Abstract 057: Adenosine Kinase Epigenetically Regulates Abdominal Aortic Aneurysm Formation

Abstract

Objectives: Abdominal aortic aneurysm (AAA) is a major cause of morbidity and mortality worldwide; however, the molecular mechanisms involved in AAA formation are not well understood. The nucleoside adenosine plays important roles in modulating vascular homeostasis. In this study, we sought to determine whether adenosine kinase (ADK), the adenosine-metabolizing enzyme, modulates AAA formation via control of intracellular adenosine level and investigate the involvement of ADK-mediated epigenetic mechanism in this aortic disease. Methods and results: ADK expression and activity were increased in murine AAA models, including calcium chloride-stimulated AAA and angiotensin II-induced AAA. Using a loss-of-function genetic mouse model, we demonstrated that genetic ADK knockout mice led to increased Intracellular adenosine level in macrophages and vascular cells and developed significantly smaller aortic expansion when subjected to AAA inductions. Notably, knockout of ADK alleviated arterial inflammation and diminished infiltration of macrophages, as well as suppressed arterial extracellular matrix degradation, which was associated with down-regulation of CXCL12, MMP2/9 and adhesion molecule expression. Mechanistically, elevation of intracellular adenosine by genetic inactivation of ADK or exogenous adenosine reduces activation of the transmethylation pathway via inactivation of SAH hydrolase (SAHH) and histone H3K4 methyltransferase (HMT), thus down-regulating expression and signaling of mitogen-activated protein kinases in activated macrophages and vascular cells with pro-inflammatory stimuli. Blocking of the H3K4 transmethylation pathway by knockdown of WDR5, a core subunit of HMT complex, abrogated the beneficial effects of ADK inactivation. Conclusions: Our findings reveal a previously unrecognized role of ADK mediated epigenetic pathways in the pathogenesis of AAA and provides a therapeutic target for the prevention of AAA.