Protection from hypertension in mice by the Mediterranean diet is mediated by nitro fatty acid inhibition of soluble epoxide hydrolase
Open accessAbstract
Soluble epoxide hydrolase (sEH) is inhibited by electrophilic lipids by their adduction to Cys521 proximal to its catalytic center. This inhibition prevents hydrolysis of the enzymes' epoxyeicosatrienoic acid (EET) substrates, so they accumulate inducing vasodilation to lower blood pressure (BP). We generated a Cys521Ser sEH redox-dead knockin (KI) mouse model that was resistant to this mode of inhibition. The electrophilic lipid 10-nitro-oleic acid (NO2-OA) inhibited hydrolase activity and also lowered BP in an angiotensin II-induced hypertension model in wild-type (WT) but not KI mice. Furthermore, EET/dihydroxy-epoxyeicosatrienoic acid isomer ratios were elevated in plasma from WT but not KI mice following NO2-OA treatment, consistent with the redox-dead mutant being resistant to inhibition by lipid electrophiles. sEH was inhibited in WT mice fed linoleic acid and nitrite, key constituents of the Mediterranean diet that elevates electrophilic nitro fatty acid levels, whereas KIs were unaffected. These observations reveal that lipid electrophiles such as NO2-OA mediate antihypertensive signaling actions by inhibiting sEH and suggest a mechanism accounting for protection from hypertension afforded by the Mediterranean diet.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Current dietary investigations have found unsaturated fatty acids such as oleic and linoleic acid and dietary nitrate to be concentrated in the traditional Mediterranean diet, a diet with beneficial effects on the development of CVD and its risk factors.
“Current dietary investigations have found these fatty acids and dietary nitrate to be concentrated in the traditional Mediterranean diet, a diet with beneficial effects on the development of CVD and its risk factors[362,375–377].”
From Enterosalivary nitrate metabolism and the microbiome: Intersection of microbial metabolism, nitric oxide and diet in cardiac and pulmonary vascular health (2017) · cites this paper as [375]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
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 1× · see citing works
“Finally, supplementation with nitrite or nitrate together and alone can also lower BP, a consequence of eventual reduction to vasodilatory NO and nitrosothiols (44, 45).”
BackgroundCommensal bacteria at the interface of host metabolism and the immune system
Brestoff, J. R., & Artis, D. (2013) · Nature Immunology · doi:10.1038/ni.2640 · Cited by 945 · see citing works
Role of Superoxide in Angiotensin II–Induced but Not Catecholamine-Induced Hypertension
Laursen, J. B., Rajagopalan, S., Galis, Z. S., Tarpey, M. M., Freeman, B. Α., & Harrison, D. G. (1997) · Circulation · doi:10.1161/01.cir.95.3.588 · Cited by 820 · see citing works
Carluccio, M. A., Siculella, L., Ancora, M. A., Massaro, M., Scoditti, E., Storelli, C., Visioli, F., Distante, A., & De Caterina, R. (2003) · Arteriosclerosis, Thrombosis, and Vascular Biology · doi:10.1161/01.atv.0000062884.69432.a0 · Cited by 640 · see citing works
Soluble epoxide hydrolase as a therapeutic target for cardiovascular diseases
Imig, J. D., & Hammock, B. D. (2009) · Nature Reviews Drug Discovery · doi:10.1038/nrd2875 · Cited by 616 · see citing works
Impact of Soluble Epoxide Hydrolase and Epoxyeicosanoids on Human Health
Morisseau, C. H. P., & Hammock, B. D. (2012) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-011112-140244 · Cited by 544 · see citing works
Soluble epoxide hydrolase is a therapeutic target for acute inflammation
Schmelzer, K. R., Kubala, L., Newman, J. W. I., Kim, I.-H., Eiserich, J. P., & Hammock, B. D. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0503279102 · Cited by 442 · see citing works
Olive oil and the cardiovascular system
Covas, M. I. (2007) · Pharmacological Research · doi:10.1016/j.phrs.2007.01.010 · Cited by 401 · see citing works
Wayman, N. S., Hattori, Y., McDonald, M. C., Mota‐Filipe, H., Cuzzocrea, S., PISANO, B., Chatterjee, P. K., & Thiemermann, C. (2002) · The FASEB Journal · doi:10.1096/fj.01-0793com · Cited by 361 · see citing works
Roles of dietary inorganic nitrate in cardiovascular health and disease
Lundberg, J. O., Carlström, M., Larsen, F. J., & Weitzberg, E. (2011) · Cardiovascular Research · doi:10.1093/cvr/cvq325 · Cited by 355 · see citing works
Novel Aspects of Dietary Nitrate and Human Health
Weitzberg, E., & Lundberg, J. O. (2013) · Annual Review of Nutrition · doi:10.1146/annurev-nutr-071812-161159 · Cited by 324 · see citing works
