Nitrite activates AMP kinase to stimulate mitochondrial biogenesis independent of soluble guanylate cyclase
Open accessAbstract
Nitrite, a dietary constituent and endogenous signaling molecule, mediates a number of physiological responses including modulation of ischemia/reperfusion injury, glucose tolerance, and vascular remodeling. Although the exact molecular mechanisms underlying nitrite's actions are unknown, the current paradigm suggests that these effects depend on the hypoxic reduction of nitrite to nitric oxide (NO). Mitochondrial biogenesis is a fundamental mechanism of cellular adaptation and repair. However, the effect of nitrite on mitochondrial number has not been explored. Herein, we report that nitrite stimulates mitochondrial biogenesis through a mechanism distinct from that of NO. We demonstrate that nitrite significantly increases cellular mitochondrial number by augmenting the activity of adenylate kinase, resulting in AMP kinase phosphorylation, downstream activation of sirtuin-1, and deacetylation of PGC1α, the master regulator of mitochondrial biogenesis. Unlike NO, nitrite-mediated biogenesis does not require the activation of soluble guanylate cyclase and results in the synthesis of more functionally efficient mitochondria. Further, we provide evidence that nitrite mediates biogenesis in vivo. In a rat model of carotid injury, 2 weeks of continuous oral nitrite treatment postinjury prevented the hyperproliferative response of smooth muscle cells. This protection was accompanied by a nitrite-dependent upregulation of PGC1α and increased mitochondrial number in the injured artery. These data are the first to demonstrate that nitrite mediates differential signaling compared to NO. They show that nitrite is a versatile regulator of mitochondrial function and number both in vivo and in vitro and suggest that nitrite-mediated biogenesis may play a protective role in the setting of vascular injury.
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Increased exposure to nitrate and nitrite has been reported to activate PGC1-α and adenosine monophosphate-activated protein kinase (AMPK) in skeletal muscle.
“Increased exposure to NO 3 -and NO 2 -has been reported to activate PGC1-α (peroxisome proliferator-activated receptor γ coactivator 1-α) (129) and adenosine monophosphate-activated protein kinase (AMPK) (101) in skeletal muscle.”
From Dietary Nitrate and Physical Performance (2018) · cites this paper as [101]
The Results section, “Nitrite mediates biogenesis through activation of PGC1, SIRT1, and AMPK” (page unavailable), supports nitrite-dependent AMPK activation. But the Methods identify the experimental cells as rat aortic smooth muscle cells, not skeletal muscle; this source also does not establish the claimed effect of nitrate. In the citing sentence, this citation is attached to AMPK, while the PGC1-α claim has a separate citation. (LLM, conf=0.88)
Experimental — accuracy not yet measuredMultiple preclinical studies suggest nitrite may be effective for prevention and/or treatment of many cardiovascular disorders or risk factors for cardiovascular disease including peripheral artery disease, atherosclerosis, chronic heart failure, stroke, diabetes, and hypertension.
“multiple studies in preclinical models suggest that nitrite also may be effective for the prevention and/or treatment of many cardiovascular disorders or risk factors for CVD including peripheral artery disease (4, 69, 146), atherosclerosis (2, 3, 5, 127), chronic heart failure (32, 122), stroke (50, 82, 150), diabetes (138), and hypertension (22, 57, 58, 128).”
From Inorganic nitrite supplementation for healthy arterial aging (2014) · cites this paper as [127]
Nitrite-induced stimulation of mitochondrial biogenesis is associated with increases in AMPK and PGC1-α signaling in aortic smooth muscle cells in an experimental model of carotid artery injury.
“A recent study reported nitrite-induced stimulation of mitochondrial biogenesis is associated with increases in adenosine monophosphate-activated protein kinase and peroxisome proliferator-activated receptor gamma coactivator 1-α signaling in aortic smooth muscle cells in an experimental model of carotid artery injury (127).”
From Inorganic nitrite supplementation for healthy arterial aging (2014) · cites this paper as [127]
NO deficiency is associated with impaired mitochondrial function.
“Emerging evidence suggests that NO deficiency is associated with impaired mitochondrial function”
From Inorganic nitrite supplementation for healthy arterial aging (2014) · cites this paper as [127]
Restoration of NO bioavailability induces mitochondrial biogenesis.
