the role of adenosine kinase in the formation of aortic aneurysm

Abdominal aortic aneurysms (AAAs) are characterized by localized structural deterioration of the aorta wall, leading to progressive aortic dilation and rupture. Many studies with animal models and patients with AAAs indicate a causal role of chronic aortic inflammation in AAA formation and progression. We have demonstrated that adenosine kinase (ADK), a critical enzyme that regulates intracellular adenosine levels, plays a key role in vascular inflammation via an epigenetic mechanism. However, the effect of ADK on AAA formation has not been studied. We recently found the following: (i) Adk expression was markedly enhanced in macrophages and vascular smooth muscle cells (VSMCs) of the vessel wall in mouse AAA; (ii) the heterozygous deficiency of Adk suppressed the formation of AAA in two murine models of AAA while endothelial Adk deficiency did not significantly suppress angiotensin II-induced AAA; (iii) decreased levels of aortic matrix metalloproteinases and proinflammatory cytokines were observed in aortas of calcium chloride-induced AAA in Adk heterozygous-deficient mice. Here, we propose a new ADK-based paradigm for the suppression of AAA. Our central hypothesis is that Adk deficiency in myeloid cells and VSMCs inhibits the expression of proinflammatory cytokines and matrix metalloproteinases, decreasing macrophage infiltration to adventitial and medial layers, extracellular matrix degradation and VSMC apoptosis, and ultimately reducing the formation of AAA. Adenosine receptor-independent histone methylation is the mechanism underlying the above effects of Adk deficiency. To test this hypothesis, both pharmacological and genetic approaches will be utilized in in vitro experiments with two murine models of AAA: angiotensin II (AngII) infusion and calcium chloride (CaCl2) application. To fulfil this objective, three specific aims will be pursued. In Aim 1, we will investigate the effect of myeloid Adk deficiency in AAA formation. In Aim 2, we will investigate the effect of Adk deficiency in VSMCs in AAA formation. In Aim 3, we will test the effect of an ADK inhibitor in AAA formation. The proposed research will generate new knowledge of ADK physiology, illuminate novel mechanisms underlying the inflammatory processes of AAA and eventually bring about important changes in therapeutic strategies of AAA. (AHA Program: Transformational Project Award)