Kidney Week

Abstract: SA-OR33

Inorganic Nitrite Supplementation Improves Endothelial Function with Aging: Translational Evidence for Suppression of Mitochondria-Derived Oxidative Stress

Session Information

• Hypertension and Vascular Disease: From the Lab to Trials
  October 24, 2020 | Location: Simulive
  Abstract Time: 05:00 PM - 07:00 PM

Category: Hypertension and CVD

• 1403 Hypertension and CVD: Mechanisms

Authors

• Rossman, Matthew J., University of Colorado Boulder College of Arts and Sciences, Boulder, Colorado, United States

Matthew J. Rossman, PhD

• Gioscia-Ryan, Rachel A., University of Colorado Boulder College of Arts and Sciences, Boulder, Colorado, United States

Rachel A. Gioscia-Ryan,

• Santos-Parker, Jessica R., University of Colorado Boulder College of Arts and Sciences, Boulder, Colorado, United States

Jessica R. Santos-Parker,

• Ziemba, Brian P., University of Colorado Boulder College of Arts and Sciences, Boulder, Colorado, United States

Brian P. Ziemba,

• Lubieniecki, Kara L., University of Colorado Boulder College of Arts and Sciences, Boulder, Colorado, United States

Kara L. Lubieniecki,

• Poliektov, Natalie E., University of Colorado Boulder College of Arts and Sciences, Boulder, Colorado, United States

Natalie E. Poliektov,

• Johnson, Lawrence C., University of Colorado Boulder College of Arts and Sciences, Boulder, Colorado, United States

Lawrence C. Johnson,

• Nagy, Erzsebet E., University of Colorado Boulder College of Arts and Sciences, Boulder, Colorado, United States

Erzsebet E. Nagy,

• Woodward, Kayla A., University of Colorado Boulder College of Arts and Sciences, Boulder, Colorado, United States

Kayla A. Woodward,

• Sindler, Amy L., University of Colorado Boulder College of Arts and Sciences, Boulder, Colorado, United States

Amy L. Sindler,

• Chonchol, Michel, University of Colorado Denver - Anschutz Medical Campus, Aurora, Colorado, United States

Michel Chonchol,

• Seals, Douglas R., University of Colorado Boulder College of Arts and Sciences, Boulder, Colorado, United States

Douglas R. Seals,

Background

We previously observed improvements in vascular endothelial function with inorganic nitrite supplementation in old mice, which we translated to older humans in a pilot study of sodium nitrite supplementation.

Methods

Here, we sought to confirm the efficacy of sodium nitrite in humans and determine mechanisms of action using: 1) a randomized, placebo-controlled, parallel-group clinical trial with sodium nitrite (80 mg/day, 12 weeks) in older adults (n=49, 68±1 yr) and 2) reverse translation experiments in young (6 mo) and old (27 mo) male C57BL6 mice.

Results

In humans, sodium nitrite increased plasma nitrite (p<0.05) and was well-tolerated over 12 weeks. Endothelial function (brachial artery flow-mediated dilation) was increased by 28% vs. baseline after nitrite supplementation (p<0.05), but unchanged with placebo. Serum from nitrite-treated subjects reduced whole-cell (CellROX) and mitochondria (mito)-specific (MitoSOX) reactive oxygen species (ROS) in human umbilical vein endothelial cell culture (p<0.05), whereas serum from placebo-treated subjects had no effect. Old mice (OC, n=9) had ~30% lower ex vivo carotid artery endothelium-dependent dilation (EDD) vs. young mice (YC, n=9) due to reduced nitric oxide (NO) bioavailability (p<0.05). Nitrite supplementation (drinking water, 50 mg/L, 8 weeks) restored EDD and NO bioavailability in old mice (ON, n=10). MitoROS suppression of EDD was present in OC (increased EDD with a mito-targeted antioxidant, p<0.05), but not in Y or ON. A mito stressor (rotenone) further impaired EDD in OC (p<0.05), whereas Y and ON were protected.

Conclusion

Nitrite supplementation improves age-related endothelial dysfunction and is associated with increased NO, reduced mito ROS and improved mitochondrial stress resistance.

Funding

• NIDDK Support