“and that restoration of NO bioavailability induces mitochondrial biogenesis (127, 135, 167, 168)”
From Inorganic nitrite supplementation for healthy arterial aging (2014) · cites this paper as [127]
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1 retracted
Mechanism of Catecholamine-Induced Proliferation of Vascular Smooth Muscle Cells
Yu, S., Tsai, S.-Y., Guh, J., Ko, F., Teng, C., & Ou, J. T. (1996) · Circulation · doi:10.1161/01.cir.94.3.547 · Cited by 87 · see citing works
RetractedWu, Z., Puigserver, P., Andersson, U., Zhang, C., Adelmant, G., Mootha, V., Troy, A., Cinti, S., Lowell, B., Scarpulla, R. C., et al. (1999) · Cell · doi:10.1016/s0092-8674(00)80611-x · Cited by 4,139 · see citing works
AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity
Cantó, C., Gerhart-Hines, Z., Feige, J. N., Lagouge, M., Noriega, L., Milne, J. C., Elliott, P. J., Puigserver, P., & Auwerx, J. (2009) · Nature · doi:10.1038/nature07813 · Cited by 3,300 · see citing works
The nitrate-nitrite-nitric oxide pathway in physiology and therapeutics
Lundberg, J. O., Weitzberg, E., & Gladwin, M. T. (2008) · Nature Reviews Drug Discovery · doi:10.1038/nrd2466 · Cited by 2,739 · cited 2× · see citing works
“Once thought to be physiologically inert, it is now recognized that NO2 is bioactivated along a decreasing physiological oxygen and pH gradient through its reaction with deoxygenated heme proteins, particularly myoglobin in the heart and smooth muscle [17-20].”
BackgroundTranscriptional co-activator PGC-1α drives the formation of slow-twitch muscle fibres
Lin, J., Wu, H., Tarr, P. T., Zhang, C.-Y., Wu, Z., Boss, O., Michael, L. F., Puigserver, P., Isotani, E., Olson, E. N., et al. (2002) · Nature · doi:10.1038/nature00904 · Cited by 2,546 · see citing works
AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy
Hardie, D. G. (2007) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2249 · Cited by 2,207 · see citing works
Chandel, N. S., McClintock, D. S., Feliciano, C. E., Wood, T. M., Melendez, J. A., Rodriguez, A. M., & Schumacker, P. T. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m001914200 · Cited by 2,000 · see citing works
Biochemical Adaptations in Muscle
Holloszy, J. O. (1967) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)96046-1 · Cited by 1,517 · see citing works
Calorie restriction promotes mitochondrial biogenesis by inducing the expression of eNOS
Nisoli, E., Tonello, C., Cardile, A., Cozzi, V., Bracale, R., Tedesco, L., Falcone, S., Valerio, A., Cantoni, O., Clementi, E., et al. (2005) · Science · doi:10.1126/science.1117728 · Cited by 1,107 · see citing works
Fulco, M., Cen, Y., Zhao, P., Hoffman, E. P., McBurney, M. W., Sauve, A. A., & Sartorelli, V. (2008) · Developmental Cell · doi:10.1016/j.devcel.2008.02.004 · Cited by 821 · see citing works
Oxygen sensing requires mitochondrial ROS but not oxidative phosphorylation
Brunelle, J. K., Bell, E. L., Quesada, N. M., Vercauteren, K., Tiranti, V., Zeviani, M., Scarpulla, R. C., & Chandel, N. S. (2005) · Cell Metabolism · doi:10.1016/j.cmet.2005.05.002 · Cited by 763 · see citing works
Calorie restriction induces mitochondrial biogenesis and bioenergetic efficiency
López-Lluch, G., Hunt, N., Jones, B., Zhu, M., Jamieson, H., Hilmer, S., Cascajo, M. V., Allard, J., Ingram, D. K., Navas, P., et al. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0510452103 · Cited by 699 · see citing works
Arany, Z., He, H., Lin, J., Hoyer, K., Handschin, C., Toka, O., Ahmad, F., Matsui, T., Chin, S., Wu, P.-H., et al. (2005) · Cell Metabolism · doi:10.1016/j.cmet.2005.03.002 · Cited by 694 · see citing works
Dietary Inorganic Nitrate Improves Mitochondrial Efficiency in Humans
Larsen, F. J., Schiffer, T. A., Borniquel, S., Sahlin, K., Ekblom, B., Lundberg, J. O., & Weitzberg, E. (2011) · Cell Metabolism · doi:10.1016/j.cmet.2011.01.004 · Cited by 689 · cited 3× · see citing works
“While we and others have shown that NO2 modulates mitochondrial function through its modification of specific respiratory chain proteins, the role of NO2 in regulating mitochondrial number is not known [30, 31].”
BackgroundResultCytoprotective effects of nitrite during in vivo ischemia-reperfusion of the heart and liver
Duranski, M. R., Greer, J. J. M., Dejam, A., Jaganmohan, S., Hogg, N., Langston, W., Patel, R. P., Yet, S.-F., Wang, X., Kevil, C. G., et al. (2005) · Journal of Clinical Investigation · doi:10.1172/jci22493 · Cited by 674 · see citing works
Webb, A., Bond, R., McLean, P., Uppal, R., Benjamin, N., & Ahluwalia, A. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0402927101 · Cited by 608 · cited 2× · see citing works
“Mechanistically, the reduction of NO2 to NO is thought to be the initial step in a number of vascular responses that NO2 mediates in vivo, including stimulation of angiogenesis [21], protection from ischemia/reperfusion injury [22-25] and reversal of intimal hyperplasia after vascular injury [26].”
