Increase of arginase activity in old apolipoprotein-E deficient mice under Western diet associated with changes in neurovascular unit.
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.
Departments of Pediatrics and Physiology, Linda University School of Medicine, Coleman Pavilion, Room A1120, 11175 Campus Street, Loma Linda, CA 92354, USA. Jbadaut@llu.edu
Jérôme
J
Badaut
Jean-Christophe
JC
Copin
Andrew M
AM
Fukuda
Yvan
Y
Gasche
Karl
K
Schaller
Rafaela F
RF
da Silva
D000375:Aging / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D001119:Arginase / Q000235:genetics / Q000378:metabolism*; D050197:Atherosclerosis / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D001812:Blood-Brain Barrier / Q000201:enzymology* / Q000503:physiopathology; D059305:Diet, High-Fat / Q000009:adverse effects*; D004789:Enzyme Activation / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics*
D001057:Apolipoproteins E; D009569:Nitric Oxide; C544448:Arg1 protein, mouse; D001119:Arginase