Abstract
Sirtuins are regulators of eNOS and endothelial function; however, no studies have examined the influence of exercise on sirtuin regulation of endothelial function. Effects of the novel sirtuin inhibitor, salermide, on vascular reactivity in rat aortas were investigated following exercise training of different durations. Male Wistar rats (8–9 months old) were divided into four groups (n = 10–12/group): sedentary (SED), 1 day (1D), 2 weeks (2WK), or 6 weeks (6WK) of exercise. Exercise consisted of running on a motor-driven treadmill at 15 m/min, 15% grade, for 40 min (1D) increased up to 1 h at the end of 2 weeks (2WK) and sustained for an additional 4 weeks (6WK). Dose responses to phenylephrine, sodium nitroprusside, and acetylcholine in the presence or absence of salermide (30 µM) were analyzed. SIRT1 and eNOS protein expression as well as nitrotyrosine levels were determined by immunoblotting. Superoxide dismutase activity was determined by colorimetric assay. Sirtuin inhibition significantly impaired acetylcholine-induced vasorelaxtion in aortas in SED, 1D, and 2WK endurance trained rats but not in 6WK. eNOS expression significantly increased ~ 2.0-fold in 1D, 2WK, and 6WK groups. SIRT1 expression and 3-nitrotyrosine levels were significantly increased in 1D and 2WK but were not significantly elevated in 6WK. SOD levels were significantly elevated in 6WK. These data suggest that chronic endurance training diminishes the role of sirtuins in regulating endothelium-dependent relaxation and appears to be related to changes in SIRT1 expression as well as redox status.
Similar content being viewed by others
Data Availability
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
Code Availability
Not applicable.
References
Nelson, M. E., Rejeski, W. J., Blair, S. N., Duncan, P. W., Judge, J. O., King, A. C., Macera, C. A., & Castaneda-Sceppa, C. (2007). Physical activity and public health in older adults: Recommendation from the American College of Sports Medicine and the American Heart Association. Medicine and Science in Sports and Exercise, 39, 1435–1445.
Green, D. J., Walsh, J. H., Maiorana, A., Burke, V., Taylor, R. R., & O’Driscoll, J. G. (2004). Comparison of resistance and conduit vessel nitric oxide-mediated vascular function in vivo: Effects of exercise training. Journal of Applied Physiology, 97, 749–755.
Starnes, J. W., & Taylor, R. P. (2007). Exercise-induced cardioprotection: Endogenous mechanisms. Medicine and Science in Sports and Exercise, 39, 1537–1543.
Hsu, C. P., Odewale, I., Alcendor, R. R., & Sadoshima, J. (2008). Sirt1 protects the heart from aging and stress. Bilogical Chemistry, 389, 221–231.
Mattagajasingh, I., Kim, C. S., Naqvi, A., Yamamori, T., Hoffman, T. A., Jung, S. B., DeRicco, J., Kasuno, K., & Irani, K. (2007). SIRT1 promotes endothelium-dependent vascular relaxation by activating endothelial nitric oxide synthase. Proceedings of the National Academy of Sciences USA, 104, 14855–14860.
Donato, A. J., Magerko, K. A., Lawson, B. R., Durrant, J. R., Lesniewski, L. A., & Seals, D. R. (2011). SIRT-1 and vascular endothelial dysfunction with ageing in mice and humans. Journal of Physiology, 589, 4545–4554.
Nisoli, E., Tonello, C., Cardile, A., Cozzi, V., Bracale, R., Tedesco, L., Falcone, S., Valerio, A., Cantoni, O., Clementi, E., Moncada, S., & Carruba, M. O. (2005). Calorie restriction promotes mitochondrial biogenesis by inducing the expression of eNOS. Science, 310, 314–317.
Guthikonda, S., & Haynes, W. G. (2006). Homocysteine: Role and implications in atherosclerosis. Current Atherosclerosis Reports, 8, 100–106.