Yang, J., Schmelzer, K. R., Georgi, K., & Hammock, B. D. (2009) · Analytical Chemistry · doi:10.1021/ac901282n · Cited by 309 · see citing works
Toledo, E., Hu, F. B., Estruch, R., Buil-Cosiales, P., Corella, D., Salas-Salvadó, J., Covas, M. I., Arós, F., Gómez-Gracia, E., Fiol, M., et al. (2013) · BMC Medicine · doi:10.1186/1741-7015-11-207 · Cited by 289 · see citing works
Nitro-fatty acid formation and signaling
Freeman, B. A., Baker, P. R. S., Schopfer, F. J., Woodcock, S. R., Napolitano, A., & d'Ischia, M. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.r800004200 · Cited by 265 · see citing works
Electrophilic nitro-fatty acids activate NRF2 by a KEAP1 cysteine 151-independent mechanism
Kansanen, E., Bonacci, G., Schopfer, F. J., Kuosmanen, S. M., Tong, K. I., Leinonen, H., Woodcock, S. R., Yamamoto, M., Carlberg, C., Ylä-Herttuala, S., et al. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.190710 · Cited by 208 · see citing works
Campbell, W. B., & Harder, D. R. (1999) · Circulation Research · doi:10.1161/01.res.84.4.484 · Cited by 205 · see citing works
Baker, P. R. S., Schopfer, F. J., Sweeney, S., & Freeman, B. A. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0402587101 · Cited by 201 · see citing works
Biology of nitrogen oxides in the gastrointestinal tract
Lundberg, J. O., & Weitzberg, E. (2013) · Gut · doi:10.1136/gutjnl-2011-301649 · Cited by 200 · see citing works
Role of Soluble Epoxide Hydrolase in Postischemic Recovery of Heart Contractile Function
Seubert, J. M., Sinal, C. J., Graves, J. P., DeGraff, L. M., Bradbury, J. A., Lee, C. R., Goralski, K. B., Carey, M. A., Luria, A., Newman, J. W. I., et al. (2006) · Circulation Research · doi:10.1161/01.res.0000237390.92932.37 · Cited by 195 · see citing works
Rudolph, V., Rudolph, T. K., Schopfer, F. J., Bonacci, G., Woodcock, S. R., Cole, M. P., Baker, P. R. S., Ramani, R., & Freeman, B. A. (2010) · Cardiovascular Research · doi:10.1093/cvr/cvp275 · Cited by 188 · see citing works
Soluble Epoxide Hydrolase Is a Main Effector of Angiotensin II–Induced Hypertension
Jung, O., Brandes, R. P., Kim, I.-H., Schweda, F., Schmidt, R., Hammock, B. D., Busse, R., & Fleming, I. (2005) · Hypertension · doi:10.1161/01.hyp.0000153792.29478.1d · Cited by 180 · see citing works
Monti, J., Fischer, J., Paskaš, S., Heinig, M., Schulz, H., Gösele, C., Heuser, A., Fischer, R., Schmidt, C., Schirdewan, A., et al. (2008) · Nature Genetics · doi:10.1038/ng.129 · Cited by 176 · see citing works
Covalent Peroxisome Proliferator-activated Receptor γ Adduction by Nitro-fatty Acids
Schopfer, F. J., Cole, M. P., Groeger, A. L., Chen, C.-S., Khoo, N. K. H., Woodcock, S. R., Golin-Bisello, F., Motanya, U. N., Li, Y., Zhang, J., et al. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.091512 · Cited by 171 · see citing works
Self-citationColes, B., Bloodsworth, A., Clark, S. R., Lewis, M. J., Cross, A. R., Freeman, B. A., & O’Donnell, V. B. (2002) · Circulation Research · doi:10.1161/01.res.0000032114.68919.ef · Cited by 168 · see citing works
Soluble epoxide hydrolase plays an essential role in angiotensin II-induced cardiac hypertrophy
Ai, D., Pang, W., Li, N., Xu, M., Jones, P. D., Yang, J., Zhang, Y., Chiamvimonvat, N., Shyy, J. Y.-J., Hammock, B. D., et al. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0811022106 · Cited by 155 · see citing works
Conjugated linoleic acid is a preferential substrate for fatty acid nitration
Bonacci, G., Baker, P. R. S., Salvatore, S. R., Shores, D., Khoo, N. K. H., Koenitzer, J. R., Vitturi, D. A., Woodcock, S. R., Golin-Bisello, F., Cole, M. P., et al. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.401356 · Cited by 147 · see citing works
Self-citationCompensatory Mechanism for Homeostatic Blood Pressure Regulation in Ephx2 Gene-disrupted Mice
Luria, A., Weldon, S. M., Kabcenell, A. K., Ingraham, R. H., Matera, D., Jiang, H., Gill, R., Morisseau, C. H. P., Newman, J. W. I., & Hammock, B. D. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m608057200 · Cited by 144 · see citing works
Nitrated lipids decompose to nitric oxide and lipid radicals and cause vasorelaxation
Lima, É. S., Bonini, M. G., Augusto, O., Barbeiro, H. V., de Souza, H. P., & Abdalla, D. S. P. (2005) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2005.04.005 · Cited by 132 · see citing works
Liu, J., Yang, J., İnceoğlu, B., Qiu, H., Ulu, A., Hwang, S. H., Chiamvimonvat, N., & Hammock, B. D. (2009) · Biochemical Pharmacology · doi:10.1016/j.bcp.2009.10.025 · Cited by 128 · see citing works
Nitro-oleic acid inhibits angiotensin II-induced hypertension
Zhang, J., Villacorta, L., Chang, L., Fan, Z., Hamblin, M., Zhu, T., Chen, C. S., Cole, M. P., Schopfer, F. J., Deng, C. X., et al. (2010) · Circulation Research · doi:10.1161/circresaha.110.218404 · Cited by 121 · see citing works
Self-citationOlives and olive oil are sources of electrophilic fatty acid nitroalkenes
Fazzari, M., Trostchansky, A., Schopfer, F. J., Salvatore, S. R., Sánchez-Calvo, B., Vitturi, D., Valderrama, R., Barroso, J. B., Radi, R., Freeman, B. A., et al. (2014) · PLoS ONE · doi:10.1371/journal.pone.0084884 · Cited by 114 · see citing works
Lim, D. G., Sweeney, S., Bloodsworth, A., White, C. R., Chumley, P. H., Krishna, N. R., Schopfer, F., O'Donnell, V. B., Eiserich, J. P., & Freeman, B. A. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.232409599 · Cited by 110 · see citing works
Oh, J. Y., Giles, N. M., Landar, A. L., & Darley-Usmar, V. M. (2008) · Biochemical Journal · doi:10.1042/bj20071189 · Cited by 106 · see citing works
Schopfer, F. J., Batthyany, C., Baker, P. R. S., Bonacci, G., Cole, M. P., Rudolph, V., Groeger, A. L., Rudolph, T. K., Nadtochiy, S., Brookes, P. S., et al. (2009) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2008.12.025 · Cited by 104 · see citing works
Characterization of linoleic acid nitration in human blood plasma by mass spectrometry
Lima, É. S., Di Mascio, P., Rubbo, H., & Abdalla, D. S. P. (2002) · Biochemistry · doi:10.1021/bi025504j · Cited by 103 · see citing works
Gomez, G. A., Morisseau, C. H. P., Hammock, B. D., & Christianson, D. W. (2005) · Protein Science · doi:10.1110/ps.051720206 · Cited by 101 · see citing works
Coles, B., Bloodsworth, A., Eiserich, J. P., Coffey, M. J., McLoughlin, R. M., Giddings, J. C., Lewis, M. J., Haslam, R. J., Freeman, B. A., & O'Donnell, V. B. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m105209200 · Cited by 98 · see citing works
Self-citationCardiovascular Therapeutic Aspects of Soluble Epoxide Hydrolase Inhibitors
Imig, J. D. (2006) · Cardiovascular Drug Reviews · doi:10.1111/j.1527-3466.2006.00169.x · Cited by 90 · see citing works
CEASER, E. K., Moellering, D. R., Shiva, S., Ramachandran, A., Landar, A. L., Venkartraman, A., Crawford, J., Patel, R. P., Dickinson, D. A., Ulasova, E., et al. (2004) · Biochemical Society Transactions · doi:10.1042/bst0320151 · Cited by 87 · see citing works
Yeh, C., Chen, T.-P., Lee, C.-H., Wu, Y., Lin, Y., & Lin, P. J. (2006) · Shock · doi:10.1097/01.shk.0000225863.56714.96 · Cited by 63 · see citing works
Burgoyne, J. R., Oviosu, O. A., & Eaton, P. (2013) · Journal of Pharmacological and Toxicological Methods · doi:10.1016/j.vascn.2013.07.001 · Cited by 62 · see citing works
Direct Blood Pressure Monitoring in Laboratory Rodents via Implantable Radio Telemetry
Huetteman, D. A., & Bogie, H. (2009) · Methods in molecular biology · doi:10.1007/978-1-60761-247-6_4 · Cited by 57 · see citing works
Charles, R. L., Burgoyne, J. R., Mayr, M., Weldon, S. M., Hübner, N., Dong, H., Morisseau, C. H. P., Hammock, B. D., Landar, A. L., & Eaton, P. (2010) · Circulation Research · doi:10.1161/circresaha.110.235879 · Cited by 56 · see citing works
Protein kinase G oxidation is a major cause of injury during sepsis
Rudyk, O., Phinikaridou, A., Prysyazhna, O. D., Burgoyne, J. R., Botnar, R. M., & Eaton, P. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1301026110 · Cited by 54 · see citing works
Nitroglycerin Fails to Lower Blood Pressure in Redox-Dead Cys42Ser PKG1α Knock-In Mouse
Rudyk, O., Prysyazhna, O. D., Burgoyne, J. R., & Eaton, P. (2012) · Circulation · doi:10.1161/circulationaha.112.101287 · Cited by 52 · see citing works
Barceló, F., Perona, J. S., Prades, J., Funari, S. S., Gómez‐Gracia, E., Conde, M., Estruch, R., & Ruíz-Gutiérrez, V. (2009) · Hypertension · doi:10.1161/hypertensionaha.109.137471 · Cited by 49 · see citing works
Napolitano, A., Panzella, L., Savarese, M. F., Sacchi, R., Giudicianni, I., Paolillo, L., & d’Ischia, M. (2004) · Chemical Research in Toxicology · doi:10.1021/tx049880b · Cited by 45 · see citing works
Soluble Epoxide Hydrolase, a Target with Multiple Opportunities for Cardiovascular Drug Discovery
Marino, J. P. (2009) · Current Topics in Medicinal Chemistry · doi:10.2174/156802609788340805 · Cited by 43 · see citing works
Siangjong, L., Gauthier, K. M., Pfister, S. L., Smyth, E. M., & Campbell, W. B. (2012) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00690.2012 · Cited by 24 · see citing works
Prostaglandin J2 Family and the Cardiovascular System
Sasaguri, T., & Miwa, Y. (2004) · Current Vascular Pharmacology · doi:10.2174/1570161043476384 · Cited by 20 · see citing works
Kriska, T., Cepura, C., Siangjong, L., Wan, T. C., Auchampach, J. A., Shaish, A., Haratz, D., Kumar, G., Falck, J. R., Gauthier, K. M., et al. (2013) · Prostaglandins & Other Lipid Mediators · doi:10.1016/j.prostaglandins.2013.07.002 · Cited by 8 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Strategies to increase nitric oxide signalling in cardiovascular disease
Lundberg, J. O., Gladwin, M. T., & Weitzberg, E. (2015) · Nature Reviews Drug Discovery · doi:10.1038/nrd4623 · Cited by 576 · see citing works
Schunck, W., Konkel, A., Fischer, R., & Weylandt, K. H. (2017) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2017.10.016 · Cited by 196 · see citing works
Koch, C. D., Gladwin, M. T., Freeman, B. A., Lundberg, J. O., Weitzberg, E., & Morris, A. (2017) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2016.12.015 · Cited by 186 · see citing works
Self-citationNitric oxide and its derivatives in the cancer battlefield
Kamm, A., Przychodzen, P., Kuban-Jankowska, A., Jacewicz, D., Dabrowska, A. M., Nussberger, S., Wozniak, M., & Gorska-Ponikowska, M. (2019) · Nitric Oxide · doi:10.1016/j.niox.2019.09.005 · Cited by 120 · see citing works
Swardfager, W., Hennebelle, M., Yu, D., Hammock, B. D., LEVITT, A. J., Hashimoto, K., & Taha, A. Y. (2018) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2018.01.010 · Cited by 75 · see citing works
Advances in Understanding the Molecular Basis of the Mediterranean Diet Effect
Corella, D., Coltell, Ó., Macián, F., & Ordovás, J. M. (2018) · Annual Review of Food Science and Technology · doi:10.1146/annurev-food-032217-020802 · Cited by 74 · see citing works
Villacorta, L., Minarrieta, L., Salvatore, S. R., Khoo, N. K. H., Rom, O., Gao, Z., Berman, R. C., Jobbagy, S., Li, L., Woodcock, S. R., et al. (2018) · Redox Biology · doi:10.1016/j.redox.2018.01.005 · Cited by 71 · see citing works
Nitro-Fatty Acid Logistics: Formation, Biodistribution, Signaling, and Pharmacology
Schopfer, F. J., & Khoo, N. K. H. (2019) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2019.04.009 · Cited by 67 · see citing works
Aljuraiban, G. S., Gibson, R., Griep, L. M. O., Okuda, N., Steffen, L. M., Horn, L. V., & Chan, Q. M. (2019) · Advances in Nutrition · doi:10.1093/advances/nmz059 · Cited by 67 · see citing works
Convergence of biological nitration and nitrosation via symmetrical nitrous anhydride
Vitturi, D. A., Minarrieta, L., Salvatore, S. R., Postlethwait, E. M., Fazzari, M., Ferrer-Sueta, G., Lancaster, J. R., Freeman, B. A., & Schopfer, F. J. (2015) · Nature Chemical Biology · doi:10.1038/nchembio.1814 · Cited by 65 · see citing works
GDF15 is a major determinant of ketogenic diet-induced weight loss
Lu, J. F., Zhu, M., Xia, B., Zhang, N., Liu, X. P., Liu, H., Zhang, R. X., Xiao, J. Y., Yang, H., Zhang, Y. Q., et al. (2023) · Cell Metabolism · doi:10.1016/j.cmet.2023.11.003 · Cited by 64 · see citing works
Distinct Regulatory Effects of Myeloid Cell and Endothelial Cell NAPDH Oxidase 2 on Blood Pressure
Sag, C. M., Schnelle, M., Zhang, J., Murdoch, C. E., Kossmann, S., Protti, A., Santos, C. X. C., Sawyer, G. J., Zhang, X., Mongue‐Din, H., et al. (2017) · Circulation · doi:10.1161/circulationaha.116.023877 · Cited by 62 · see citing works
Khoo, N. K. H., Li, L., Salvatore, S. R., Schopfer, F. J., & Freeman, B. Α. (2018) · Scientific Reports · doi:10.1038/s41598-018-20460-8 · Cited by 63 · see citing works
Turell, L., Vitturi, D. A., Coitiño, E. L., Lebrato, L., Möller, M. N., Sagasti, C., Salvatore, S. R., Woodcock, S. R., Álvarez, B., & Schopfer, F. J. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.756288 · Cited by 60 · see citing works
da Silva, S. R. A., Bronze, M. R., Figueira, M. E., Siwy, J., Mischak, H., Combet, E., & Mullen, W. (2014) · American Journal of Clinical Nutrition · doi:10.3945/ajcn.114.094219 · Cited by 56 · see citing works
Mills, C. E., Khatri, J., Maskell, P., Odongerel, C., & Webb, A. J. (2016) · British Journal of Clinical Pharmacology · doi:10.1111/bcp.12918 · Cited by 55 · see citing works
Jobbagy, S., Vitturi, D. A., Salvatore, S. R., Turell, L., Pires, M. F., Kansanen, E., Batthyány, C., Lancaster, J. R., Freeman, B. Α., & Schopfer, F. J. (2018) · Redox Biology · doi:10.1016/j.redox.2018.11.008 · Cited by 57 · see citing works
Nitro-fatty acids in cardiovascular regulation and diseases characteristics and molecular mechanisms
Villacorta, L. (2015) · Frontiers in bioscience · doi:10.2741/4425 · Cited by 50 · see citing works
Nitro-fatty acid pharmacokinetics in the adipose tissue compartment
Fazzari, M., Khoo, N., Woodcock, S. R., Jorkasky, D. K., Li, L., Schopfer, F. J., & Freeman, B. Α. (2016) · Journal of Lipid Research · doi:10.1194/jlr.m072058 · Cited by 49 · see citing works
Role of dietary pro‐oxidants in the maintenance of health and resilience to oxidative stress
