Abstract
Aging and atherosclerosis are well-recognized risk factors for cardiac and neurovascular diseases. The Apolipoprotein E deficient (ApoE−/−) mouse on a high-fat diet is a classical model of atherosclerosis, characterized by the presence of atherosclerotic plaques in extracranial vessels but not in cerebral arteries. Increase in arginase activity was shown to participate in vascular dysfunction in the peripheral arteries of atherosclerotic mice by changing the level of nitric oxide (NO). NO plays a key role in the physiological functions of the neurovascular unit (NVU). However, the regulation of arginase expression and activity in the brain was never investigated in association with changes in the NVU, ApoE deficiency and high fat diet.Fourteen-month-old ApoE−/− mice on high-fat diet exhibited deposition of lipids in the NVU, impairment of blood–brain barrier properties, astrogliosis and an increase of aquaporin 4 staining. In association with these changes, brain arginase activity was significantly increased in the old ApoE−/− mice as compared to old wild type mice, with an increase in the level of arginase type I in the blood vessels.In conclusion, aging in this classical mouse model of atherosclerosis induces an increase in the level and activity of arginase I that may impair NO synthesis and contribute to changes in the NVU leading to blood–brain barrier leakage and inflammation.
Highlights
Apolipoprotein E deficient (ApoE−/−) mice have been widely used as animal models to study the pathophysiology of atherosclerosis
high density lipoprotein (HDL), and low density lipoprotein (LDL) in young and old wild type (WT) and ApoE−/− mice As stated in the introduction, the ApoE−/− mouse on a Western diet is a well-characterized model of atherosclerosis with high blood levels of cholesterol, HDL and LDL contributing to the formation of plaques in peripheral blood vessels
There was no change in plasma concentrations of cholesterol, HDL and LDL between young and old WT mice
Summary
Apolipoprotein E deficient (ApoE−/−) mice have been widely used as animal models to study the pathophysiology of atherosclerosis These mice have the propensity to spontaneously develop atherosclerotic lesions, and ingestion of a Western diet exacerbates the development of plaques in peripheral blood vessels [1]. The model is characterized by a 5 to 10 times increase in serum cholesterol levels and by the local deposition of lipids in the arterial wall These mice develop a complex endothelial dysfunction [2], with adhesion of a large number of T cells and macrophages leading to chronic inflammation systemically and at intraplaques [3,4]. In the brain of ApoE−/− mice, the deficiency of ApoE was associated with gliosis stimulation, microglia activation [11] and xanthoma accumulation around blood vessels Despite these changes, no intravascular plaques were formed [12]
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