Absence of Akt1 reduces vascular smooth muscle cell migration and survival and induces features of plaque vulnerability and cardiac dysfunction during atherosclerosis.
OBJECTIVE
Deletion of Akt1 leads to severe atherosclerosis and occlusive coronary artery disease. Vascular smooth muscle cells (VSMCs) are an important component of atherosclerotic plaques, responsible for promoting plaque stability in advanced lesions. Fibrous caps of unstable plaques contain less collagen and ECM components and fewer VSMCs than caps from stable lesions. Here, we investigated the role of Akt1 in VSMC proliferation, migration, and oxidative stress-induced apoptosis. In addition, we also characterized the atherosclerotic plaque morphology and cardiac function in an atherosclerosis-prone mouse model deficient in Akt1.


RESULTS
Absence of Akt1 reduces VSMC proliferation and migration. Mechanistically, the proliferation and migratory phenotype found in Akt1-null VSMCs was linked to reduced Rac-1 activity and MMP-2 secretion. Serum starvation and stress-induced apoptosis was enhanced in Akt1 null VSMCs as determined by flow cytometry using Annexin V/PI staining. Immunohistochemical analysis of atherosclerotic plaques from Akt1(-/-ApoE-/-) mice showed a dramatic increase in plaque vulnerability characteristics such as enlarged necrotic core and reduced fibrous cap and collagen content. Finally, we show evidence of myocardial infarcts and cardiac dysfunction in Akt1(-/-ApoE-/-) mice analyzed by immunohistochemistry and echocardiography, respectively.


CONCLUSIONS
Akt1 is essential for VSMC proliferation, migration, and protection against oxidative stress-induced apoptosis. Absence of Akt1 induces features of plaque vulnerability and cardiac dysfunction in a mouse model of atherosclerosis.
Fernández-Hernando
Carlos
C
Department of Pharmacology and Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, Conn., USA.
József
Levente
L
Jenkins
Deborah
D
Di Lorenzo
Annarita
A
Sessa
William C
WC
D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D017209:Apoptosis; D050197:Atherosclerosis / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D002465:Cell Movement; D049109:Cell Proliferation; D002470:Cell Survival; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006321:Heart / Q000503:physiopathology*; D020935:MAP Kinase Signaling System; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D009203:Myocardial Infarction / Q000209:etiology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000473:pathology* / Q000502:physiology*; D018384:Oxidative Stress; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D054462:p21-Activated Kinases / Q000378:metabolism; D020744:rac GTP-Binding Proteins / Q000378:metabolism
D001057:Apolipoproteins E; D010982:Platelet-Derived Growth Factor; C514862:Akt1 protein, mouse; C515905:Pak1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D054462:p21-Activated Kinases; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse; D020744:rac GTP-Binding Proteins