BackgroundShiva, S., Sack, M. N., Greer, J. J., Duranski, M., Ringwood, L. A., Burwell, L., Wang, X., MacArthur, P. H., Shoja, A., Raghavachari, N., et al. (2007) · The Journal of Experimental Medicine · doi:10.1084/jem.20070198 · Cited by 555 · see citing works
Self-citationNitrite is a signaling molecule and regulator of gene expression in mammalian tissues
Bryan, N. S., Fernandez, B. O., Bauer, S. M., Garcia-Saura, M. F., Milsom, A. B., Rassaf, T., Maloney, R. E., Bharti, A., Rodriguez, J., & Feelisch, M. (2005) · Nature Chemical Biology · doi:10.1038/nchembio734 · Cited by 518 · see citing works
Mitochondrial biogenesis by NO yields functionally active mitochondria in mammals
Nisoli, E., Falcone, S., Tonello, C., Cozzi, V., Palomba, L., Fiorani, M., Pisconti, A., Brunelli, S., Cardile, A., Francolini, M., et al. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0405432101 · Cited by 495 · see citing works
Almeida, Á., Moncada, S., & Bolaños, J. P. (2003) · Nature Cell Biology · doi:10.1038/ncb1080 · Cited by 481 · see citing works
Nitrite as Regulator of Hypoxic Signaling in Mammalian Physiology
van Faassen, E. E., Bahrami, S., Feelisch, M., Hogg, N., Kelm, M., Kim‐Shapiro, D. B., Kozlov, A. V., Li, H., Lundberg, J. O., Mason, R., et al. (2009) · Medicinal Research Reviews · doi:10.1002/med.20151 · Cited by 435 · see citing works
Self-citationCalvert, J. W., Gundewar, S., Jha, S., Greer, J. J. M., Bestermann, W. H., Tian, R., & Lefer, D. J. (2008) · Diabetes · doi:10.2337/db07-1098 · Cited by 422 · see citing works
Hendgen-Cotta, U. B., Merx, M. W., Shiva, S., Schmitz, J., Becher, S., Klare, J. P., Steinhoff, H.-J., Goedecke, A., Schrader, J., Gladwin, M. T., et al. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0801336105 · Cited by 418 · see citing works
Self-citationEffects of exercise on mitochondrial content and function in aging human skeletal muscle
Menshikova, E. V., Ritov, V. B., Fairfull, L., Ferrell, R. E., Kelley, D. E., & Goodpaster, B. H. (2006) · The Journals of Gerontology Series A: Biological Sciences and Medical Sciences · doi:10.1093/gerona/61.6.534 · Cited by 398 · see citing works
Carlström, M., Larsen, F. J., Nyström, T., Hezel, M., Borniquel, S., Weitzberg, E., & Lundberg, J. O. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1008872107 · Cited by 382 · see citing works
Erythrocytes are the major intravascular storage sites of nitrite in human blood
Dejam, A. (2005) · Blood · doi:10.1182/blood-2005-02-0567 · Cited by 350 · see citing works
Dietary nitrite supplementation protects against myocardial ischemia-reperfusion injury
Bryan, N. S., Calvert, J. W., Elrod, J. W., Gundewar, S., Ji, S. Y., & Lefer, D. J. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0706579104 · Cited by 347 · see citing works
Baldus, S. E., Eiserich, J. P., Mani, A. R., Castro, L., Figueroa, M., Chumley, P. H., Ma, W., Tousson, A., White, C. R., Bullard, D. C., et al. (2001) · Journal of Clinical Investigation · doi:10.1172/jci12617 · Cited by 332 · see citing works
Response of Skeletal Muscle Mitochondria to Hypoxia
Hoppeler, H. H., Vogt, M., Weibel, E. R., & Flück, M. (2003) · Experimental Physiology · doi:10.1113/eph8802513 · Cited by 329 · see citing works
In Vivo Correction of COX Deficiency by Activation of the AMPK/PGC-1α Axis
Viscomi, C. F., Bottani, E., Civiletto, G., Cerutti, R., Moggio, M. G., Fagiolari, G., Schon, E. A., Lamperti, C., & Zeviani, M. (2011) · Cell Metabolism · doi:10.1016/j.cmet.2011.04.011 · Cited by 291 · see citing works
Baldus, S. E., Eiserich, J. P., Mani, A. R., et al. (2001) · Journal of Clinical Investigation · doi:10.1172/jci200112617 · Cited by 281 · see citing works
Catalytic generation of N2O3 by the concerted nitrite reductase and anhydrase activity of hemoglobin
Basu, S., Grubina, R., Huang, J., Conradie, J., Huang, Z., Jeffers, A., Jiang, A., He, X., Azarov, I., Seibert, R., et al. (2007) · Nature Chemical Biology · doi:10.1038/nchembio.2007.46 · Cited by 224 · see citing works
Lu, Z., Xu, X., Hu, X., Fassett, J., Zhu, G., Tao, Y., Li, J., Huang, Y., Zhang, P., Zhao, B., et al. (2010) · Antioxidants & Redox Signaling · doi:10.1089/ars.2009.2940 · Cited by 215 · see citing works
Nitrite regulates hypoxic vasodilation via myoglobin-dependent nitric oxide generation
Totzeck, M., Hendgen-Cotta, U. B., Luedike, P., Berenbrink, M., Klare, J. P., Steinhoff, H.-J., Semmler, D., Shiva, S., Williams, D., Kipar, A., et al. (2012) · Circulation · doi:10.1161/circulationaha.111.087155 · Cited by 202 · see citing works
Self-citationRole of the anion nitrite in ischemia-reperfusion cytoprotection and therapeutics
DEZFULIAN, C., RAAT, N., SHIVA, S., & GLADWIN, M. (2007) · Cardiovascular Research · doi:10.1016/j.cardiores.2007.05.001 · Cited by 198 · cited 1× · see citing works
“Mechanistically, the reduction of NO2 to NO is thought to be the initial step in a number of vascular responses that NO2 mediates in vivo, including stimulation of angiogenesis [21], protection from ischemia/reperfusion injury [22-25] and reversal of intimal hyperplasia after vascular injury [26].”
