Loss of Akt1 leads to severe atherosclerosis and occlusive coronary artery disease.

The Akt signaling pathway controls several cellular functions in the cardiovascular system; however, its role in atherogenesis is unknown. Here, we show that the genetic ablation of Akt1 on an apolipoprotein E knockout background (ApoE(-/-)Akt1(-/-)) increases aortic lesion expansion and promotes coronary atherosclerosis. Mechanistically, lesion formation is due to the enhanced expression of proinflammatory genes and endothelial cell and macrophage apoptosis. Bone marrow transfer experiments showing that macrophages from ApoE(-/-)Akt1(-/-) donors were not sufficient to worsen atherogenesis when transferred to ApoE(-/-) recipients suggest that lesion expansion in the ApoE(-/-)Akt1(-/-) strain might be of vascular origin. In the vessel wall, the loss of Akt1 increases inflammatory mediators and reduces eNOS phosphorylation, suggesting that Akt1 exerts vascular protection against atherogenesis. The presence of coronary lesions in ApoE(-/-)Akt1(-/-) mice provides a new model for studying the mechanisms of acute coronary syndrome in humans.