Hyperglycemia Inhibits AAA Expansion: Examining the Role of Lysyl Oxidase

Abdominal aortic aneurysm (AAA) is a common, progressive and potentially fatal dilation of the most distal aortic segment. Multiple studies with longitudinal follow-up of AAA have identified markedly slower progression among patients affected with diabetes. Understanding the molecular pathway responsible for the growth inhibition could have implications for therapy in nondiabetic AAA patients. Toward this end, we investigated the effects of hyperglycemia in a murine model of AAA and a carefully monitored cohort of AAA patients from the Noninvasive Treatment of AAA-Clinical Trial (NTA3CT). In mice with hyperglycemia, AAA growth was inhibited to a similar degree (≈ 30%) as seen in patients with diabetes. AAA growth correlated inversely to levels of hyperglycemia in mice and AAA patients. Inhibiting lysyl oxidase (LOX) activity increases aneurysm growth and matrix degradation in this model. Hyperglycemia increased LOX concentration in aortic SMCs but not in murine AAA tissue. Inhibiting LOX activity completely blocked the growth inhibitory effect of hyperglycemia. Lysyl oxidase-like 2 (LOXL2), the primary arterial isoform of LOX, is expressed in the same area as type IV collagen along the outer media in murine AAA tissue. There is a significant inverse correlation between LOXL2 and AAA growth rate in patients. Taken together, these studies suggest a role for LOXL2-mediated type IV collagen crosslinking in slowing AAA growth in the setting of hyperglycemia.