BackgroundSelf-citationZuckerbraun, B. S., Shiva, S., Ifedigbo, E., Mathier, M. A., Mollen, K. P., Rao, J., Bauer, P. M., Choi, J. J. W., Curtis, E., Choi, A. M. K., et al. (2010) · Circulation · doi:10.1161/circulationaha.109.891077 · Cited by 192 · see citing works
Self-citationChronic sodium nitrite therapy augments ischemia-induced angiogenesis and arteriogenesis
Kumar, D., Branch, B. G., Pattillo, C. B., Hood, J., Thoma, S., Simpson, S., Illum, S., Arora, N., Chidlow, J. H., Langston, W., et al. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0711480105 · Cited by 187 · see citing works
PGC-1alpha Down-Regulation Affects the Antioxidant Response in Friedreich's Ataxia
Marmolino, D., Manto, M. U., Acquaviva, F., Vergara, P., Ravella, A., Monticelli, A., & Pandolfo, M. (2010) · PLoS ONE · doi:10.1371/journal.pone.0010025 · Cited by 145 · see citing works
Agard, C., Rolli‐Derkinderen, M., de la Roque, E. D., Rio, M., Sagan, C., Savineau, J., Loirand, G., & Pacaud, P. (2009) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2009.00445.x · Cited by 128 · see citing works
Convergence of nitric oxide and lipid signaling: Anti-inflammatory nitro-fatty acids
Baker, P. R. S., Schopfer, F. J., O’Donnell, V. B., & Freeman, B. Α. (2008) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2008.11.021 · Cited by 124 · see citing works
Bezafibrate for an Inborn Mitochondrial Beta-Oxidation Defect
Bonnefont, J., Bastin, J., Béhin, A., & Djouadi, F. (2009) · New England Journal of Medicine · doi:10.1056/nejmc0806334 · Cited by 122 · see citing works
Joseph, A.-M., Pilegaard, H., Litvintsev, A., Leick, L., & Hood, D. A. (2006) · Essays in Biochemistry · doi:10.1042/bse0420013 · Cited by 111 · see citing works
Alef, M. J., Vallabhaneni, R., Carchman, E., Morris, S. M., Shiva, S., Wang, Y., Kelley, E. E., Tarpey, M. M., Gladwin, M. T., Tzeng, E., et al. (2011) · Journal of Clinical Investigation · doi:10.1172/jci44079 · Cited by 101 · see citing works
Self-citationMcLeod, C. J., Pagel, I., & Sack, M. N. (2005) · Trends in Cardiovascular Medicine · doi:10.1016/j.tcm.2005.05.001 · Cited by 91 · see citing works
Liver and heart mitochondria in rats submitted to chronic hypobaric hypoxia
Costa, L. E., Boveris, A. D., Koch, O. R., & Taquini, A. C. (1988) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.1988.255.1.c123 · Cited by 91 · see citing works
PGC‐1α activation as a therapeutic approach in mitochondrial disease
Wenz, T. (2009) · IUBMB Life · doi:10.1002/iub.261 · Cited by 90 · see citing works
Cerqueira, F. M., Laurindo, F. R. M., & Kowaltowski, A. J. (2011) · PLoS ONE · doi:10.1371/journal.pone.0018433 · Cited by 87 · see citing works
Cytochrome c: a catalyst and target of nitrite-hydrogen peroxide-dependent protein nitration
Castro, L., Eiserich, J. P., Sweeney, S., Radi, R., & Freeman, B. A. (2004) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2003.08.033 · Cited by 84 · see citing works
Martinelli, M., Winterhalder, R., Cerretelli, P., HOWALD, H., & Hoppeler, H. H. (1990) · Cellular and Molecular Life Sciences · doi:10.1007/bf01939930 · Cited by 72 · see citing works
Oxygen Regulates Tissue Nitrite Metabolism
Curtis, E., Hsu, L. L., Noguchi, A. C., Geary, L., & Shiva, S. (2012) · Antioxidants & Redox Signaling · doi:10.1089/ars.2011.4242 · Cited by 46 · cited 2× · see citing works
“01%) and subjected to tri-iodide based reductive chemiluminescence in the presence and absence of acidified sulfanilamide (15% in 2M HCl) and mercuric chloride as described in [33].”
