{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T06:52:40Z","timestamp":1785307960737,"version":"3.55.0"},"reference-count":35,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2021,1,30]],"date-time":"2021-01-30T00:00:00Z","timestamp":1611964800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["ES019217"],"award-info":[{"award-number":["ES019217"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["GM103436"],"award-info":[{"award-number":["GM103436"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P30ES030283"],"award-info":[{"award-number":["P30ES030283"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Carnosine is a naturally occurring dipeptide (\u03b2-alanine-L-histidine) which supports physiological homeostasis by buffering intracellular pH, chelating metals, and conjugating with and neutralizing toxic aldehydes such as acrolein. However, it is not clear if carnosine can support cardiovascular function or modify cardiovascular disease (CVD) risk. To examine this, we measured urinary levels of nonconjugated carnosine and its acrolein conjugates (carnosine-propanal and carnosine-propanol) in participants of the Louisville Healthy Heart Study and examined associations with indices of CVD risk. We found that nonconjugated carnosine was significantly associated with hypertension (p = 0.011), heart failure (p = 0.015), those categorized with high CVD risk (p &lt; 0.001), body mass index (BMI; p = 0.007), high sensitivity C-reactive protein (hsCRP; p = 0.026), high-density lipoprotein (HDL; p = 0.007) and certain medication uses. Levels of carnosine-propanal and carnosine-propanol demonstrated significant associations with BMI, blood glucose, HDL and diagnosis of diabetes. Carnosine-propanal was also associated with heart failure (p = 0.045) and hyperlipidemia (p = 0.002), but no associations with myocardial infarction or stroke were identified. We found that the positive associations of carnosine conjugates with diabetes and HDL remain statistically significant (p &lt; 0.05) in an adjusted, linear regression model. These findings suggest that urinary levels of nonconjugated carnosine, carnosine-propanal and carnosine-propanol may be informative biomarkers for the assessment of CVD risk\u2014and particularly reflective of skeletal muscle injury and carnosine depletion in diabetes.<\/jats:p>","DOI":"10.3390\/ijms22031383","type":"journal-article","created":{"date-parts":[[2021,1,30]],"date-time":"2021-01-30T06:22:20Z","timestamp":1611987740000},"page":"1383","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Urinary Levels of the Acrolein Conjugates of Carnosine Are Associated with Cardiovascular Disease Risk"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1773-1523","authenticated-orcid":false,"given":"Timothy E.","family":"O\u2019Toole","sequence":"first","affiliation":[{"name":"Department of Medicine, University of Louisville, Louisville, KY 40202, USA"},{"name":"Christina Lee Brown Envirome Institute, University of Louisville, Louisville, KY 40208, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaohong","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Anatomical Sciences and Neurobiology, University of Louisville, Louisville, KY 40202, USA"},{"name":"KBRIN Bioinformatics Core, University of Louisville, Louisville, KY 40202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel W.","family":"Riggs","sequence":"additional","affiliation":[{"name":"Christina Lee Brown Envirome Institute, University of Louisville, Louisville, KY 40208, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David J.","family":"Hoetker","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Louisville, Louisville, KY 40202, USA"},{"name":"Christina Lee Brown Envirome Institute, University of Louisville, Louisville, KY 40208, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shahid P.","family":"Baba","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Louisville, Louisville, KY 40202, USA"},{"name":"Christina Lee Brown Envirome Institute, University of Louisville, Louisville, KY 40208, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aruni","family":"Bhatnagar","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Louisville, Louisville, KY 40202, USA"},{"name":"Christina Lee Brown Envirome Institute, University of Louisville, Louisville, KY 40208, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,1,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1803","DOI":"10.1152\/physrev.00039.2012","article-title":"Physiology and pathophysiology of carnosine","volume":"93","author":"Boldyrev","year":"2013","journal-title":"Physiol. Rev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1002\/biof.5520240109","article-title":"Carnosine and related dipeptides as quenchers of reactive carbonyl species: From structural studies to therapeutic perspectives","volume":"24","author":"Aldini","year":"2005","journal-title":"Biofactors"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1016\/S0006-291X(02)02545-7","article-title":"Carnosine is a quencher of 4-hydroxy-nonenal: Through what mechanism of reaction?","volume":"298","author":"Aldini","year":"2002","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"996","DOI":"10.1002\/jms.517","article-title":"Acrolein-sequestering ability of endogenous dipeptides: Characterization of carnosine and homocarnosine\/acrolein adducts by electrospray ionization tandem mass spectrometry","volume":"38","author":"Carini","year":"2003","journal-title":"J. Mass Spectrom."},{"key":"ref_5","first-page":"H935","article-title":"Formation of 4-hydroxy-2-nonenal-modified proteins in ischemic rat heart","volume":"276","author":"Eaton","year":"1999","journal-title":"Am. J. Physiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"8212","DOI":"10.1021\/bi025896u","article-title":"Identification of bovine heart cytochrome c oxidase subunits modified by the lipid peroxidation product 4-hydroxy-2-nonenal","volume":"41","author":"Musatov","year":"2002","journal-title":"Biochemistry"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"642","DOI":"10.1016\/S0891-5849(00)00351-8","article-title":"Metabolism of lipid peroxidation product, 4-hydroxynonenal (HNE) in rat erythrocytes: Role of aldose reductase","volume":"29","author":"Srivastava","year":"2000","journal-title":"Free Radic. Biol. