Abstract 332: Deletion of the T Cell Chemokine CXCL10 Promotes Aortic Aneurysm Formation and Rupture
Background. Multiple lines of investigation have shown that T helper type 1 (Th1) cells and their related pro-inflammatory cytokines promote atherogenesis, but emerging studies have suggested that these same cytokines may actually protect against the formation of abdominal aortic aneurysms (AAA). CXCL10 is a chemoattractant for activated Th1 T cells, and its deletion has recently been shown to greatly reduce plaque formation in atherosclerosis-susceptible murine strains. Here we tested the hypothesis that CXCL10 deletion would have an opposite effect on aneurysms; that is, increasing AAA development in a well-established murine model that creates AAA’s without modulating blood pressure.
Methods. Chow-fed Apoe−/− and Apoe−/− /Cxcl10−/− mice were treated with angiotensin II (angII, 1000 ng/kg/min) or vehicle control via Alzet osmotic pumps beginning at 20 weeks of age. After 4 weeks of infusion, mice were sacrificed for blood collection, and morphometric analyses were performed with IP Lab software by blinded observers.
Results. All mice had comparable cholesterol and triglyceride levels, thus excluding these confounding variables. Compared to the single knockout mice, compound deficient Apoe−/− Cxcl10−/− mice had a higher incidence of death due to aortic rupture (42% versus 13%, n ≥15, P <0.05). We also found a concordant increase in the size of the aneurysms, with a larger suprarenal-to-infrarenal aortic area ratio (7.07 ± 0.44 versus 5.67 ± 0.29, n ≥11; P =0.016), and worse morphological grades of aneurysms based on a previously published four-point classification (n ≥15, χ2 P <0.05). Whereas this model is known to create suprarenal aneurysms, Apoe−/− /Cxcl10−/− mice had a significantly higher number of aneurysms involving the thoracic aorta (45% versus 9%, n ≥11, P < 0.05), including spiral dissections.
Conclusions. In contrast to its effects on plaque formation, here we have shown that CXCL10 deletion increases the severity and complications of aneurysms. These new data further suggest a Th1 versus Th2 dichotomy of plaque versus aneurysm formation in vascular disease.