MethodSelf-citationHemoglobin as a Nitrite Anhydrase: Modeling Methemoglobin‐Mediated N2O3 Formation
Hopmann, K. H., Cardey, B., Gladwin, M. T., Kim‐Shapiro, D. B., & Ghosh, A. (2011) · Chemistry - A European Journal · doi:10.1002/chem.201003578 · Cited by 42 · see citing works
Qu, A., Jiang, C., Xu, M., Zhang, Y., Zhu, Y., Xu, Q., Zhang, C., & Wang, X. (2009) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00469.2008 · Cited by 35 · see citing works
Lynn, E. G., Lu, Z., Minerbi, D. C., & Sack, M. N. (2007) · Antioxidants and Redox Signaling · doi:10.1089/ars.2007.1700 · Cited by 23 · see citing works
Ferri, N. (2011) · Vascular Pharmacology · doi:10.1016/j.vph.2011.10.003 · Cited by 20 · see citing works
Chronic hypoxemia increases myocardial cytochrome oxidase
Piel, D., Khan, A. R., Waibel, R., Birbach, M., Cohen, M. S., Spray, T. L., Deutschman, C. S., Gaynor, J. W., & Levy, R. J. (2005) · Journal of Thoracic and Cardiovascular Surgery · doi:10.1016/j.jtcvs.2005.06.030 · Cited by 12 · see citing works
Effect of Chronic Hypoxia on the Kinetics of Energy Transformation in Heart Mitochondria
Reynafarje, B. (2008) · Cardiology · doi:10.1159/000169362 · Cited by 12 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
PINK1 deficiency impairs mitochondrial homeostasis and promotes lung fibrosis
Bueno, M., Lai, Y.-C., Romero, Y., Brands, J., St. Croix, C. M., Kamga, C., Corey, C., Herazo-Maya, J. D., Sembrat, J., Lee, J. S., et al. (2015) · Journal of Clinical Investigation · doi:10.1172/jci74942 · Cited by 627 · see citing works
Self-citationKapil, V., Khambata, R. S., Jones, D. A., Rathod, K., Primus, C., Massimo, G., Fukuto, J. M., & Ahluwalia, A. (2020) · Pharmacological Reviews · doi:10.1124/pr.120.019240 · Cited by 248 · see citing works
Nitrite: A physiological store of nitric oxide and modulator of mitochondrial function
Shiva, S. (2013) · Redox Biology · doi:10.1016/j.redox.2012.11.005 · Cited by 207 · see citing works
Self-citationDietary Nitrate and Physical Performance
Jones, A. M., Thompson, C., Wylie, L. J., & Vanhatalo, A. (2018) · Annual Review of Nutrition · doi:10.1146/annurev-nutr-082117-051622 · Cited by 206 · see citing works
Cárdenes, N., Corey, C. G., Geary, L., Jain, S., Zharikov, S. I., Barge, S., Novelli, E. M., & Shiva, S. (2014) · Blood · doi:10.1182/blood-2013-09-529420 · Cited by 148 · see citing works
Self-citationNitrite Reduction and Cardiovascular Protection
Omar, S. A., & Webb, A. J. (2014) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2014.01.012 · Cited by 121 · see citing works
He, J., Hu, B., Shi, X., Weidert, E. R., Lu, P., Xu, M., Huang, M., Kelley, E. E., & Xie, W. (2013) · Molecular and Cellular Biology · doi:10.1128/mcb.01658-12 · Cited by 116 · see citing works
More answers to the still unresolved question of nitrate tolerance
Münzel, T. F., Daiber, A., & Gori, T. (2013) · European Heart Journal · doi:10.1093/eurheartj/eht249 · Cited by 99 · see citing works
Pride, C. K., Mo, L., Quesnelle, K., Dagda, R. K., Murillo, D., Geary, L., Corey, C., Portella, R., Zharikov, S., St Croix, C., et al. (2014) · Cardiovascular Research · doi:10.1093/cvr/cvt224 · Cited by 97 · see citing works
Self-citationThe redox interplay between nitrite and nitric oxide: From the gut to the brain
Pereira, C., Ferreira, N. R., Rocha, B. S., Barbosa, R. M., & Laranjinha, J. (2013) · Redox Biology · doi:10.1016/j.redox.2013.04.004 · Cited by 92 · see citing works
Hydrogen sulfide regulates cardiac mitochondrial biogenesis via the activation of AMPK
Shimizu, Y., Polavarapu, R., Eskla, K., Nicholson, C. K., Koczor, C. A., Wang, R., Lewis, W., Shiva, S., Lefer, D. J., & Calvert, J. W. (2018) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2018.01.011 · Cited by 88 · see citing works
Self-citationNitrate/Nitrite as Critical Mediators to Limit Oxidative Injury and Inflammation
