Brief hypercholesterolemia induces athero‐protective pathways on the patho‐susceptible aortic side endothelium of swine aortic valves

Abstract

The aortic valve of humans and swine is preferentially susceptible to calcific sclerosis on the aortic side of the leaflets. Side‐specific endothelial gene expression in normal valves revealed a balance between pro‐pathologic and protective phenotypes on the aortic side (Simmons et al. 2005). We studied the effect of a modest exposure to hypercholesterolemia on the balance of endothelial phenotypes in a side‐specific manner. Eleven adult male swine were fed a normal chow diet (NC; n=6) or an isocaloric high cholesterol diet (HC; n=5) for 2 weeks. Transcript profiles of aortic (A) and ventricular (V) sides of the aortic valves of NC and HC animals were compared. The patho‐susceptible A side showed a markedly greater number of differentially expressed genes than the patho‐protected V side (1325 vs 87; false discovery rate 25%) indicating higher sensitivity to the risk factor on the susceptible side. These phenotypic differences were mirrored at the tissue level with early pathological changes confined to the A side of the leaflets of the HC animals. Pathway analysis showed that the HC treatment decreased TNF and NFkB pathway‐associated gene expression on the A side of the valve relative to the V side, and that a PPARgamma program was activated by the HC treatment on the A side. Together, these findings suggest a risk factor‐driven upregulation of athero‐protective pathways on the susceptible aortic side. NHLBI support.