carotid Artery Diseases - metabolism; Carotid Artery Diseases - pathology; Carotid Artery Diseases - physiopathology; Cell Division - physiology; Cells, Cultured; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Endothelium, Vascular - cytology; Endothelium, Vascular - metabolism; Genetic Vectors; Graft Survival - physiology; Humans; Hyperplasia; Inhibitor of Apoptosis Proteins; Jugular Veins - pathology; Jugular Veins - transplantation; Medical sciences; Microtubule-Associated Proteins - genetics; Microtubule-Associated Proteins - metabolism; Muscle, Smooth, Vascular - cytology; Muscle, Smooth, Vascular - metabolism; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Neovascularization, Pathologic - metabolism; Neovascularization, Pathologic - pathology; Neovascularization, Pathologic - physiopathology; Platelet-Derived Growth Factor - metabolism; Rabbits; Saphenous Vein - cytology; Signal Transduction - physiology; Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases; Surgery of the heart; Survivin; Vascular surgery: aorta, extremities, vena cava. Surgery of the lymphatic vessels; Vascular disease; Angiogenesis; survivin; proliferation; Hyperplasia; Atherosclerosis; Cardiovascular disease; intimal hyperplasia; Apoptosis
• DOI: 10.1161/01.ATV.0000183885.66153.8a
• ISSN: 1079-5642

OBJECTIVE—Survivin (SVV) is an inhibitor of apoptosis protein (IAP) that is upregulated in cancer and has recently been implicated in vascular injury. We sought to investigate the role of SVV in vein graft hyperplasia. METHODS AND RESULTS—Adenoviral constructs expressing a dominant-negative (AdT34A) and wild-type (AdWT) SVV were used. Proliferation and apoptosis were assayed on endothelial cells (ECs) and smooth muscle cells (SMCs) from human saphenous vein. A rabbit carotid interposition vein graft model (N=31) was used, with adventitial gene transfer of SVV constructs. In vitro, overexpression of SVV was associated with protection from cytokine-induced apoptosis in ECs and SMCs; conversely, AdT34A directly induced apoptosis in these cells. SMC proliferation was increased by AdWT infection, whereas AdT34A reduced proliferation; both effects were serum-dependent. Expression of platelet-derived growth factor (PDGF) in SMCs was regulated by functional SVV expression in analogous fashion. In vivo, proliferation and apoptosis (7 days), as well as wall thickness (30 days), were modified by adenoviral-mediated SVV expression. Adventitial angiogenesis was regulated by the SVV-expressing constructs in a fashion parallel to wall thickness changes. CONCLUSIONS—SVV is a critical regulator of multiple processes, including proliferation, apoptosis, and angiogenesis, that determine the remodeling response of vein grafts following arterialization.