Waltz, P., Escobar, D., Botero, A. M., & Zuckerbraun, B. S. (2015) · Antioxidants & Redox Signaling · doi:10.1089/ars.2015.6256 · Cited by 70 · see citing works
Self-citationInorganic nitrite supplementation for healthy arterial aging
Sindler, A. L., DeVan, A. E., Fleenor, B. S., & Seals, D. R. (2014) · Journal of Applied Physiology · doi:10.1152/japplphysiol.01100.2013 · Cited by 68 · see citing works
Redox control of vascular smooth muscle cell function and plasticity
Durgin, B. G., & Straub, A. C. (2018) · Laboratory Investigation · doi:10.1038/s41374-018-0032-9 · Cited by 69 · see citing works
On the mechanism by which dietary nitrate improves human skeletal muscle function
Affourtit, C., Bailey, S. J., Jones, A. M., Smallwood, M. J., & Winyard, P. G. (2015) · Frontiers in Physiology · doi:10.3389/fphys.2015.00211 · Cited by 58 · see citing works
Peleli, M., Ferreira, D. M. S., Tarnawski, L., Haworth, S. M., Xuechen, L., Zhuge, Z., Newton, P. T., Massart, J., Chagin, A. S., Olofsson, P. S., et al. (2019) · Redox Biology · doi:10.1016/j.redox.2019.101387 · Cited by 58 · see citing works
Kim, S., Joe, Y., Zheng, M., Kim, H. J., Yu, J.-K., Cho, G. J., Chang, K. C., Kim, H. K., Han, J., Ryter, S. W., et al. (2013) · Antioxidants and Redox Signaling · doi:10.1089/ars.2012.5138 · Cited by 57 · see citing works
Thompson, C., Wylie, L. J., Blackwell, J. R., Fulford, J., Black, M. I., Kelly, J., McDonagh, S. T. J., Carter, J., Bailey, S. J., Vanhatalo, A., et al. (2017) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00909.2016 · Cited by 51 · see citing works
Rocha, M., Apostolova, N., Herance, J. R., Rovira‐Llopis, S., Hernández‐Mijares, A., & Víctor, V. M. (2013) · Medicinal Research Reviews · doi:10.1002/med.21285 · Cited by 51 · see citing works
Wu, F. Y., Szczepaniak, W. S., Shiva, S., Liu, H., Wang, Y., Wang, L., Wang, Y., Kelley, E. E., Chen, A. F., Gladwin, M. T., et al. (2014) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.00063.2014 · Cited by 51 · see citing works
Self-citationDietary nitrate supplementation in cardiovascular health: an ergogenic aid or exercise therapeutic?
Woessner, M. N., McIlvenna, L. C., Ortiz de Zevallos, J., Neil, C. J., & Allen, J. D. (2018) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00414.2017 · Cited by 50 · see citing works
Electrophilic nitro-oleic acid reverses obesity-induced hepatic steatosis
Khoo, N. K. H., Fazzari, M., Chartoumpekis, D. V., Li, L., Guimarães, D. A., Arteel, G. E., Shiva, S., & Freeman, B. Α. (2019) · Redox Biology · doi:10.1016/j.redox.2019.101132 · Cited by 45 · see citing works
Self-citationBarnett, C. F., Moreno‐Ulloa, A., Shiva, S., Ramírez‐Sánchez, I., Taub, P. R., Su, Y., Ceballos, G. M., Dugar, S., Schreiner, G. F., & Villarreal, F. J. (2015) · Food & Function · doi:10.1039/c4fo00596a · Cited by 43 · see citing works
Self-citationThompson, C., Vanhatalo, A., Kadach, S., Wylie, L. J., Fulford, J., Ferguson, S. K., Blackwell, J. R., Bailey, S. J., & Jones, A. M. (2018) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00047.2018 · Cited by 32 · see citing works
Khoo, N. K. H., Mo, L., Zharikov, S. I., Kamga, C., Quesnelle, K. M., Golin-Bisello, F., Li, L., Wang, Y., & Shiva, S. (2014) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2014.02.009 · Cited by 29 · see citing works
Self-citationBhaswant, M., Brown, L., McAinch, A. J., & Mathai, M. L. (2017) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.201700478 · Cited by 30 · see citing works
Caveolin-1 controls mitochondrial function through regulation of m-AAA mitochondrial protease
Volonté, D., Liu, Z., Shiva, S., & Galbiati, F. (2016) · Aging · doi:10.18632/aging.101051 · Cited by 27 · see citing works
Self-citationXu, Z., Li, E., Xu, C., Gan, L., Qin, J. G., & Chen, L. (2016) · Aquatic Toxicology · doi:10.1016/j.aquatox.2016.05.020 · Cited by 24 · see citing works
