Yung-Hsin Yeh1, Shang-Hung Chang2, Shin-Yu Chen2, Chih-Jen Wen3, Fu-Chan Wei3, Rui Tang4, Sam Achilefu4, Tze-Chein Wun5, Wei-Jan Chen6. 1. Cardiovascular Division, Chang-Gung Memorial Hospital, Chang-Gung University College of Medicine, Taoyuan, Taiwan. Electronic address: yeongshinn@cgmh.org.tw. 2. Cardiovascular Division, Chang-Gung Memorial Hospital, Chang-Gung University College of Medicine, Taoyuan, Taiwan. 3. College of Medicine, Chang-Gung University, Center for Vascularized Composite Allotransplantation, Chang-Gung Medical Foundation, Department of Plastic and Reconstructive Surgery and Center for Vascularized Composite Allotransplantation, Chang-Gung Memorial Hospital, Taoyuan, Taiwan. 4. Department of Radiology, Washington University Medical School, St Louis, MO 63110, USA. 5. EVAS Therapeutics, LLC, 613 Huntley Heights Drive, Ballwin, MO 63021, USA. 6. Cardiovascular Division, Chang-Gung Memorial Hospital, Chang-Gung University College of Medicine, Taoyuan, Taiwan. Electronic address: wjchen@cgmh.org.tw.
Abstract
BACKGROUND: Systemic administrations of conventional antithrombotics reduce neointima formation after angioplasty in experimental animals. However, clinical translation of these results has not been successful due to high risk for bleeding. OBJECTIVES: We sought to determine whether novel annexin-V (ANV)-Kunitz protease inhibitor fusion proteins, TAP-ANV and ANV-6L15, can specifically target to vascular injury site and limit neointima formation without inducing systemic hypo-coagulation in a rat carotid artery balloon angioplasty injury model. METHODS: Near infrared imaging was carried out after balloon-injury and injection of fluorescent ANV or ANV-6L15 to examine their bio-distributions. For peri-procedure treatment, TAP-ANV or ANV-6L15 was administered as i.v. boluses 3 times: 30-minutes before balloon-injury, immediate after procedure, and 120-minutes post-balloon-injury. For extended treatment, additional i.v. bolus injection was given on day-2, day-3 and every other day thereafter. Carotid arteries were collected on day-7 and day-14 for analysis. Blood was collected for measurement of clotting parameters. RESULTS: Near infrared imaging and immunochemistry showed that fluorescent ANV and ANV-6L15 specifically localized to injured carotid artery and significant amount of ANV-6L15 remained bound to the injured artery after 24-h. Peri-procedure injections of TAP-ANV or ANV-6L15 resulted in decrease of intima/media ratio by 56%. Extended injections of both yielded similar results. Both decreased the expression of PCNA on day-7 and increased the expression calponin on day-14 in the intima post-balloon-injury. CONCLUSIONS: TAP-ANV and ANV-6L15 can specifically localize to balloon injured carotid arteries after i.v. bolus injections, resulting in substantial attenuation of intimal hyperplasia without inducing a state of systemic hypo-coagulation.
BACKGROUND: Systemic administrations of conventional antithrombotics reduce neointima formation after angioplasty in experimental animals. However, clinical translation of these results has not been successful due to high risk for bleeding. OBJECTIVES: We sought to determine whether novel annexin-V (ANV)-Kunitz protease inhibitor fusion proteins, TAP-ANV and ANV-6L15, can specifically target to vascular injury site and limit neointima formation without inducing systemic hypo-coagulation in a ratcarotid artery balloon angioplasty injury model. METHODS: Near infrared imaging was carried out after balloon-injury and injection of fluorescent ANV or ANV-6L15 to examine their bio-distributions. For peri-procedure treatment, TAP-ANV or ANV-6L15 was administered as i.v. boluses 3 times: 30-minutes before balloon-injury, immediate after procedure, and 120-minutes post-balloon-injury. For extended treatment, additional i.v. bolus injection was given on day-2, day-3 and every other day thereafter. Carotid arteries were collected on day-7 and day-14 for analysis. Blood was collected for measurement of clotting parameters. RESULTS: Near infrared imaging and immunochemistry showed that fluorescent ANV and ANV-6L15 specifically localized to injured carotid artery and significant amount of ANV-6L15 remained bound to the injured artery after 24-h. Peri-procedure injections of TAP-ANV or ANV-6L15 resulted in decrease of intima/media ratio by 56%. Extended injections of both yielded similar results. Both decreased the expression of PCNA on day-7 and increased the expression calponin on day-14 in the intima post-balloon-injury. CONCLUSIONS:TAP-ANV and ANV-6L15 can specifically localize to balloon injured carotid arteries after i.v. bolus injections, resulting in substantial attenuation of intimal hyperplasia without inducing a state of systemic hypo-coagulation.
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