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.
Department of Pharmacology and Vascular Biology and Therapeutics, Amistad Building, 10 Amistad St., Yale University School of Medicine, New Haven, CT 06511, USA.
Carlos
C
Fernández-Hernando
Eric
E
Ackah
Jun
J
Yu
Yajaira
Y
Suárez
Takahisa
T
Murata
Yasuko
Y
Iwakiri
Jay
J
Prendergast
Robert Q
RQ
Miao
Morris J
MJ
Birnbaum
William C
WC
Sessa
D054058:Acute Coronary Syndrome / Q000209:etiology; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D017209:Apoptosis; D050197:Atherosclerosis / Q000209:etiology* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D016026:Bone Marrow Transplantation; D054059:Coronary Occlusion / Q000209:etiology* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000473:pathology; D005260:Female; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D008264:Macrophages / Q000473:pathology / Q000502:physiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D051057:Proto-Oncogene Proteins c-akt / Q000172:deficiency* / Q000235:genetics / Q000502:physiology
D001057:Apolipoproteins E; D018836:Inflammation Mediators; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; C514862:Akt1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt