Vascular respiratory uncoupling increases blood pressure and atherosclerosis.
The observations that atherosclerosis often occurs in non-smokers without elevated levels of low-density lipoprotein cholesterol, and that most atherosclerosis loci so far identified in mice do not affect systemic risk factors associated with atherosclerosis, suggest that as-yet-unidentified mechanisms must contribute to vascular disease. Arterial walls undergo regional disturbances of metabolism that include the uncoupling of respiration and oxidative phosphorylation, a process that occurs to some extent in all cells and may be characteristic of blood vessels being predisposed to the development of atherosclerosis. To test the hypothesis that inefficient metabolism in blood vessels promotes vascular disease, we generated mice with doxycycline-inducible expression of uncoupling protein-1 (UCP1) in the artery wall. Here we show that UCP1 expression in aortic smooth muscle cells causes hypertension and increases dietary atherosclerosis without affecting cholesterol levels. UCP1 expression also increases superoxide production and decreases the availability of nitric oxide, evidence of oxidative stress. These results provide proof of principle that inefficient metabolism in blood vessels can cause vascular disease.
Bernal-Mizrachi
Carlos
C
Department of Medicine, Division of Endocrinology, Metabolism & Lipid Research, Washington University School of Medicine, St Louis, Missouri 63110, USA.
Gates
Allison C
AC
Weng
Sherry
S
Imamura
Takuji
T
Knutsen
Russell H
RH
DeSantis
Pascual
P
Coleman
Trey
T
Townsend
R Reid
RR
Muglia
Louis J
LJ
Semenkovich
Clay F
CF
D000154:Aconitate Hydratase / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000166:cytology*; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D001161:Arteriosclerosis / Q000235:genetics / Q000503:physiopathology*; D001794:Blood Pressure / Q000502:physiology*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D019069:Cell Respiration / Q000502:physiology*; D002784:Cholesterol / Q000097:blood; D004032:Diet; D004318:Doxycycline / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D007473:Ion Channels; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D024101:Mitochondrial Proteins; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D018384:Oxidative Stress; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D012083:Renin / Q000097:blood; D012964:Sodium / Q000652:urine; D013481:Superoxides / Q000378:metabolism; D019076:Transgenes / Q000235:genetics; D014475:Uncoupling Agents / Q000378:metabolism*; D000071256:Uncoupling Protein 1
D001057:Apolipoproteins E; D002352:Carrier Proteins; D007473:Ion Channels; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; C000604372:Ucp1 protein, mouse; D014475:Uncoupling Agents; D000071256:Uncoupling Protein 1; D013481:Superoxides; D002784:Cholesterol; D012964:Sodium; D012083:Renin; D000154:Aconitate Hydratase; D004318:Doxycycline