The role of peri-transplant ischemia and reperfusion injury in cardiac allograft vasculopathy

Heart transplantation is often the only therapeutic option for patients with end stage heart disease. Allograft organs are in short supply. Thus, preserving the life of a grafted organ is extremely important. Cardiac allograft vasculopathy (CAV) is an expression of chronic rejection that accounts fo...

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Main Author: Hunter, Arwen Leigh
Format: Others
Language:English
Published: University of British Columbia 2008
Subjects:
Online Access:http://hdl.handle.net/2429/2503
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spelling ndltd-LACETR-oai-collectionscanada.gc.ca-BVAU.-25032013-06-05T04:16:51ZThe role of peri-transplant ischemia and reperfusion injury in cardiac allograft vasculopathyHunter, Arwen LeighIschemiaReperfusionCytochrome p450sHeart transplantation is often the only therapeutic option for patients with end stage heart disease. Allograft organs are in short supply. Thus, preserving the life of a grafted organ is extremely important. Cardiac allograft vasculopathy (CAV) is an expression of chronic rejection that accounts for the greatest loss of graft function in transplanted hearts. Peri-transplant ischemia/reperfusion (I/R)-injury occurs during transplantation when blood flow is stopped to remove the heart from the donor and then is reinstated upon implantation of the donor heart into the recipient. This oxidative injury contributes to vascular dysfunction and CAV. In this dissertation, I hypothesize that prevention and/or reduction of I/R during transplantation reduces post-transplant vascular dysfunction and CAV. In this regard, myself and my colleagues examined the roles of apoptosis repressor with caspase recruitment domain (ARC) and cytochrome p450 (CYP) 2C enzymes in UR-induced vascular dysfunction and CAV. ARC expression was detected in endothelial cells (ECs) and smooth muscle cells (SMCs); however, increased levels of ARC do not protect against oxidant injury. ARC overexpression did protect against oxidant-induced cell death in H9c2 rat embryonic myoblasts. We observed that ARC-overexpression prevented H9c2 differentiation into muscle cells. With our focus on vascular injury, we turned our attention to the CYP 2C enzymes. Both endothelium-dependent and independent vascular function was impaired following I/R. Pre-treatment with the CYP 2C inhibitor sulfaphenazole (SP) restored endothelial sensitivity to acetylcholine, but did not restore sensitivity to endothelium-independent vasodilators. Rat heterotopic heart transplants were performed with rats being treated with SP or vector control prior to surgery. Rats treated with SP showed significantly reduced luminal narrowing and had decreased SMC proliferation, oxidant and interferon-y levels. No differences were detected in immune infiltration or apoptosis. Complementary studies in cultured vascular cells revealed that CYP 2C9 expression decreased viability and increased ROS production following hypoxia and re-oxygenation in ECs but not in SMCs. In summary, we did not detect protection of vascular cells by ARC, but did discover a novel role for ARC in differentiation. CYP 2C contributes to post-ischemic vascular dysfunction and CAV through increased oxidative stress and endothelial dysfunction.University of British Columbia2008-10-09T13:01:45Z2008-10-09T13:01:45Z20082008-10-09T13:01:45Z2008-05Electronic Thesis or Dissertation11086181 bytesapplication/pdfhttp://hdl.handle.net/2429/2503eng
collection NDLTD
language English
format Others
sources NDLTD
topic Ischemia
Reperfusion
Cytochrome p450s
spellingShingle Ischemia
Reperfusion
Cytochrome p450s
Hunter, Arwen Leigh
The role of peri-transplant ischemia and reperfusion injury in cardiac allograft vasculopathy
description Heart transplantation is often the only therapeutic option for patients with end stage heart disease. Allograft organs are in short supply. Thus, preserving the life of a grafted organ is extremely important. Cardiac allograft vasculopathy (CAV) is an expression of chronic rejection that accounts for the greatest loss of graft function in transplanted hearts. Peri-transplant ischemia/reperfusion (I/R)-injury occurs during transplantation when blood flow is stopped to remove the heart from the donor and then is reinstated upon implantation of the donor heart into the recipient. This oxidative injury contributes to vascular dysfunction and CAV. In this dissertation, I hypothesize that prevention and/or reduction of I/R during transplantation reduces post-transplant vascular dysfunction and CAV. In this regard, myself and my colleagues examined the roles of apoptosis repressor with caspase recruitment domain (ARC) and cytochrome p450 (CYP) 2C enzymes in UR-induced vascular dysfunction and CAV. ARC expression was detected in endothelial cells (ECs) and smooth muscle cells (SMCs); however, increased levels of ARC do not protect against oxidant injury. ARC overexpression did protect against oxidant-induced cell death in H9c2 rat embryonic myoblasts. We observed that ARC-overexpression prevented H9c2 differentiation into muscle cells. With our focus on vascular injury, we turned our attention to the CYP 2C enzymes. Both endothelium-dependent and independent vascular function was impaired following I/R. Pre-treatment with the CYP 2C inhibitor sulfaphenazole (SP) restored endothelial sensitivity to acetylcholine, but did not restore sensitivity to endothelium-independent vasodilators. Rat heterotopic heart transplants were performed with rats being treated with SP or vector control prior to surgery. Rats treated with SP showed significantly reduced luminal narrowing and had decreased SMC proliferation, oxidant and interferon-y levels. No differences were detected in immune infiltration or apoptosis. Complementary studies in cultured vascular cells revealed that CYP 2C9 expression decreased viability and increased ROS production following hypoxia and re-oxygenation in ECs but not in SMCs. In summary, we did not detect protection of vascular cells by ARC, but did discover a novel role for ARC in differentiation. CYP 2C contributes to post-ischemic vascular dysfunction and CAV through increased oxidative stress and endothelial dysfunction.
author Hunter, Arwen Leigh
author_facet Hunter, Arwen Leigh
author_sort Hunter, Arwen Leigh
title The role of peri-transplant ischemia and reperfusion injury in cardiac allograft vasculopathy
title_short The role of peri-transplant ischemia and reperfusion injury in cardiac allograft vasculopathy
title_full The role of peri-transplant ischemia and reperfusion injury in cardiac allograft vasculopathy
title_fullStr The role of peri-transplant ischemia and reperfusion injury in cardiac allograft vasculopathy
title_full_unstemmed The role of peri-transplant ischemia and reperfusion injury in cardiac allograft vasculopathy
title_sort role of peri-transplant ischemia and reperfusion injury in cardiac allograft vasculopathy
publisher University of British Columbia
publishDate 2008
url http://hdl.handle.net/2429/2503
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