Abstract 16436: Genetic Loss of Periostin Protects Against Atherosclerotic Lesion Formation
Extracellular matrix remodeling contributes to the size, stability and integrity of atherosclerotic plaques. Periostin (Pn), a secreted protein of the fasciclin family, is a matrix protein that is involved in remodeling, collagen maturation and mesenchymal cell differentiation. Pn has been shown to be re-expressed following vascular injury and is abundant in human advanced atherosclerotic lesions. We assessed the hypothesis that periostin stimulates phenotypic cellular changes and accelerates the formation of plaques. To evaluate this hypothesis, we utilized ApoE-deficient, high-fat diet (HFD) fed mice. Genetic loss of Pn in this background (ApoE-/- Pn-/-) resulted in a 50-60% reduction in atherosclerosclerotic lesion area (en Face, Sudan staining) as compared to ApoE-/- Pn+/+ control animals. This was evident at both early (0.57% ± 0.21, n=6 vs. 1.3% ± 0.5, n=10, p< 0.01) and late (5.8% ± 1.3, n=9 vs.10.2% ± 2.2, n=8, p<0.01) time points. Values were calculated as mean % disease, defined as atherosclerotic lesions divided by total atherosclerotic area. There was not only a decrease in the amount of plaque but the plaques of the ApoE-/- Pn-/- mice are more cellular, with less cholesterol clefts and a more organized fibrous cap. Interestingly, there is an increase in proliferating cells evident by EDU staining, in plaques of ApoE-/-Pn-/- (5.7%, n=4 vs. 2.9%, n=9, p< 0.05) mice after 6 weeks of HFD. There was no significant difference in plasma cholesterol and triglyceride levels between all groups receiving HFD, suggesting that loss of Pn did not alter lipid metabolism. In addition, periostin mRNA was found to be upregulated in the thoracic aorta of Apo E-/- mice and this positively correlated with time on HFD. In parallel, circulating plasma levels of Pn, as detected by ELISA, were also found to increase with time on HFD. In conclusion, these data suggest that Pn is a prominent mediator in the development of atherosclerosis by affecting the proliferation of vascular smooth muscle cells and altering the cellular transition from a contractile to a synthetic phenotype. Future studies aimed at defining a mechanistic role for Pn in atherogenesis may yield exciting and novel therapeutics against vascular disease.
- © 2012 by American Heart Association, Inc.