de Roos, B., & Duthie, G. G. (2014) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.201400568 · Cited by 45 · 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
Piesche, M., Roos, J., Kuhn, B. R., Fettel, J., Hellmuth, N., Brat, C., Maucher, I. V., Awad, O., Matrone, C., Comerma-Steffensen, S., et al. (2020) · Frontiers in Pharmacology · doi:10.3389/fphar.2020.01297 · Cited by 44 · see citing works
Snyder, N. W., Golin-Bisello, F., Gao, Y., Blair, I. A., Freeman, B. Α., & Wendell, S. G. (2014) · Chemico-Biological Interactions · doi:10.1016/j.cbi.2014.10.029 · Cited by 43 · see citing works
Freeman, B. Α., O’Donnell, V. B., & Schopfer, F. J. (2018) · Nitric Oxide · doi:10.1016/j.niox.2018.05.002 · Cited by 43 · see citing works
Nitric oxide signalling and neuronal nitric oxide synthase in the heart under stress
Zhang, Y. H. (2017) · F1000Research · doi:10.12688/f1000research.10128.1 · Cited by 42 · see citing works
Melo, T., Montero‐Bullón, J., Domingues, P. M., & Domingues, M. R. (2019) · Redox Biology · doi:10.1016/j.redox.2019.101106 · Cited by 44 · see citing works
Fazzari, M., Vitturi, D. A., Woodcock, S. R., Salvatore, S. R., Freeman, B. Α., & Schopfer, F. J. (2018) · Journal of Lipid Research · doi:10.1194/jlr.m088815 · Cited by 39 · see citing works
Ca2+ signaling in the myocardium by (redox) regulation of PKA/CaMKII
Johnston, A. S., Lehnart, S. E., & Burgoyne, J. R. (2015) · Frontiers in Pharmacology · doi:10.3389/fphar.2015.00166 · Cited by 39 · see citing works
Revol-Cavalier, J., Quaranta, A., Newman, J. W. I., BRASH, A. R., Hámberg, M., & Wheelock, C. E. (2024) · Chemical Reviews · doi:10.1021/acs.chemrev.3c00520 · Cited by 44 · see citing works
Evaluation of 10-Nitro Oleic Acid Bio-Elimination in Rats and Humans
Salvatore, S. R., Vitturi, D. A., Fazzari, M., Jorkasky, D. K., & Schopfer, F. J. (2017) · Scientific Reports · doi:10.1038/srep39900 · Cited by 36 · see citing works
Wendell, S. G., Golin-Bisello, F., Wenzel, S. E., Sobol, R. W., Holguín, F., & Freeman, B. Α. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.635151 · Cited by 36 · see citing works
Angelini, F., Pagano, F., Bordin, A., Milan, M., Chimenti, I., Peruzzi, M., Valenti, V., Marullo, A. G. M., Schirone, L., Palmerio, S., et al. (2017) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2017/2712751 · Cited by 34 · see citing works
Electrophilic characteristics and aqueous behavior of fatty acid nitroalkenes
Grippo, V., Mojović, M., Pavićević, A. A., Kabeláč, M., Hubatka, F., Tuřánek, J., Zatloukalová, M., Freeman, B. Α., & Vacek, J. (2020) · Redox Biology · doi:10.1016/j.redox.2020.101756 · Cited by 35 · see citing works
Generation and esterification of electrophilic fatty acid nitroalkenes in triacylglycerides
Fazzari, M., Khoo, N. K. H., Woodcock, S. R., Li, L., Freeman, B. Α., & Schopfer, F. J. (2015) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2015.05.033 · Cited by 34 · see citing works
Impact of adherence to the Mediterranean diet on stroke risk
Ungvari, Z. I., Fekete, M., Varga, P., Fekete, J. T., Buda, A., Szappanos, Á., Lehoczki, A., Mózes, N., Grosso, G., Menyhárt, O., et al. (2025) · GeroScience · doi:10.1007/s11357-024-01491-8 · Cited by 33 · see citing works
Nitrated fatty acids: from diet to disease
Khoo, N., & Schopfer, F. (2019) · Current Opinion in Physiology · doi:10.1016/j.cophys.2019.04.013 · Cited by 31 · see citing works
Bassi, R., Burgoyne, J. R., Nicola, G. F. D., Rudyk, O., DeSantis, V., Charles, R. L., Eaton, P., & Marber, M. S. (2017) · Journal of Biological Chemistry · doi:10.1074/jbc.m117.785410 · Cited by 30 · see citing works
Altinoz, M. A., & Elmacı, İ. (2017) · Nitric Oxide · doi:10.1016/j.niox.2017.10.001 · Cited by 29 · see citing works
Nitrated fatty acids in cardiovascular diseases
Mollenhauer, M., Mehrkens, D., & Rudolph, V. (2018) · Nitric Oxide · doi:10.1016/j.niox.2018.03.016 · Cited by 29 · see citing works
Virgin Olive Oil and Hypertension
López, S., Bermúdez, B., la Paz, S. M., Jaramillo, S., Abia, R., & Muriana, F. J. G. (2016) · Current Vascular Pharmacology · doi:10.2174/1570161114666160118105137 · Cited by 28 · see citing works
The Role of Olive Oil in Cardiometabolic Risk
Salvo, A., & Tuttolomondo, A. (2025) · Metabolites · doi:10.3390/metabo15030190 · Cited by 28 · see citing works
Nitro Fatty Acids (NO2-FAs): An Emerging Class of Bioactive Fatty Acids
Koutoulogenis, G. S., & Kokotos, G. (2021) · Molecules · doi:10.3390/molecules26247536 · Cited by 26 · see citing works
Conjugated Linoleic Acid Modulates Clinical Responses to Oral Nitrite and Nitrate
Hughan, K. S., Wendell, S. G., Delmastro-Greenwood, M. M., Helbling, N. L., Corey, C. G., Bellavia, L., Potti, G. K., Grimes, G. J., Goodpaster, B. H., Kim‐Shapiro, D. B., et al. (2017) · Hypertension · doi:10.1161/hypertensionaha.117.09016 · Cited by 26 · see citing works
