The role of Akt1 kinase in cardiac dysfunction and atherosclerosis is hotly contested. Many models use transient Akt1 activation or deletion to study its function in cardiac diseases. The effects of Akt1 knockout were tested in mouse models dependent on short-term Western diets to induce atherosclerotic lesions; however, in these models, the complete cascade ending in infarction does not occur. In contrast, the ApoE
-/-
/SR-BI
-/-
double knockout (DKO) mouse represents a model of spontaneous myocardial infarction resulting from severe dyslipidemia and atherosclerosis leading to death between 5-7 weeks of age. In DKO mice and humans, dyslipidemia and inflamed arterial occlusions lead to plaque rupture and myocardial infarction. Importantly, Akt1 activation is dramatically elevated in the myocardium and endothelium of DKO vs. WT mice. To assess the role of chronic Akt1 activation in atherosclerosis, we generated ApoE
-/-
/SR-BI
-/-
/Akt1
-/-
triple knockout (TKO) mice. We found that TKO mice exhibited decreased cardiac dysfunction and hypertrophy resulting in longer lifespan vs. DKO. In addition, TKO mice have diminished endothelial VCAM expression, decreased atherosclerotic lesions
in vivo
, and reduced foam cell formation
in vitro
. ROS production, which is regulated by Akt1 signaling and contributes to atherosclerosis during dyslipidemia, was reduced in TKO hearts, plasma, endothelial cells, and macrophages. This led to reduced proatherogenic lipid oxidation product accumulation in TKO vs. DKO. Moreover, Akt1 deletion in TKO mice decreased levels of CD36, the main oxidized lipid receptor, in hearts, on endothelial cells, and on macrophages. Thus, during dyslipidemia, chronic Akt1 activation results in elevated oxidative stress, generation of proatherogenic lipid oxidation products, and expression of CD36 (a known atherothrombotic regulator) resulting in enhanced atherosclerosis and spontaneous myocardial infarction. Inhibition of Akt1 by genetic deletion results in partial rescue of mice leading to decreased atherosclerosis, improved cardiac function, and elongated lifespan. Continued study of chronic Akt1 activation and its effects on atherosclerosis will enable the development of additional targets for heart disease therapeutics.
Determination of lipid oxidation products in vegetable oils and marine omega-3 supplements
