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Vascular respiratory uncoupling increases blood pressure and atherosclerosis

Nature volume 435, pages 502–506 (2005)Cite this article

Abstract

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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References

  1. Allayee, H., Gharalpour, A. & Lusis, A. J. Using mice to dissect genetic factors in atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 23, 1501–1509 (2003)

    Article  CAS  Google Scholar 

  2. Heuper, W. C. General reviews. Arch. Pathol. 38, 162–181 (1944)

    Google Scholar 

  3. Santerre, R. F., Nicolosi, R. J. & Smith, S. C. Respiratory control in preatherosclerotic susceptible and resistant pigeon aortas. Exp. Mol. Pathol. 20, 397–406 (1974)

    Article  CAS  Google Scholar 

  4. Dröge, W. Free radicals in the physiological control of cell function. Physiol. Rev. 82, 47–95 (2002)

    Article  Google Scholar 

  5. Nohl, H. Generation of superoxide radicals as byproduct of cellular respiration. Ann. Biol. Clin. (Paris) 52, 199–204 (1994)

    CAS  Google Scholar 

  6. Skulachev, V. P. Uncoupling: New approaches to an old problem of bioenergetics. Biochim. Biophys. Acta 1363, 100–124 (1998)

    Article  CAS  Google Scholar 

  7. Echtay, K. S. et al. Superoxide activates mitochondrial uncoupling proteins. Nature 415, 96–99 (2002)

    Article  ADS  CAS  Google Scholar 

  8. Nishikawa, T. et al. Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature 404, 787–790 (2000)

    Article  ADS  CAS  Google Scholar 

  9. Blanc, J. et al. Protective role of uncoupling protein 2 in atherosclerosis. Circulation 107, 388–390 (2003)

    Article  CAS  Google Scholar 

  10. Pettersson, G. Effect of dinitrophenol and anoxia on isometric tension in rabbit colon smooth muscle. Acta Pharmacol. Toxicol. (Copenh.) 57, 184–189 (1985)

    Article  CAS  Google Scholar 

  11. Moessler, H. et al. The SM 22 promoter directs tissue-specific expression in arterial but not in venous or visceral smooth muscle cells in transgenic mice. Development 122, 2415–2425 (1996)

    CAS  PubMed  Google Scholar 

  12. Manning, M. W., Cassis, L. A. & Daugherty, A. Differential effects of doxycycline, a broad-spectrum matrix metalloproteinase inhibitor, on angiotensin II-induced atherosclerosis and abdominal aortic aneurysms. Arterioscler. Thromb. Vasc. Biol. 23, 483–488 (2003)

    Article  CAS  Google Scholar 

  13. Heaton, J. M. The distribution of brown adipose tissue in the human. J. Anat. 112, 35–39 (1972)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  14. Szekely, M., Kellermayer, M., Cholnoky, G. & Sumegi, I. Thermoregulatory heat production by periaortic brown adipose tissue in the non-cold-acclimatized rat. Experientia 26, 1314–1315 (1970)

    Article  CAS  Google Scholar 

  15. Kanski, J., Behring, A., Pelling, J. & Schöneich, C. Proteomic identification of 3-nitrotyrosine-containing rat cardiac proteins: effect of biological aging. Am. J. Physiol. Heart Circ. Physiol. 288, H371–H381 (2005)

    Article  CAS  Google Scholar 

  16. Su, B. et al. Redox regulation of vascular smooth muscle cell differentiation. Circ. Res. 89, 39–46 (2001)

    Article  CAS  Google Scholar 

  17. Zai, A., Rudd, M. A., Scribner, A. W. & Loscalzo, J. Cell-surface protein disulfide isomerase catalyzes transnitrosation and regulates intracellular transfer of nitric oxide. J. Clin. Invest. 103, 393–399 (1999)

    Article  CAS  Google Scholar 

  18. Tamarit, J., Cabiscol, E. & Ros, J. Identification of the major oxidatively damaged proteins in Escherichia coli cells exposed to oxidative stress. J. Biol. Chem. 273, 3027–3032 (1998)

    Article  CAS  Google Scholar 

  19. Gardner, P. R. Aconitase: Sensitive target and measure of superoxide. Methods Enzymol. 349, 9–23 (2002)

    Article  CAS  Google Scholar 

  20. Watts, H. in Evolution of the Atherosclerotic Plaque (ed. Jones, R. J.) 117 (Univ. Chicago, Chicago, 1963)

    Google Scholar 

  21. Chen, J. et al. Hypertension does not account for the accelerated atherosclerosis and development of aneurysms in male apolipoprotein E/endothelial nitric oxide synthase double knockout mice. Circulation 104, 2391–2394 (2001)

    Article  CAS  Google Scholar 

  22. Knowles, J. W. et al. Enhanced atherosclerosis and kidney dysfunction in eNOS-/- apoE-/- mice are ameliorated by enalapril treatment. J. Clin. Invest. 105, 451–458 (2000)

    Article  CAS  Google Scholar 

  23. Levin, M. et al. Mapping of ATP, glucose, glycogen and lactate concentrations within the arterial wall. Arterioscler. Thromb. Vasc. Biol. 25, 1801–1807 (2003)

    Article  Google Scholar 

  24. Jennings, R. B., Kaltenbach, J. P. & Sommers, H. M. Mitochondrial metabolism in ischemic injury. Arch. Pathol. 84, 15–19 (1967)

    CAS  PubMed  Google Scholar 

  25. Smith, E. B. The effects of age and of early atheromata on the intimal lipids in men. Biochem. J. 84, 49P (1962)

    Google Scholar 

  26. Smith, E. B. Lipids carried by Sf 0–12 lipoprotein in normal and hypercholesterolaemic serum. Lancet 2, 530–534 (1962)

    Article  CAS  Google Scholar 

  27. Klein, P. D. & Johnson, R. M. Phosphorus metabolism in unsaturated fatty acid-deficient rats. J. Biol. Chem. 211, 103–110 (1954)

    CAS  PubMed  Google Scholar 

  28. Hayashida, T. & Portman, O. W. Swelling of liver mitochondria from rats fed diets deficient in essential fatty acids. Proc. Soc. Exp. Biol. Med. 103, 656–659 (1960)

    Article  CAS  Google Scholar 

  29. Cornwell, D. G. & Panganamala, R. V. Atherosclerosis: an intracellular deficiency in essential fatty acids. Prog. Lipid Res. 20, 365–376 (1981)

    Article  CAS  Google Scholar 

  30. Sjodin, B., Hellsten Westing, Y. & Apple, F. S. Biochemical mechanisms for oxygen free radical formation during exercise. Sports Med. 10, 236–254 (1990)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

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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Author notes

  1. Carlos Bernal-Mizrachi and Allison C. Gates: *These authors contributed equally to this work

Authors and Affiliations

  1. Department of Medicine, Division of Endocrinology, Metabolism & Lipid Research,

    Carlos Bernal-Mizrachi, Allison C. Gates, Sherry Weng, Pascual DeSantis, Trey Coleman, R. Reid Townsend & Clay F. Semenkovich

  2. Department of Pediatrics, Washington University School of Medicine, St Louis, Missouri, 63110, USA

    Takuji Imamura & Louis J. Muglia

  3. Department of Cell Biology & Physiology, Washington University School of Medicine, St Louis, Missouri, 63110, USA

    Russell H. Knutsen & Clay F. Semenkovich

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  1. Carlos Bernal-Mizrachi
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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). https://doi.org/10.1038/nature03527

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