TY - JOUR
T1 - Akt2/LDLr double knockout mice display impaired glucose tolerance and develop more complex atherosclerotic plaques than LDLr knockout mice
AU - Rensing, Katrijn L.
AU - de Jager, Saskia C. A.
AU - Stroes, Erik S.
AU - Vos, Mariska
AU - Twickler, Marcel Th B.
AU - Dallinga-Thie, Geesje M.
AU - de Vries, Carlie J. M.
AU - Kuiper, Johan
AU - Bot, Ilze
AU - von der Thüsen, Jan H.
PY - 2014
Y1 - 2014
N2 - To characterize the phenotype of Akt2/low-density-lipoprotein receptor double knockout (dKO) (Akt2/LDLr dKO) mice with respect to insulin resistance and features of atherosclerotic plaque progression. Metabolic profile and atherosclerotic plaque progression were compared between LDLr KO mice and Akt2/LDLr dKO mice. Total cholesterol, glucose, and insulin levels were significantly higher and oral glucose tolerance test (GTT) was more impaired in Akt2/LDLr dKO mice than in LDLr KO mice. Although atherosclerotic plaques at both the carotid artery and the aortic root of Akt2/LDLr dKO mice were significantly smaller (P < 0.05) compared with LDLr KO controls, plaque composition in these mice was more complex, showing 34-50% reduced collagen content (P < 0.01), 1.4-fold larger necrotic cores (P < 0.05) and six-fold more TUNEL-positive cells (P < 0.01). In situ zymography revealed a more than two-fold higher gelatinolytic activity in Akt2/LDLr dKO mice (P < 0.05). In vitro analyses showed that deletion of Akt2 caused decreased migration, proliferation, and collagen content of vascular smooth muscle cells (VSMCs) and disturbed the balance of metalloproteinases (MMPs) and tissue inhibitor of metalloproteinase (TIMP) mRNA expression in macrophages and VSMCs. Akt2/LDLr dKO mice develop insulin resistance and complex atherosclerotic lesions. These phenotypic characteristics make Akt2/LDLr dKO mice an interesting mouse model to study the effects of insulin resistance on the development and progression of atherosclerosis
AB - To characterize the phenotype of Akt2/low-density-lipoprotein receptor double knockout (dKO) (Akt2/LDLr dKO) mice with respect to insulin resistance and features of atherosclerotic plaque progression. Metabolic profile and atherosclerotic plaque progression were compared between LDLr KO mice and Akt2/LDLr dKO mice. Total cholesterol, glucose, and insulin levels were significantly higher and oral glucose tolerance test (GTT) was more impaired in Akt2/LDLr dKO mice than in LDLr KO mice. Although atherosclerotic plaques at both the carotid artery and the aortic root of Akt2/LDLr dKO mice were significantly smaller (P < 0.05) compared with LDLr KO controls, plaque composition in these mice was more complex, showing 34-50% reduced collagen content (P < 0.01), 1.4-fold larger necrotic cores (P < 0.05) and six-fold more TUNEL-positive cells (P < 0.01). In situ zymography revealed a more than two-fold higher gelatinolytic activity in Akt2/LDLr dKO mice (P < 0.05). In vitro analyses showed that deletion of Akt2 caused decreased migration, proliferation, and collagen content of vascular smooth muscle cells (VSMCs) and disturbed the balance of metalloproteinases (MMPs) and tissue inhibitor of metalloproteinase (TIMP) mRNA expression in macrophages and VSMCs. Akt2/LDLr dKO mice develop insulin resistance and complex atherosclerotic lesions. These phenotypic characteristics make Akt2/LDLr dKO mice an interesting mouse model to study the effects of insulin resistance on the development and progression of atherosclerosis
U2 - https://doi.org/10.1093/cvr/cvt252
DO - https://doi.org/10.1093/cvr/cvt252
M3 - Article
C2 - 24220638
SN - 0008-6363
VL - 101
SP - 277
EP - 287
JO - Cardiovascular research
JF - Cardiovascular research
IS - 2
ER -