Nitrite potentiates the vasodilatory signaling of S-nitrosothiols
Liu, T., Zhang, M., Terry, M. H., Schroeder, H. J., Wilson, S. M., Power, G. G., Li, Q., Tipple, T. E., Borchardt, D., & Blood, A. B. (2018) · Nitric Oxide · doi:10.1016/j.niox.2018.01.011 · Cited by 23 · see citing works
Nitrate-containing beetroot enhances myocyte metabolism and mitochondrial content
Vaughan, R. A., Gannon, N. P., & Carriker, C. R. (2015) · Journal of Traditional and Complementary Medicine · doi:10.1016/j.jtcme.2014.11.033 · Cited by 23 · see citing works
Portella, R. D. L., Bickta, J., & Shiva, S. (2015) · Antioxidants and Redox Signaling · doi:10.1089/ars.2015.6260 · Cited by 21 · see citing works
Self-citationLenčová-Popelová, O., Jirkovský, E., Jansová, H., Jirkovská, A., Vostatková, L., Mazurová, Y., Adamcová, M., Chládek, J., Hroch, M., Pokorná, Z., et al. (2015) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2015.12.021 · Cited by 21 · see citing works
Differential mitochondrial dinitrosyliron complex formation by nitrite and nitric oxide
Thomas, D. D., Corey, C. G., Hickok, J. R., Wang, Y., & Shiva, S. (2017) · Redox Biology · doi:10.1016/j.redox.2017.12.007 · Cited by 21 · see citing works
Self-citationAxton, E. R., Beaver, L. M., Mary, L. S., Truong, L., Logan, C. R., Spagnoli, S., Prater, M. C., Keller, R. M., García‐Jaramillo, M., Ehrlicher, S. E., et al. (2019) · Journal of Nutrition · doi:10.1093/jn/nxz202 · Cited by 19 · see citing works
Meschiari, C. A., Pinheiro, L. C., Guimarães, D. A., Gerlach, R. F., & Tanus-Santos, J. E. (2015) · Naunyn-Schmiedeberg s Archives of Pharmacology · doi:10.1007/s00210-015-1192-4 · Cited by 16 · see citing works
Oliveira‐Paula, G. H., Batista, R. I. M., Stransky, S., Conde-Tella, S. O., Ferreira, G. C., Portella, R. L., Pinheiro, L. C., de Angelis, C. D., Riascos‐Bernal, D. F., Sidoli, S., et al. (2023) · Biochemical Pharmacology · doi:10.1016/j.bcp.2023.115571 · Cited by 14 · see citing works
Therapeutic Implications of Nitrite in Hypertension
Ling, W. C., Mustafa, M. R., & Murugan, D. D. (2019) · Journal of Cardiovascular Pharmacology · doi:10.1097/fjc.0000000000000771 · Cited by 14 · see citing works
Kavcı, Z., Ozan, M., Buzdağlı, Y., Savaş, A., & Uçar, H. (2024) · Journal of the International Society of Sports Nutrition · doi:10.1080/15502783.2024.2445609 · Cited by 16 · see citing works
Rocha, B. S., Nunes, C., & Laranjinha, J. A. N. (2016) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2016.10.021 · Cited by 10 · see citing works
Shiva, S., Castro, L., & Brookes, P. S. (2017) · Elsevier eBooks · doi:10.1016/b978-0-12-804273-1.00011-9 · Cited by 10 · see citing works
Self-citationMiyamoto, L., Yamane, M., Tomida, Y., Kono, M., Yamaoka, T., Kawasaki, A., Hatano, A., Tsuda, K., Xu, W., Ikeda, Y., et al. (2017) · Biological and Pharmaceutical Bulletin · doi:10.1248/bpb.b17-00316 · Cited by 10 · see citing works
Carter, S. J., Blechschmid, T. H., Baranauskas, M. N., Long, E. B., Gruber, A. H., Raglin, J. S., Lim, K. J., & Coggan, A. R. (2024) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00150.2024 · Cited by 8 · see citing works
Nan, A., Suciu, M., Ardelean, I., Șenilă, M., & Turcu, R. P. (2020) · Analytical Letters · doi:10.1080/00032719.2020.1731522 · Cited by 8 · see citing works
Conjugated linoleic acid and nitrite attenuate mitochondrial dysfunction during myocardial ischemia
Hoose, P. M. V., Kelm, N. Q., Piell, K. M., & Cole, M. P. (2016) · The Journal of Nutritional Biochemistry · doi:10.1016/j.jnutbio.2016.04.001 · Cited by 7 · see citing works
Majerczak, J., Drzymała‐Celichowska, H., Grandys, M., Kij, A., Kuś, K., Celichowski, J., Kryściak, K., Molik, W. A., Szkutnik, Z., & Zoladz, J. A. (2024) · Journal of the American Heart Association · doi:10.1161/jaha.123.031085 · Cited by 6 · see citing works
Nitrate and Nitrite in Aging and Age-Related Disease
