Akt3 deficiency in macrophages promotes foam cell formation and atherosclerosis in mice.
Akt, a serine-threonine protein kinase, exists as three isoforms. The Akt signaling pathway controls multiple cellular functions in the cardiovascular system, and the atheroprotective endothelial cell-dependent role of Akt1 has been recently demonstrated. The role of Akt3 isoform in cardiovascular pathophysiology is not known. We explored the role of Akt3 in atherosclerosis using mice with a genetic ablation of the Akt3 gene. Using hyperlipidemic ApoE(-/-) mice, we demonstrated a macrophage-dependent, atheroprotective role for Akt3. In vitro experiments demonstrated differential subcellular localization of Akt1 and Akt3 in macrophages and showed that Akt3 specifically inhibits macrophage cholesteryl ester accumulation and foam cell formation, a critical early event in atherogenesis. Mechanistically, Akt3 suppresses foam cell formation by reducing lipoprotein uptake and promoting ACAT-1 degradation via the ubiquitin-proteasome pathway. These studies demonstrate the nonredundant atheroprotective role for Akt3 exerted via the previously unknown link between the Akt signaling pathway and cholesterol metabolism.
Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
Liang
L
Ding
Sudipta
S
Biswas
Richard E
RE
Morton
Jonathan D
JD
Smith
Nissim
N
Hay
Tatiana V
TV
Byzova
Maria
M
Febbraio
Eugene A
EA
Podrez
D000101:Acetyl-CoA C-Acetyltransferase / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000201:enzymology* / Q000209:etiology; D001854:Bone Marrow Cells / Q000201:enzymology; D002470:Cell Survival; D002478:Cells, Cultured; D002784:Cholesterol / Q000096:biosynthesis / Q000097:blood / Q000378:metabolism; D002788:Cholesterol Esters / Q000378:metabolism; D005260:Female; D005487:Foam Cells / Q000201:enzymology*; D006949:Hyperlipidemias / Q000150:complications / Q000201:enzymology; D008074:Lipoproteins / Q000097:blood / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000201:enzymology* / Q000378:metabolism; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D059748:Proteolysis; D051057:Proto-Oncogene Proteins c-akt / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D012850:Sinus of Valsalva / Q000473:pathology; D014280:Triglycerides / Q000097:blood
D001057:Apolipoproteins E; D002788:Cholesterol Esters; D008074:Lipoproteins; D014280:Triglycerides; D002784:Cholesterol; C506641:Acat1 protein, mouse; D000101:Acetyl-CoA C-Acetyltransferase; C514862:Akt1 protein, mouse; C491753:Akt3 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D046988:Proteasome Endopeptidase Complex