Fulco, M., Schiltz, R. L., Iezzi, S., King, M. T., Zhao, P., Kashiwaya, Y., Hoffman, E., Veech, R. L., & Sartorelli, V. (2003). Sir2 regulates skeletal muscle differentiation as a potential sensor of the redox state. Molecular Cell, 12, 51–62.
Guarente, L. (2006). Sirtuins as potential targets for metabolic syndrome. Nature, 444, 868–874.
White, A. T., & Schenk, S. (2012). NAD/NADH and skeletal muscle mitochondrial adaptations to exercise. American Journal of Physiology-Endocrinology and Metabolism, 303, E308–E321.
Delp, M. D., McAllister, R. M., & Laughlin, M. H. (1993). Exercise training alters endothelium-dependent vasoreactivity of rat abdominal aorta. Journal of Applied Physiology, 75, 1354–1363.
Kojda, G., & Hambrecht, R. (2005). Molecular mechanisms of vascular adaptations to exercise. Physical activity as an effective antioxidant therapy? Cardiovascular Research, 67(2), 187–97.
Di Francescomarino, S., Sciartilli, A., Di Valerio, V., Di Baldassarre, A., & Gallina, S. (2009). The effect of physical exercise on endothelial function. Sports Medicine, 39, 797–812.
Santos, L., Escande, C., & Denicola, A. (2016). Potential modulation of sirtuins by oxidative stress. Oxidative Medicine and Cellular Longevity, 2016, 9831825.
Lara, E., Mai, A., Calvanese, V., Altucci, L., Lopez-Nieva, P., Martinez-Chantar, M. L., Varela-Rey, M., Rotili, D., Nebbioso, A., Ropero, S., Montoya, G., Oyarzabal, J., Velasco, S., Serrano, M., Witt, M., Villar-Garea, A., Imhof, A., Mato, J. M., Esteller, M., & Fraga, M. F. (2009). Salermide, a Sirtuin inhibitor with a strong cancer-specific proapoptotic effect. Oncogene, 28, 781–791.
Yao, Q. P., Qi, Y. X., Zhang, P., Cheng, B. B., Yan, Z. Q., & Jiang, Z. L. (2013). SIRT1 and Connexin40 Mediate the normal shear stress-induced inhibition of the proliferation of endothelial cells co-cultured with vascular smooth muscle cells. Cellular Physiology and Biochemistry, 31(2–3), 389–399.
Ali, T. K., Matragoon, S., Pillai, B. A., Liou, G. I., & El-Remessy, A. B. (2008). Peroxynitrite mediates retinal neurodegeneration by inhibiting nerve growth factor survival signaling in experimental and human diabetes. Diabetes, 57, 889–898.
Suwa, M., Nakano, H., Radak, Z., & Kumagai, S. (2008). Endurance exercise increases the SIRT1 and peroxisome proliferator-activated receptor gamma coactivator-1alpha protein expressions in rat skeletal muscle. Metabolism, 57, 986–998.
Gurd, B. J., Yoshida, Y., McFarlan, J. T., Holloway, G. P., Moyes, C. D., Heigenhauser, G. J. F., Spriet, L., & Bonen, A. (2011). Nuclear SIRT1 activity, but not protein content, regulates mitochondrial biogenesis in rat and human skeletal muscle. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 301, R67–R75.
Chabi, B., Adhihetty, P. J., O’Leary, M. F. N., Menzies, K. J., & Hood, D. A. (2009). Relationship between Sirt1 expression and mitochondrial proteins during conditions of chronic muscle use and disuse. Journal of Applied Physiology, 107, 1730–1735.
Huffman, D. M., Moellering, D. R., Grizzle, W. E., Stockard, C. R., Johnson, M. S., & Nagy, T. R. (2008). Effect of exercise and calorie restriction on biomarkers of aging in mice. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 294, R1618–R1627.
Li, L., Mühlfeld, C., Niemann, B., Pan, R., Li, R., Hilfiker-Kleiner, D., Chen, Y., & Rohrbach, S. (2011). Mitochondrial biogenesis and PGC-1α deacetylation by chronic treadmill exercise: Differential response in cardiac and skeletal muscle. Basic Research in Cardiology, 106, 1221–1234.
