Attenuated expression of profilin-1 confers protection from atherosclerosis in the LDL receptor-null mouse

Atherosclerosis- related events are a major cause of morbidity and death worldwide, but the mechanisms underlying atherogenesis are not fully understood. We showed in previous studies that the actin- binding protein profilin- 1 ( pfn) was upregulated in atherosclerotic plaques and in endothelial cells ( ECs) treated with oxidized low- density lipoproteins ( oxLDL). The present study addressed the role of pfn in atheroma formation. To this end, mice with heterozygous deficiency of pfn, Pfn(+/-), were crossed with Ldlr(-/-) mice. After 2 months under a 1.25% cholesterol atherogenic diet, Pfn(+/-) Ldlr(-/-)( PfnHet) exhibited a significant reduction in lesion burden compared with Ldlr(-/-) control mice ( PfnWT), whereas total cholesterol and triglyceride levels were similar in the 2 groups. Relevant atheroprotective changes were identified in PfnHet. When compared with PfnWT, aortas from PfnHet mice showed preserved endothelial nitric oxide synthase ( eNOS) activation and nitric oxide ( NO)- dependent signaling, and reduced vascular cell adhesion molecule ( VCAM)- 1 expression and macrophage accumulation at lesion-prone sites. Similarly, knockdown of pfn in cultured aortic ECs was protective against endothelial dysfunction triggered by oxLDL. Finally, bone marrow - derived macrophages from PfnHet showed blunted internalization of oxLDL and oxLDL- induced inflammation. These studies demonstrate that pfn levels modulate processes critical for early atheroma formation and suggest that pfn heterozygosity confers atheroprotection through combined endothelial- and macrophage-dependent mechanisms.