Isoform-specific function
of Akt in atherosclerosis

In normal physiological conditions, cholesterol levels are tightly regulated by a variety of homeostatic machinery and mechanisms. One such mechanism is the clearance of excess cholesterol by macrophages. However, excess dietary fat and cholesterol in the Western diet push the homeostatic machinery beyond its physiological range. Under these conditions, macrophages become overwhelmed with cholesterol and undergo cell death, forming a plaque. Progression of this process leads to the growth of an atherosclerotic plaque that impedes blood flow and can result in stroke or heart attack.

A recent study in the Journal of Lipid Research investigated the role of macrophage Akt isoforms in atherosclerosis. Akt is a serine/threonine kinase that is an important regulator of a variety of cellular processes including signaling, metabolism and cell survival. Macrophages express three constitutively active isoforms of Akt (Akt1, Akt2 and Akt3). However, it is unclear whether Akt isoforms have specific or redundant function in macrophages and, more importantly, what the role of these specific isoforms are in the development of atherosclerosis.  

In the JLR study, researchers from Vanderbilt University Medical Center sought to elucidate the functional relevance of Akt1 and Akt2 in atherosclerosis. They utilized a genetic loss of function approach in order to selectively and specifically study the loss of these Akt isoforms in macrophages in a mouse model that lacks the low-density lipoprotein receptor.

Loss of Akt2, and not Akt1, in macrophages reduced both early and advanced atherosclerosis. This was demonstrated by a reduction in lesion area. Interestingly, when the plaques were stained for macrophages, loss of Akt2 resulted in a reduction in the number of macrophages that had invaded the plaque. In addition, the researchers went on to show that the reduced number of macrophages in the plaque resulted from a reduction in expression of macrophage chemokine C-C motif receptor 2, known as CCR2 for short, which plays a critical role in their ability to migrate into the plaque. This indicates that deficiency of Akt2 in macrophages may have a protective role in atherosclerosis, potentially by reducing plaque invasion by macrophages.

To further determine the mechanism of this reduction in atherosclerosis, the researcher investigated whether loss of either Akt1 or Akt2 altered macrophage identity. Indeed, macrophages lacking Akt2 demonstrated an immunosuppressive M2 phenotype, whereas those lacking Akt1 demonstrated a pro-inflammatory M1 phenotype. “Modulation of macrophage phenotype and CCR2 expression may be a promising strategy to treat atherosclerotic vascular disease,” says MacRae Linton, who led the study.

David Iaea David B. Iaea is a graduate student in the Tri-Institutional Program in Chemical Biology at Weill Cornell Medical College.