Johnson, L. C., DeVan, A. E., Justice, J. N., & Seals, D. R. (2017) · Springer eBooks · doi:10.1007/978-3-319-46189-2_18 · Cited by 5 · see citing works
Liu, Y., Croft, K. D., Hodgson, J. M., Mori, T. A., & Ward, N. C. (2021) · Journal of Functional Foods · doi:10.1016/j.jff.2021.104447 · Cited by 4 · see citing works
Carlström, M., & Lundberg, J. O. (2016) · Circulation · doi:10.1161/circulationaha.116.021905 · Cited by 3 · see citing works
Lai, Y., & Gladwin, M. T. (2016) · Circulation · doi:10.1161/circulationaha.116.023201 · Cited by 3 · see citing works
The Mitochondrion: A Physiological Target of Nitrite
Guimarães, D. A., Reyes, C., & Shiva, S. (2017) · Springer eBooks · doi:10.1007/978-3-319-46189-2_5 · Cited by 2 · see citing works
Self-citationInvestigation of Six-Week Beetroot Juice Ingestion on VO2max in Female Soccer Players
Lotfi, M., Azizi, M., Tahmasebi, W., & Bashiri, P. (2019) · Zahedan Journal of Research in Medical Sciences · doi:10.5812/zjrms.86250 · Cited by 2 · see citing works
An, W., Reyes, C., Espinosa‐Díez, C., Patel, P., Guimaraes, D., Villareal, F., Jessup, M., Croix, C. S., Gomez, D. A., Rao, K., et al. (2026) · Redox Biology · doi:10.1016/j.redox.2026.104169 · Cited by 1 · see citing works
Self-citationReghuvaran, A. C., Bhavya, B., Jayakumar, K., Sreelatha, H. V., & Gopala, S. (2020) · Toxicology in Vitro · doi:10.1016/j.tiv.2020.105048 · Cited by 1 · see citing works
Inorganic nitrite and conduit artery function
Omar, S. A. (2015)
Thompson, C. (2017) · Open Research Exeter (University of Exeter)
Update on Nitrite Reduction in Ischemic Disease: Mechanisms and Clinical Translation
Jones, D. A., Rathod, K. S., & Ahluwalia, A. (2017) · Elsevier eBooks · doi:10.1016/b978-0-12-804273-1.00015-6
What might Donald Rumsfeld know about nitrate, nitrite and hypertension?
Kapil, V., & Ahluwalia, A. (2022) · Hypertension News · doi:10.30824/2212-15
Yang, H., Li, M., Lu, J., He, Y., Wang, L., Zhang, Q., Li, D., & Li, L. (2026) · Water Biology and Security · doi:10.1016/j.watbs.2026.100710
Investigating the role of nitric oxide clones in cardiovascular conditions
Arif, S. (2014) · University of Birmingham Institutional Research Archive (University of Birmingham)
- Authors
- Mo, L., Wang, Y., Geary, L., Corey, C., Alef, M. J., Beer-Stolz, D., Zuckerbraun, B. S., & Shiva, S.
- Affiliations
- University of Pittsburgh (US)
- Corresponding author
- Shiva, Sruti
- Venue
- Free Radical Biology and Medicine
- Publisher
- Elsevier BV
- Published
- 2012-10
- Volume
- 53
- Issue
- 7
- Pages
- 1440-1450
- ISSN
- 0891-5849 (ISSN-L)
- PMC
- PMC3477807
- OpenAlex
- W2068775181
- Cited by
- 62
- References
- 55
- Citations by year
- 2026: 2 · 2024: 4 · 2023: 1 · 2022: 2 · 2021: 1 · 2020: 3 · 2019: 5 · 2018: 5 · 2017: 9 · 2016: 7 · 2015: 9 · 2014: 7 · 2013: 7
- FWCI
- 4.93
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Free Radical Biology and Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Heart, Lung, and Blood Institute (R01HL096973)
- National Institute of General Medical Sciences (R01GM082830)
- Topics
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Keywords
- nitrite, mitochondrial biogenesis, AMP kinase, adenylate kinase, SIRT1, PGC-1α, soluble guanylate cyclase, nitric oxide, carotid artery injury, vascular smooth muscle cell proliferation, vascular remodeling
- MeSH terms
- Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Adenosine Triphosphate, Adenylate Kinase, Administration, Oral, Animals, Aorta, Carotid Arteries, Enzyme Activation, Guanylate Cyclase, Male, Mitochondria, Oxygen Consumption, Phosphorylation, Sodium Nitrite, Transcription Factors, Signal Transduction, Gene Expression, RNA-Binding Proteins, Rats, Sprague-Dawley, Reactive Oxygen Species, Carotid Artery Injuries, Myocytes, Smooth Muscle, Rats, Sirtuin 1, Primary Cell Culture, Mitochondrial Turnover
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