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Chronic Exercise Mitigates the Effects of Sirtuin Inhibition by Salermide on Endothelium-Dependent Vasodilation

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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.

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Data Availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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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).

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  1. Molecular and Cardiovascular Physiology Laboratory, Department of Health Sciences, William & Mary, Williamsburg, VA, 23187-8795, USA

    M. Brennan Harris, Rebecka M. Hoffman & Matthew Olesiak

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  1. M. Brennan Harris
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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.

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Correspondence to M. Brennan Harris.

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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.

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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

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