Dougan, Tammy (2014) The role of kinin receptors in abdominal aortic aneurysm. PhD thesis, James Cook University.

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Abstract

Abdominal aortic aneurysm (AAA) is an important cause of mortality in older adults. An AAA is an abnormal dilatation of the body's main blood vessel, the aorta, within the abdominal region. If left undetected rupture is one of the end-stage results of aortic expansion. There is currently no drug treatment available for AAA, and surgery remains the only option. AAA is often associated with atherosclerosis. Aortic infiltration of cells of both the innate and adaptive immune systems is believed to play a critical role in the pathogenesis of AAA. Chronic inflammation can be observed in human AAA tissue sections.

The kallikrein-kinin system has long been recognised for its role as part of the innate immune system but its role in AAA has been little studied. Bradykinin is the principle effector of the KKS, acting via two types of Bradykinin receptors, B1 and B2. Under physiological conditions, Bradykinin signalling through the B2 receptor has a central role in the modulation of cardiovascular function, but the B1 receptor is barely detectable under normal physiological conditions and its expression is up-regulated in injured or inflamed tissue.

The focus of this study was to elucidate the importance of the kinin receptors in AAA development and atheroma severity in a mouse model of vascular disease. The angiotensin II (AII) mouse model has been used extensively by many groups to study the contribution of AIIinduced hypertension to several vascular pathologies, such as atherosclerosis and the formation of AAAs. It was hypothesised that:

1. Bradykinin receptor deficiency in the apolipoprotein E-deficient (ApoE ⁻/⁻) mouse limits angiotensin II (AII)-induced AAA and atherosclerosis.

2. Kinin receptor deficiency promotes cardiac hypertrophy in an AII mouse model.

3. Activation of neutrophils via kinin receptor signalling stimulates release of the serine protease myeloperoxidase (MPO)

Specifically, the aims of this project were:

1. Assess aortic expression of kinin B1r and B2r in Apo E ⁻/⁻ mice

2. Determine if kinin receptor deficiency inhibits aneurysm development and atheroma severity in the AII-infused ApoE ⁻/⁻ mouse model

3. Compare the circulating profile of monocytes, neutrophils, and pro-inflammatory cytokines in control and kinin receptor-deficient AII-infused ApoE ⁻/⁻ mice

4. To assess the effect of kinin receptor deficiency on cardiac function in the AII-infused ApoE ⁻/⁻ mice model, this includes cardiac hypertrophy, the regulation of blood pressure and heart rate, and to assess the B1 and B2 kinin receptor expression in mice hearts and whether up regulation of B1 receptor expression compensates for lack of B2 receptor expression in the mice

5. Determine the pattern of B1 and B2 kinin receptor expression in ApoE ⁻/⁻ mice neutrophils

6. Assess the action of kinin receptor-agonists and antagonists on neutrophil activation and MPO production, in vitro

We demonstrate that in a mouse model of AAA kinin receptor deficiency, inhibited AAA development and progression. Study outcomes demonstrated that both B2r and B1rB2r deficiency decreased aortic dilatation. Deficiency in both B1 and B2 receptors promoted model survival.

The effect of kinin receptor deficiency on atheroma severity was also investigated. In the current study it was noted that ApoE ⁻/⁻ control mice had a significantly greater development of atheroma in the aortic arch compared to either of the B2r ⁻/⁻ApoE ⁻/⁻ or B1rB2r ⁻/⁻ApoE ⁻/⁻ mice.

A significant effect of kinin receptor deficiency was observed in systolic blood pressure (SBP), prior to AII infusion, with an increased SBP in mice deficient in both receptors. SBP over time in ApoE ⁻/⁻, B1rB2r ⁻/⁻ApoE ⁻/⁻ and B2r ⁻/⁻ApoE ⁻/⁻ mice, was significantly higher in B1rB2r ⁻/⁻ApoE ⁻/⁻ mice compared to both B2r ⁻/⁻ApoE ⁻/⁻ mice and ApoE ⁻/⁻ controls throughout AII infusion. In addition, a greater degree of cardiac hypertrophy was observed in B1rB2r ⁻/⁻ApoE ⁻/⁻ and B2r ⁻/⁻ ApoE ⁻/⁻ mice compared to ApoE ⁻/⁻ controls.

In vitro, the B2 receptor agonist stimulated neutrophil activation and myeloperoxidase production. Plasma concentration of MPO was markedly lower in mice that were deficient in kinin B2 receptors compared to control mice, suggesting that the inhibition of aortic dilatation in response to AII in these mice was potentially associated with a reduced state of neutrophil activation within the vessel wall.

Together, these findings implicate kinin receptors in the promotion of AAA via activation of neutrophils for the first time. Targeting the kinin signalling pathway may be a novel therapeutic strategy for AAA.

Item ID:	40831
Item Type:	Thesis (PhD)
Keywords:	abdomen; abdominal aneurysm; abdominal aorta; animal models; bradykinin; cardiology; cardiovascular diseases; cardiovascular system; cellular immunology; cytokines; cytokinins; haematology; in vitro; inflammation; innate immunity; kallikrein; kinins; mouse motels; murine models
Date Deposited:	14 Oct 2015 05:30
FoR Codes:	11 MEDICAL AND HEALTH SCIENCES > 1102 Cardiovascular Medicine and Haematology > 110201 Cardiology (incl Cardiovascular Diseases) @ 33% 11 MEDICAL AND HEALTH SCIENCES > 1107 Immunology > 110704 Cellular Immunology @ 33% 11 MEDICAL AND HEALTH SCIENCES > 1107 Immunology > 110707 Innate Immunity @ 34%
SEO Codes:	92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920103 Cardiovascular System and Diseases @ 100%
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