Nitro-Oleic Acid Regulates Endothelin Signaling in Human Endothelial Cells
Kansanen, E., Linna-Kuosmanen, S., Ruotsalainen, A., Hynynen, H., & Levonen, A. (2017) · Molecular Pharmacology · doi:10.1124/mol.117.109751 · Cited by 25 · see citing works
D’Amore, A., Fazzari, M., Jiang, H., Luketich, S. K., Luketich, M. E., Hoff, R., Jacobs, D. L., Gu, X., Badylak, S. F., Freeman, B. Α., et al. (2017) · Tissue Engineering Part A · doi:10.1089/ten.tea.2017.0349 · Cited by 23 · see citing works
Lu, H., Sun, J., Liang, W., Zhang, J., Rom, O., Garcia-Barrio, M. T., Li, S., Villacorta, L., Schopfer, F. J., Freeman, B. Α., et al. (2019) · Physiological Genomics · doi:10.1152/physiolgenomics.00127.2018 · Cited by 23 · see citing works
The chemical foundations of nitroalkene fatty acid signaling through addition reactions with thiols
Turell, L., Steglich, M., & Álvarez, B. (2018) · Nitric Oxide · doi:10.1016/j.niox.2018.03.014 · Cited by 22 · see citing works
Inflammatory signaling and metabolic regulation by nitro-fatty acids
Rom, O., Khoo, N. K. H., Chen, Y. E., & Villacorta, L. (2018) · Nitric Oxide · doi:10.1016/j.niox.2018.03.017 · Cited by 20 · see citing works
Soluble Epoxide Hydrolase and Diabetes Complications
Anita, N. Z., & Swardfager, W. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23116232 · Cited by 19 · see citing works
da Silva, S. R. A., Combet, E., Figueira, M. E., Koeck, T., Mullen, W., & Bronze, M. R. (2015) · Proceedings of The Nutrition Society · doi:10.1017/s0029665115002323 · Cited by 19 · see citing works
Comparison of the anti-angiogenic potential of hydroxytyrosol and five derivatives
López-Jiménez, A., Gallardo, E., Espartero, J. L., Madrona, A., Quesada, A. R., & Medina, M. Á. (2018) · Food & Function · doi:10.1039/c8fo01140k · Cited by 19 · see citing works
Zhao, Y., Chang, Z., Zhao, G., Lu, H., Xiong, W., Liang, W., Wang, H. H., Villacorta, L., Garcia-Barrio, M. T., Zhu, T., et al. (2020) · Cardiovascular Drugs and Therapy · doi:10.1007/s10557-020-07031-8 · Cited by 18 · see citing works
Abis, G., Pacheco‐Gómez, R., Bui, T. T. T., & Conte, M. R. (2019) · Analytical Chemistry · doi:10.1021/acs.analchem.9b01847 · Cited by 17 · see citing works
Neuroprotective actions of a fatty acid nitroalkene in Parkinson’s disease
Maio, R. D., Keeney, M. T., Cechova, V., Mortimer, A. D., Sekandari, A., Rowart, P., Greenamyre, J. T., Freeman, B. Α., & Fazzari, M. (2023) · npj Parkinson s Disease · doi:10.1038/s41531-023-00502-3 · Cited by 18 · see citing works
Essandoh, K., Teuber, J. P., & Brody, M. J. (2024) · Biochemical Society Transactions · doi:10.1042/bst20221296 · Cited by 16 · see citing works
Neves, B., Duarte, S., Domingues, P. M., Pérez‐Sala, D., Oliveira, M. M., Domingues, M. R., & Melo, T. (2020) · Molecules · doi:10.3390/molecules25092120 · Cited by 15 · see citing works
Sánchez-Calvo, B., Cassina, A., Ríos, N., Peluffo, G., Boggia, J. G., Radí, R., Rubbo, H., & Trostchansky, A. (2016) · PLoS ONE · doi:10.1371/journal.pone.0150459 · Cited by 15 · see citing works
Georgoulis, M., Damigou, E., Derdelakou, E., Kosti, R. I., Chrysohoou, C. A., Barkas, F., Kravvariti, E., Tsioufis, C. P., Pitsavos, C. S., Liberopoulos, E. N., et al. (2024) · European Journal of Clinical Nutrition · doi:10.1038/s41430-024-01440-w · Cited by 14 · see citing works
Fatty acid nitroalkenes – Multi-target agents for the treatment of sickle cell disease
Chowdhury, F. A., Colussi, N., Sharma, M., Wood, K. C., Xu, J. Z., Freeman, B. Α., Schopfer, F. J., & Straub, A. C. (2023) · Redox Biology · doi:10.1016/j.redox.2023.102941 · Cited by 12 · see citing works
The chemical biology of dinitrogen trioxide
Möller, M. N., & Vitturi, D. A. (2024) · Redox Biochemistry and Chemistry · doi:10.1016/j.rbc.2024.100026 · Cited by 13 · see citing works
Nitro-fatty acids: promising agents for the development of new cancer therapeutics
Roos, J., Manolikakes, G., Schlomann, U., Klinke, A., Schopfer, F. J., Neumann, C. A., & Maier, T. J. (2024) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2024.09.009 · Cited by 13 · see citing works
Müller, M., Schubert, T., Welke, C., Maske, T., Patschkowski, T., Donhauser, E., Heinen‐Weiler, J., Hormann, F.-L., Heiles, S., Schulz, T. J., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-59192-5 · Cited by 13 · see citing works
Rosenblat, M., Rom, O., Volkova, N., & Aviram, M. (2016) · Lipids · doi:10.1007/s11745-016-4169-2 · Cited by 13 · see citing works
Nitric Oxide Formation From Inorganic Nitrate
Lundberg, J. O., & Weitzberg, E. (2017) · Elsevier eBooks · doi:10.1016/b978-0-12-804273-1.00012-0 · Cited by 12 · see citing works
