The Biologic Contribution of Adenosine 2A receptor, and the Functional Role of 5-Lipoxygenase in Abdominal Aortic Aneurysms
Bhamidipati, Castigliano Murthy, Department of Molecular Physiology and Biological Physics, University of Virginia
Ailawadi, Gorav, Department of Molecular Physiology and Biological Physics, University of Virginia
Abdominal aortic aneurysm (AAA) is associated with the dilatation of all the layers of the arterial wall. The formation of degenerative AAA includes upregulation of proteases, inflammation, smooth muscle cell (SMC) apoptosis, oxidative stress, and loss of extracellular matrix (ECM). There are several mechanisms that in concert worsen the prognosis of AAA. Immunomodulatory cells are key mediators of inflammation, and cytokine induced cellular degradation that contributes to worsening aneurysm formation. Innate and adaptive immune cells lead to SMC dysfunction and subsequent aneurysm dilatation. Due to the complexity of the mechanisms that surround the events that incite and progress AAA, achieving adequate medical therapy remains a challenge. Surgery has a high societal cost burden and is the only available treatment. Collectively, AAA is a significant medical problem that requires investment towards understanding the pathogenesis of disease. Activation of the Adenosine 2A receptor (A2AR) on immune cells is thought to play an important regulatory role in cardiovascular diseases through its anti-inflammatory signaling properties. We investigated the significance of A2AR signaling in AAA formation, and demonstrate that indeed perturbations in A2AR expression result in alterations in AAA development. Separately, 5-Lipoxygenase (5-LO) catalyzed proteins from immune vii cells have been shown to be increased in human AAA tissue samples, yet the experimental data implicating the 5-LO pathway in AAA has been inconsistent. To increase our understanding of the role of 5-LO in AAA, we used a combination of experimental approaches in distinct mouse models, and compared prophylactic and therapeutic treatment regimes of inhibiting the 5-LO pathway. These experiments strengthen the relevance to human disease, and provide evidence for the involvement of the 5-LO pathway in AAA progression. There are other cellular mechanisms such as the various components of immune regulation and apoptosis, in the context of A2AR and 5-LO mediated AAA disease, which require further investigation. Insomuch as basic biology needs more examination, treatment strategies that provide potential for therapy are also equally important to research. In closing, several avenues of further exploration are discussed that would significantly add to our current core understanding of the pathophysiology of AAA, and to the repertoire of therapy options.
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PHD (Doctor of Philosophy)
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