Abstract 269: Tenascin-C Gene Deletion Induces Plaque Hemorrhage and Markedly Accelerates Atherosclerosis in Apo E null Mice: Potential Role of Mast Cells and Eotaxin
Background: Tenascin-C (TN) is an extracellular matrix protein that is expressed in human and murine atherosclerotic plaques but its role in atherogenesis is unknown. To understand the role of TN in atherosclerosis, we developed TN−/− /apoE−/− double knockout mice (TN/E).
Results: TN deletion had no effect on the lipid profile in apo E−/− mice (apo E). The overall extent of aortic atherosclerosis was significantly increased in TN/E mice compared to apo E mice at all ages examined. Oil red O staining of total aorta revealed that in mice fed high-fat diet for 8 weeks, the average lesions were 5.35±0.695% of the total aortic area in apo E group and 9.43±0.82% of the total aortic area in the TN/E group (P=0.007). At 12 weeks, the total aortic lesion area for apo E group was 9.06±0.74% and for TN/E group was 16.6±1.8% (P=0.0017). At 18 weeks, the total lesional area for apo E group was 19.09±1.94% and for TN/E group was 30.99±2.95% (P=0.0058). Nearly 70% of TN/E mice demonstrated extensive intraplaque hemorrhage in aortic and or carotid plaques. Unlike apo E mice, TN/E mice showed massive infiltration of mast cells within the arterial adventitia and plaque. Mouse cytokine array analysis of serum with subsequent ELISA showed significantly elevated levels of CC chemokine Eotaxin in TN/E mice. Eotaxin levels of TN/E and apo E groups before initiation of high-fat diet feeding was 908.3±40.05 (n=12) and 421.7±27.55 (n=15, P<0.0001), respectively. At 4 weeks on a high-fat diet, the level of Eotaxin for the TN/E group was 1357±62.41 (n=14) and for the apo E group was 649.7±50.35 (n=10, P<0.0001). At 24 weeks on high-fat diet, the Eotaxin level for TN/E group was 3170±216.0 (n=12) and for the apo E group was 839.0±92.09 (n=11, P<0.0001).
Conlusions: deletion of TN gene accelerates atherosclerosis, induces intraplaque hemorrhage, mast cell accumulation, and Eoxtaxin over-expression in apo E mice. Since Eotaxin is known to stimulate myelopoiesis, development of mast cells, and angiogenesis, we propose that TN deficiency accelerates atherosclerosis and induces intraplaque hemorrhage possibly through up-regulation of Eotaxin expression.