Cho, H.-J., Switzer, C., Kamynina, A., Charles, R. L., Rudyk, O., Ng, T., Burgoyne, J. R., & Eaton, P. (2019) · Redox Biology · doi:10.1016/j.redox.2019.101405 · Cited by 13 · see citing works
Association of Epoxide Hydrolase 2 Gene Arg287Gln with the Risk for Primary Hypertension in Chinese
Ma, L., Zhao, H., Yu, M., Wen, Y., Zhao, T., Yan, M., Liu, Q., Jiang, Y., Cao, Y., Li, P., et al. (2020) · International Journal of Hypertension · doi:10.1155/2020/2351547 · Cited by 12 · see citing works
Liu, J., Morisseau, C. H. P., Huang, H., & Hammock, B. D. (2016) · Journal of Ethnopharmacology · doi:10.1016/j.jep.2016.09.044 · Cited by 12 · see citing works
Zhao, C., Chen, W., Wang, W.-Z., Gong, F., Fan, C.-Q., Li, Y., Lan, T., Wang, W., & Yuan, M. (2023) · Asian Journal of Andrology · doi:10.4103/aja202331 · Cited by 11 · see citing works
Charles, R. L., Abis, G., Fernandez, B. F., Guttzeit, S., Buccafusca, R., Conte, M. R., & Eaton, P. (2021) · Redox Biology · doi:10.1016/j.redox.2021.102107 · Cited by 11 · see citing works
Hellmuth, N., Brat, C., Awad, O., George, S., Kahnt, A. S., Bauer, T., Phuoc, H. P. H., Steinhilber, D., Angioni, C., Hassan, M. E., et al. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.715076 · Cited by 11 · see citing works
Qiu, Q., Abis, G., Mattingly-Peck, F., Lynham, S., Fraternali, F., & Conte, M. R. (2022) · Journal of Molecular Biology · doi:10.1016/j.jmb.2022.167600 · Cited by 11 · see citing works
Two Pools of Epoxyeicosatrienoic Acids in Humans
Elijovich, F., Milne, G. L., Brown, N. J., Schwartzman, M. L., & Laffer, C. L. (2017) · Hypertension · doi:10.1161/hypertensionaha.117.10392 · Cited by 11 · see citing works
Redox Regulation of Soluble Epoxide Hydrolase—Implications for Cardiovascular Health and Disease
Charles, R. L., & Eaton, P. (2022) · Cells · doi:10.3390/cells11121932 · Cited by 10 · see citing works
Understanding the chemically-reactive proteome
Jones, L. H. (2015) · Molecular BioSystems · doi:10.1039/c5mb00760g · Cited by 8 · see citing works
Burgoyne, J. R., & Eaton, P. (2025) · Physiological Reviews · doi:10.1152/physrev.00051.2024 · Cited by 7 · see citing works
Healthy lifestyles to prevent dementia and reduce dementia symptoms
Hogervorst, E. (2017) · Working with Older People · doi:10.1108/wwop-12-2016-0036 · Cited by 7 · see citing works
Freeman, B. Α., Pekarová, M., Rubbo, H., & Trostchansky, A. (2017) · Elsevier eBooks · doi:10.1016/b978-0-12-804273-1.00016-8 · Cited by 7 · see citing works
Nitro-fatty acids: mechanisms of action, roles in metabolic diseases, and therapeutics
Ni, H., Tan, X., Du, J., & Wang, Y. (2024) · Current Medicine · doi:10.1007/s44194-024-00030-z · Cited by 6 · see citing works
Bioactive lipids in hypertension
Imig, J. D. (2023) · Advances in pharmacology · doi:10.1016/bs.apha.2023.01.001 · Cited by 5 · see citing works
Brat, C., Phuoc, H. P. H., Awad, O., Parmar, B. S., Hellmuth, N., Heinicke, U., Amr, S., Grimmer, J., Sürün, D., Husnjak, K., et al. (2023) · Cell chemical biology · doi:10.1016/j.chembiol.2023.06.017 · Cited by 5 · see citing works
Fatty acid nitroalkenes regulate intestinal lipid absorption
Schopfer, F. J., Teng, L., Sekandari, A., Ekhator, E. S., Kohan, A. B., Freeman, B. Α., & Fazzari, M. (2025) · Journal of Lipid Research · doi:10.1016/j.jlr.2025.100855 · Cited by 4 · see citing works
Zinc-Mediated Inhibition of Soluble Epoxide Hydrolase Promotes Pulmonary Hypertension
de Jesus, D. S., Buffonge, S., Abis, G., Buccafusca, R., Baliga, R. S., Warren, H. R., Hobbs, A. J., Ruppert, C., Weiß, A., SCHERMULY, R. T., et al. (2025) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.202409-1763oc · Cited by 4 · see citing works
Nitro-fatty acid signaling: Therapeutic potential in inflammatory diseases
Rubbo, H., & Trostchansky, A. (2024) · Redox Biochemistry and Chemistry · doi:10.1016/j.rbc.2024.100027 · Cited by 4 · see citing works
Chartoumpekis, D. V., Chen, I., Salvatore, S. R., Schopfer, F. J., Freeman, B. Α., & Khoo, N. K. H. (2024) · Nitric Oxide · doi:10.1016/j.niox.2024.06.002 · Cited by 3 · see citing works
Beneficial properties of plants and their derived extracts on the cardiovascular system
Colombo, M. L., Chiara, F., Maffè, S., & Davanzo, F. (2014) · Nutrafoods · doi:10.1007/s13749-014-0046-x · Cited by 2 · see citing works
Nitro-arachidonic Acid: Downstream Signaling and Therapeutics
Rubbo, H., González-Perilli, L., Mastrogiovanni, M., Sánchez-Calvo, B., & Trostchansky, A. (2016) · Springer eBooks · doi:10.1007/978-3-319-45865-6_6 · Cited by 2 · see citing works
Thiol modification and signaling by biological electrophiles
