Bolus injections of novel thrombogenic site-targeted fusion proteins comprising annexin-V and Kunitz protease inhibitors attenuate intimal hyperplasia after balloon angioplasty

Yung Hsin Yeh; Shang Hung Chang; Shin Yu Chen; Chih Jen Wen; Fu Chan Wei; Rui Tang; Sam Achilefu; Tze Chein Wun; Wei Jan Chen

doi:10.1016/j.ijcard.2017.03.150

Bolus injections of novel thrombogenic site-targeted fusion proteins comprising annexin-V and Kunitz protease inhibitors attenuate intimal hyperplasia after balloon angioplasty

Yung Hsin Yeh, Shang Hung Chang, Shin Yu Chen, Chih Jen Wen, Fu Chan Wei, Rui Tang, Sam Achilefu, Tze Chein Wun, Wei Jan Chen

Research output: Contribution to journal › Article › peer-review

3 Scopus citations

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.

Original language	English (US)
Pages (from-to)	339-346
Number of pages	8
Journal	International Journal of Cardiology
Volume	240
DOIs	https://doi.org/10.1016/j.ijcard.2017.03.150
State	Published - Aug 1 2017
Externally published	Yes

Keywords

Anticoagulants
Balloon angioplasty
Intimal hyperplasia
Recombinant Kunitz protease inhibitor
Thrombosis

ASJC Scopus subject areas

Cardiology and Cardiovascular Medicine

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10.1016/j.ijcard.2017.03.150

Cite this

Yeh, Y. H., Chang, S. H., Chen, S. Y., Wen, C. J., Wei, F. C., Tang, R., Achilefu, S., Wun, T. C., & Chen, W. J. (2017). Bolus injections of novel thrombogenic site-targeted fusion proteins comprising annexin-V and Kunitz protease inhibitors attenuate intimal hyperplasia after balloon angioplasty. International Journal of Cardiology, 240, 339-346. https://doi.org/10.1016/j.ijcard.2017.03.150

Bolus injections of novel thrombogenic site-targeted fusion proteins comprising annexin-V and Kunitz protease inhibitors attenuate intimal hyperplasia after balloon angioplasty. / Yeh, Yung Hsin; Chang, Shang Hung; Chen, Shin Yu et al.
In: International Journal of Cardiology, Vol. 240, 01.08.2017, p. 339-346.

Research output: Contribution to journal › Article › peer-review

Yeh, YH, Chang, SH, Chen, SY, Wen, CJ, Wei, FC, Tang, R, Achilefu, S, Wun, TC & Chen, WJ 2017, 'Bolus injections of novel thrombogenic site-targeted fusion proteins comprising annexin-V and Kunitz protease inhibitors attenuate intimal hyperplasia after balloon angioplasty', International Journal of Cardiology, vol. 240, pp. 339-346. https://doi.org/10.1016/j.ijcard.2017.03.150

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title = "Bolus injections of novel thrombogenic site-targeted fusion proteins comprising annexin-V and Kunitz protease inhibitors attenuate intimal hyperplasia after balloon angioplasty",

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.",

keywords = "Anticoagulants, Balloon angioplasty, Intimal hyperplasia, Recombinant Kunitz protease inhibitor, Thrombosis",

author = "Yeh, {Yung Hsin} and Chang, {Shang Hung} and Chen, {Shin Yu} and Wen, {Chih Jen} and Wei, {Fu Chan} and Rui Tang and Sam Achilefu and Wun, {Tze Chein} and Chen, {Wei Jan}",

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doi = "10.1016/j.ijcard.2017.03.150",

language = "English (US)",

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T1 - Bolus injections of novel thrombogenic site-targeted fusion proteins comprising annexin-V and Kunitz protease inhibitors attenuate intimal hyperplasia after balloon angioplasty

AU - Yeh, Yung Hsin

AU - Chang, Shang Hung

AU - Chen, Shin Yu

AU - Wen, Chih Jen

AU - Wei, Fu Chan

AU - Tang, Rui

AU - Achilefu, Sam

AU - Wun, Tze Chein

AU - Chen, Wei Jan

PY - 2017/8/1

Y1 - 2017/8/1

N2 - 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.

AB - 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.

KW - Anticoagulants

KW - Balloon angioplasty

KW - Intimal hyperplasia

KW - Recombinant Kunitz protease inhibitor

KW - Thrombosis

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Bolus injections of novel thrombogenic site-targeted fusion proteins comprising annexin-V and Kunitz protease inhibitors attenuate intimal hyperplasia after balloon angioplasty

Abstract

Keywords

ASJC Scopus subject areas

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