Atherosclerotic plaque formation is the result of lipid accumulation in the arterial intima leading to foam cell formation and is exacerbated by high fat diet feeding. The accumulation of lipids in arterial plaques can be viewed as a problem of lipid storage, i.e. adipose depots are not able to efficiently buffer the excessive lipid intake. Insufficient storage capacity can lead to lipid deposition in other metabolic organs, particularly the liver, resulting in a cholesterol imbalance. Fatty liver subsequently results in increased plasma lipids which underlie lipid plaque formation. We have recently demonstrated that a protein previously uncharacterized in the cardiovascular system, phosphoprotein enriched in astrocytes (PEA)−15, plays a central role in maintaining normal arterial function, particularly in response to stress stimuli. PEA-15 acts as a brake on extracellular signal-regulated kinases (ERK) 1/2-dependent gene expression. ERK1/2 are signalling enzymes that control a large variety of cellular processes. Importantly, ERK1/2 activity is also a critical component during adipose tissue expansion. In the current study we hypothesized that PEA-15 can regulate adipose tissue expansion which could ultimately control lipid plaque formation in atherosclerosis.
We generated a novel, double knockout (KO) transgenic mouse line null for both PEA-15 and apolipoprotein E (ApoE). Mice were fed a high fat/cholesterol diet (HFD) (42% kcal from fat) for 16 weeks to induce plaque formation. After 16 weeks of HFD, the PEA-15/ApoE KO mice weighed significantly more than ApoE KO mice (PEA-15/ApoE KO - 44.1±1.7 g versus ApoE KO - 38.4±1.3 g, p<0.05, n=6). This was the result of increased white adipose tissue depots in PEA-15/ApoE KO mice. Surprisingly, despite this increased adipose tissue weight, total plaque area in the thoracic aorta was significant decreased in PEA-15/ApoE KO mice (as measured by contrast microscopy 17.8%±2.2% versus 27.6±3.3% in ApoE KO, p<0.05, n=6). In cross sections of these plaques, we found that the caps of the plaques in the PEA-15/ApoE KO mice were thicker. To investigate the lipid storage after the high fat diet, cross sections of the abdominal adipose tissue were examined in these mice. Adipocytes in PEA-15/ApoE KO mice were significant larger (5.7±0.5 μm2 compared to 4.2±0.5 μm2 in ApoE KO, p<0.05, n=7). This suggests that PEA-15 plays a role in the lipid storage capacity of adipocytes. To determine if this is a protective mechanism against lipid deposition in other important peripheral metabolic tissues, such as the liver, we examined hepatic lipid levels. Hepatic triglyceride levels were significantly decreased in PEA-15/ApoE KO mice (72.7±10.2 µg/mg liver versus 114.9±11.1 µg/mg liver in ApoE, p<0.05, n=5–7).
Our observations together suggest that PEA-15 plays a role in plaque formation through involvement in lipid deposition. This study demonstrates that PEA-15 protein deletion attenuates atherosclerotic plaque formation. This coincides with an increased lipid storage capacity in adipocytes, thereby protecting other metabolic organs from the associated increased lipid burden. Therefore, decreasing PEA-15 levels and/or activity may be a therapeutic target to alter the progression of atherosclerosis.
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