Abstract 621: Attenuated Expression of Profilin-1 Confers Protection from Atherosclerosis in the LDL Receptor-null Mouse
INTRODUCTION. Atherosclerosis-related events are a major cause of morbidity and death worldwide. The mechanisms underlying atherogenesis are not fully understood. We showed in previous studies that the actin-binding protein profilin-1 (pfn) was upregulated in atheroscle-rotic lesions and in endothelial cells (EC) treated with oxidized LDL (oxLDL).
HYPOTHESIS. In the present study, we tested the hypothesis that pfn levels play a role in early atheroma formation.
RESULTS. Since Pfn −/− mice die during embryonic development, we tested the role of pfn in atherogenesis by crossing adult Pfn +/− mice, which are viable and display a ∼50% reduction in pfn levels, into the Ldlr −/− mouse model of atherosclerosis. Atherosclerotic lesion burden was assessed in Pfn +/−Ldlr −/− (PfnHet) and Ldlr −/−control mice (PfnWT) fed an atherogenic high-cholesterol diet (HCD) for two months. Both males and females PfnHet exhibited a significant reduction in the percent lesion area in the descending aorta, when compared to PfnWT (females: 1.1 Â 27> 0.1 vs PfnWT 4.17 Â27> 0.49%, n=10; males: 1.34 Â 27> 0.22 vs PfnWT 3.4 Â 27> 0.36%, n=6). Similarly, aortic arch lesions were reduced in PfnHet (0.08 Â 27> 0.3 vs PfnWT 0.20 Â 27> 0.05 mm2, n=10). Total cholesterol and triglyceride levels were comparable in the two groups. Relevant atheroprotective changes were identified in PfnHet. When compared to PfnWT, aortas from PfnHet mice showed preserved eNOS activation, NO production and NO-dependent signaling. These changes were observed under HCD but not under a normal diet, thus indicating that pfn levels modified the response of the endothelium to atherogenic injury rather than its basal function. Similarly, knockdown of pfn in cultured aortic EC was protective against endothelial dysfunction triggered by oxLDL. Also, bone marrow-derived macrophages from PfnHet showed reduced internalization of oxLDL and oxLDL-induced inflammatory pathways, including activation of p38.
CONCLUSIONS. These studies demonstrate that pfn levels modulate critical processes for atherosclerotic lesion formation through combined endothelial- and macrophage-dependent mechanisms.