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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 atherosclerosis1, suggest that as-yet-unidentified mechanisms must contribute to vascular disease. Arterial walls undergo regional disturbances of metabolism2 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 atherosclerosis3. 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.

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Figure 1: Inducible expression of vascular wall UCP1.
Figure 2: Effects of vascular UCP1 expression on blood pressure, plasma renin activity and urinary sodium.
Figure 3: Effects of vascular UCP1 expression on diet-induced atherosclerosis and serum cholesterol.
Figure 4: Involvement of oxidative stress in the vascular phenotype after UCP1 induction.


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This study was supported by grants from the National Institutes of Health, Clinical Nutrition Research Unit, Diabetes Research and Training Center, an American Diabetes Association Mentor-Based Postdoctoral Fellowship, and by institutional resources provided by Washington University and the Siteman Cancer Center to the Proteomics Center at Washington University.

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Correspondence to Clay F. Semenkovich.

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Supplementary information

Supplementary Figure S1

Body weight and serum chemistries in Dox-treated SM22-TRE UCP1 mice. (EPS 335 kb)

Supplementary Figure S2

Blood pressure as determined by telemetry in SM22-TRE UCP1 mice (panel a) and SM22-TRE UCP1 apoE-/- mice (panel b). (EPS 300 kb)

Supplementary Figure S3

Effects of UCP1 induction on atherosclerosis and serum cholesterol in chow-fed mice. (EPS 587 kb)

Supplementary Figure S4

Metabolic characterization and glucose tolerance in SM22-TRE UCP1 apoE-/- mice with Western diet feeding. (EPS 360 kb)

Supplementary Figure S5

UCP1 expression in extra-aortic arteries. (EPS 307 kb)

Supplementary Figure S6

Effect of tempol on tail cuff blood pressure in Dox-treated SM22-TRE UCP1 apoE-/- mice. (EPS 303 kb)

Supplementary Figure Legends S1-S6

This file contains legends for Supplementary Figures 1-6. (DOC 11 kb)

Supplementary Methodology

This file contains Supplementary Methodology. (DOC 8 kb)

Supplementary Notes

This file contains additional references. (DOC 12 kb)

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Bernal-Mizrachi, C., Gates, A., Weng, S. et al. Vascular respiratory uncoupling increases blood pressure and atherosclerosis. Nature 435, 502–506 (2005).

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