Monash University

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The role of arginase I and II in the vasculature

posted on 2017-02-06, 03:13 authored by Khong, Sacha
The work presented in this thesis focuses on the enzyme arginase, and the role it plays in regulating NO bioavailability in the vasculature as well as in the progression of atherosclerosis. The interest in this work was sparked by previous work done in our laboratory and others showing the ability of arginase, an enzyme well known for its role in the urea cycle in the liver, and recently discovered to exist in the vasculature, to influence NO production and bioavailability. In the first instance, recent findings from the laboratory suggesting that the tolerance to acetylcholine did not develop in the rat aorta in the presence of arginase inhibitors, led to the studies in chapter two. In this Chapter the effects of arginase II inhibition on tolerance to the commonly prescribed nitrate, glyceryl trinitrate (GTN) are presented. Indeed, tolerance to GTN is abolished in the absence of arginase II in mice, which is most likely due to the reduced reactive oxygen species (ROS) production in the ArgII -/- mouse and reduced uncoupling of endothelial nitric oxide synthase (eNOS). Confirming that arginase had an influence on the NO pathway in the vasculature, and considering that arginase existed as two isoforms, arginase I and arginase II, transgenic mice with the endothelial overexpression of arginase I (hArgI Tg) and arginase II (hArgII Tg) were made by our collaborator, Dr Alan Remaley at the National Institutes of Health (NIH). In Chapter Three, the characterization of the hArgII Tg mice, is presented while chapter four comprises of the characterization of the hArgI Tg mice. In chapter three, our results suggest that endothelial overexpression of arginase II induces endothelial dysfunction and high blood pressure when compared to their wild type littermate controls. These hArgII Tg mice were then crossed with ApoE knock out (ApoE -/-) to determine the contribution of arginase II in plaque development. These mice had severe atherosclerosis when compared to their ApoE -/- counterparts. In contrast, in chapter four, our findings show overexpression of arginase I had atheroprotective effects in the vasculature, with increased NO production in small mesenteric arteries, the absence of endothelial dysfunction and lowered blood pressure; in parallel to studies done in chapter three, these mice were crossed with ApoE -/- mice and found to be protected from atherosclerosis. Discovering that both the isoforms had opposing effects on the NO pathway was intriguing, and having a special interest in peripheral arterial occlusive disease (PAOD) and understanding the therapeutic difficulties attributed to PAOD, we wanted to investigate the potential of arginase as a therapeutic target in PAOD. However, to the best of our knowledge clinically relevant mouse models of PAOD are not yet described. Hence in chapter five, we attempted to create a model of PAOD utilizing the transgenic mice. The model was promising in the first instance, with the demonstration of decreased mean walking distance, which is the first clinical assessment of these patients. However, the model failed to show the initiation of neointima or plaque. In conclusion, this thesis has demonstrated that arginase inhibition is a suitable and potential adjunct therapy in the treatment of the symptoms of coronary artery disease with GTN. As well, this thesis delineates the contribution of the different arginase isoforms to NO regulation and atherosclerotic progression.


Principal supervisor

Jaye Chin-Dusting

Additional supervisor 1

Karen Andrews

Year of Award


Department, School or Centre

Monash University. Faculty of Medicine, Nursing and Health Sciences. Medicine (Alfred)

Campus location



Doctor of Philosophy

Degree Type



Faculty of Medicine Nursing and Health Sciences

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