Cacicedo, J. M., Gauthier, M. S., Lebrasseur, N. K., Jasuja, R., Ruderman, N. B., & Ido, Y. (2011). Acute exercise activates AMPK and eNOS in the mouse aorta. American Journal of Physiology-Heart and Circulatory Physiology, 301, H1255–H1265.
Sun, M. W., Zhong, M. F., Gu, J., Qian, F. L., Gu, J. Z., & Chen, H. (2008). Effects of different levels of exercise volume on endothelium-dependent vasodilation: Roles of nitric oxide synthase and heme oxygenase. Hypertension Research, 31, 805–816.
Chen, Z., Peng, I. C., Cui, X., Li, Y. S., Chien, S., & Shyy, J. Y. J. (2010). Shear stress, SIRT1, and vascular homeostasis. Proceedings of the National Academy of Sciences, 107, 10268–10273.
Potente, M., & Dimmeler, S. (2008). Emerging roles of SIRT1 in vascular endothelial homeostasis. Cell Cycle, 7, 2117–2122.
Suvorava, T., & Kojda, G. (2007). Prevention of transient endothelial dysfunction in acute exercise: A friendly fire? Thrombosis and Haemostasis-Stuttgart, 97, 331.
Ahsan, H. (2013). 3-Nitrotyrosine: A biomarker of nitrogen free radical species modified proteins in systemic autoimmunogenic conditions. Human Immunology, 74, 1392–1399.
Adachi, T. (2010). Modulation of vascular sarco/endoplasmic reticulum calcium ATPase in cardiovascular pathophysiology. Advanced Pharmacology, 59, 165–195.
Higashi, Y., & Yoshizumi, M. (2004). Exercise and endothelial function: Role of endothelium-derived nitric oxide and oxidative stress in healthy subjects and hypertensive patients. Pharmacology and Therapeutics, 102, 87.
Gielen, S., Sandri, M., Erbs, S., & Adams, V. (2011). Exercise-induced modulation of endothelial nitric oxide production. Current Pharmaceutical Biotechnology, 12, 1375–1384.
Zhang, J., Wang, C., Nie, H., Wu, D., & Ying, W. (2016). SIRT2 plays a significant role in maintaining the survival and energy metabolism of PIEC endothelial cells. International Journal of Physiology, Pathophysiology and Pharmacology, 8(3), 120.
Roque, F. R., Hernanz, R., Salaices, M., & Briones, A. M. (2013). Exercise training and cardiometabolic diseases: Focus on the vascular system. Current Hypertension Reports, 15, 204–214.
Acknowledgements
The authors would like to thank Dr. Robin Looft-Wilson for review of this manuscript.
Funding
This work was supported by the National Heart, Lung, and Blood Institute 1R15HL10842828-01A1 (MBH). This work was supported by Thomas F. and Kate Miller Jeffress Memorial Trust J-930 (MBH). This work was supported by The Charles Center Honors Fellowship (RMH).
Author information
Authors and Affiliations
Contributions
All authors whose names appear on the submission made substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data.
Corresponding author
Ethics declarations
Conflict of interest
The authors have no conflicts of interest to declare that are relevant to the content of this article.
Ethical Approval
Experiments were approved by the Institutional Animal Care and Use Committee of The College of William & Mary and adhered to the Guide for the Care and Use of Laboratory Animals published by the U.S. National Institutes of Health and the principles of laboratory animal care (NIH publication No. 86-23, revised 1985) were followed.
Consent to Participate
Not applicable.
Consent for Publication
Not applicable.
Additional information
Handling Editor: Y. Robert Li.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Harris, M.B., Hoffman, R.M. & Olesiak, M. Chronic Exercise Mitigates the Effects of Sirtuin Inhibition by Salermide on Endothelium-Dependent Vasodilation. Cardiovasc Toxicol 21, 790–799 (2021). https://doi.org/10.1007/s12012-021-09669-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12012-021-09669-8