Schopfer, F. J., & Vitturi, D. A. (2022) · Elsevier eBooks · doi:10.1016/b978-0-323-90219-9.00027-3 · Cited by 1 · see citing works
A novel inhibitor of soluble epoxide hydrolase that adducts C521 is cardioprotective
Charles, R. L., Fernández-Caggiano, M., Rudyk, O., Tyson-Hirst, I., Ehteramyan, M., Switzer, C., Buccafusca, R., Rajeeve, V., Bianchi, K., Morales, V., et al. (2025) · Redox Biology · doi:10.1016/j.redox.2025.103974 · Cited by 1 · see citing works
Nitric oxide functions in the heart
Kıvrak, T., Erdem, K., & Karaca, I. (2017) · Archives of Anatomy and Physiology · doi:10.17352/aap.000007 · Cited by 1 · see citing works
Redox regulation of soluble epoxide hydrolase does not affect pain behavior in mice
Wack, G., Eaton, P., Schmidtko, A., & Kallenborn-Gerhardt, W. (2020) · Neuroscience Letters · doi:10.1016/j.neulet.2020.134798 · Cited by 1 · see citing works
Theoretical Photophysics (DFT) of Fluorescent Benzothiadiazole Probes
Mota, A. A. R., Corrêa, J. R., Lopes, T. O., de Oliveira, H. C. B., & Neto, B. A. D. (2015) · Revista Virtual de Química · doi:10.5935/1984-6835.20150018 · Cited by 1 · see citing works
Neuroprotective actions of a fatty acid nitroalkene in Parkinson’s disease.Preprint
Fazzari, M., Maio, R. D., Keeney, M. T., Cechova, V., Mortimer, A. D., Rowart, P., Greenamyre, J. T., & Freeman, B. Α. (2022) · Research Square · doi:10.21203/rs.3.rs-2367066/v1 · Cited by 1 · see citing works
Müller, M., Schubert, T., Welke, C., Schulz, T. J., Patschkowski, T., Maske, T., Lengenfelder, L. A., Landwehrjohann, L., Donhauser, E., Vogt, E. T., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.02.20.581137 · Cited by 1 · see citing works
Durand, G. (2025) · Wiley eBooks · doi:10.1002/9781119790419.ch21
NITROALKENE FATTY ACIDS: FORMATION, METABOLISM, REACTIVITY, AND SIGNALING
Steglich, M., Sosa, M., Schopfer, F. J., & Turell, L. (2025) · Wiley eBooks · doi:10.1002/9781119790419.ch20
Allosteric Ensembles Elucidate Mechanisms of Inhibition in Human Soluble Epoxide HydrolasePreprint
Conte, M. R., Qiu, Q., Carmona, O. G., Abis, G., & Fraternali, F. (2025) · Research Square · doi:10.21203/rs.3.rs-8030999/v1
Rodríguez, L., Fernandez-Rojas, M., Morales-Malvarez, L., Eduardo Fuentes, Q., & Trostchansky, A. (2025) · Food Bioscience · doi:10.1016/j.fbio.2025.108175
Endothelial nitric oxide signaling in cellular and systemic metabolism
Siragusa, M., Dunaway, L. S., Lammert, E., Fleming, I., Isakson, B. E., & Cortese-Krott, M. M. (2026) · Redox Biology · doi:10.1016/j.redox.2026.104443
- Authors
- Charles, R. L., Rudyk, O., Prysyazhna, O., Kamynina, A., Yang, J., Morisseau, C., Hammock, B. D., Freeman, B. A., & Eaton, P.
- Affiliations
- St Thomas' Hospital (GB)
- UC Davis Comprehensive Cancer Center (US)
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261
- Corresponding author
- Eaton, Philip
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2014-05-19
- Volume
- 111
- Issue
- 22
- Pages
- 8167-8172
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC4050620
- OpenAlex
- W2161301563
- Cited by
- 100
- References
- 51
- Citations by year
- 2026: 1 · 2025: 11 · 2024: 9 · 2023: 6 · 2022: 5 · 2021: 3 · 2020: 6 · 2019: 9 · 2018: 11 · 2017: 15 · 2016: 10 · 2015: 10 · 2014: 4
- FWCI
- 5.74
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Research Portal (King's College London) (submittedVersion)
- Funders
- National Institute for Health and Care Research
- British Heart Foundation (PG/10/98/28655, FS/11/45/28859, RG/12/12/29872)
- Fondation Leducq
- National Institutes of Health (DK097154, ES002710)
- Medical Research Council (MR/L009684/1)
- Biotechnology and Biological Sciences Research Council (BB/C503646/1)
- National Heart, Lung, and Blood Institute (R01HL064937, R37HL058115, R01HL058115, P01HL103455, R01HL132550)
- National Institute of Diabetes and Digestive and Kidney Diseases (U24DK097154)
- National Institute of Environmental Health Sciences (P42ES004699, R01ES002710)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Eicosanoids and Hypertension Pharmacology
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Renin-Angiotensin System Studies
- Keywords
- soluble epoxide hydrolase, nitro-fatty acids, Mediterranean diet, hypertension, blood pressure, epoxyeicosatrienoic acids, angiotensin II-induced hypertension, linoleic acid, nitrite, vasodilation
- MeSH terms
- Angiotensin II, Animals, Blood Pressure, Cellulase, Disease Models, Animal, Epoxide Hydrolases, Fatty Acids, Cardiomegaly, Hypertension, Mice, Inbred C57BL, Mice, Mutant Strains, Nitrates, Nitrites, Sulfhydryl Compounds, Vasoconstrictor Agents, Vasodilation, Diet, Mediterranean, Mice, Gene Knock-In Techniques
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