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1027","DOI":"10.1002\/oby.21434","article-title":"Effects of carnosine supplementation on glucose metabolism: Pilot clinical trial","volume":"24","author":"Jakubova","year":"2016","journal-title":"Obesity"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"27224","DOI":"10.1038\/srep27224","article-title":"A carnosine intervention study in overweight human volunteers: Bioavailability and reactive carbonyl species sequestering effect","volume":"6","author":"Regazzoni","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1339","DOI":"10.1111\/j.1582-4934.2010.01101.x","article-title":"The carbonyl scavenger carnosine ameliorates dyslipidaemia and renal function in Zucker obese rats","volume":"15","author":"Aldini","year":"2011","journal-title":"J. Cell. Mol. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1177","DOI":"10.1007\/s00726-018-2592-9","article-title":"Carnosine and advanced glycation end products: A systematic review","volume":"50","author":"Ghodsi","year":"2018","journal-title":"Amino Acids"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e015222","DOI":"10.1161\/JAHA.119.015222","article-title":"Cardiospecific Overexpression of ATPGD1 (Carnosine Synthase) Increases Histidine Dipeptide Levels and Prevents Myocardial Ischemia Reperfusion Injury","volume":"9","author":"Zhao","year":"2020","journal-title":"J. Am. Heart Assoc."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1162","DOI":"10.1161\/ATVBAHA.112.300572","article-title":"Dietary carnosine prevents early atherosclerotic lesion formation in apolipoprotein E-null mice","volume":"33","author":"Barski","year":"2013","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"e013041","DOI":"10.1161\/JAHA.119.013041","article-title":"Carnosine Supplementation Mitigates the Deleterious Effects of Particulate Matter Exposure in Mice","volume":"8","author":"Abplanalp","year":"2019","journal-title":"J. Am. Heart Assoc."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1002\/mrm.10384","article-title":"The carnosine C-2 proton\u2019s chemical shift reports intracellular pH in oxidative and glycolytic muscle fibers","volume":"49","author":"Damon","year":"2003","journal-title":"Magn. Reson. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1161\/CIRCULATIONAHA.117.029468","article-title":"Metabolic Predictors of Incident Coronary Heart Disease in Women","volume":"137","author":"Paynter","year":"2018","journal-title":"Circulation"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1038\/nature10146","article-title":"Progress and challenges in translating the biology of atherosclerosis","volume":"473","author":"Libby","year":"2011","journal-title":"Nature"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1172\/JCI119176","article-title":"Human neutrophils employ the myeloperoxidase-hydrogen peroxide-chloride system to convert hydroxy-amino acids into glycolaldehyde, 2-hydroxypropanal, and acrolein. A mechanism for the generation of highly reactive alpha-hydroxy and alpha, beta-unsaturated aldehydes by phagocytes at sites of inflammation","volume":"99","author":"Anderson","year":"1997","journal-title":"J. Clin. Investig."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/S1050-1738(99)00016-X","article-title":"Current status of acrolein as a lipid peroxidation product","volume":"9","author":"Uchida","year":"1999","journal-title":"Trends Cardiovasc. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"28163","DOI":"10.1074\/jbc.M113.504753","article-title":"Role of aldose reductase in the metabolism and detoxification of carnosine-acrolein conjugates","volume":"288","author":"Baba","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Baye, E., Ukropec, J., de Courten, M.P.J., Mousa, A., Kurdiova, T., Johnson, J., Wilson, K., Plebanski, M., Aldini, G., and Ukropcova, B. (2018). Carnosine Supplementation Improves Serum Resistin Concentrations in Overweight or Obese Otherwise Healthy Adults: A Pilot Randomized Trial. Nutrients, 10.","DOI":"10.3390\/nu10091258"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1767","DOI":"10.1152\/japplphysiol.00007.2018","article-title":"Exercise alters and beta-alanine combined with exercise augments histidyl dipeptide levels and scavenges lipid peroxidation products in human skeletal muscle","volume":"125","author":"Hoetker","year":"2018","journal-title":"J. Appl. Physiol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"468","DOI":"10.1080\/08958378.2020.1845257","article-title":"Urinary levels of the acrolein conjugates of carnosine are associated with inhaled toxicants","volume":"32","author":"Li","year":"2020","journal-title":"Inhal. Toxicol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/0891-5849(91)90192-6","article-title":"Chemistry and biochemistry of 4-hydroxynonenal, malonaldehyde and related aldehydes","volume":"11","author":"Esterbauer","year":"1991","journal-title":"Free Radic Biol Med"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"H479","DOI":"10.1152\/ajpheart.00817.2003","article-title":"Cardiovascular pathophysiology of environmental pollutants","volume":"286","author":"Bhatnagar","year":"2004","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"10893","DOI":"10.1074\/jbc.273.18.10893","article-title":"Metabolism of the lipid peroxidation product, 4-hydroxy-trans-2-nonenal, in isolated perfused rat heart","volume":"273","author":"Srivastava","year":"1998","journal-title":"J. Biol. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1161\/CIRCRESAHA.114.305518","article-title":"Genetic Deficiency of Glutathione S-Transferase P Increases Myocardial Sensitivity to Ischemia-Reperfusion Injury","volume":"117","author":"Conklin","year":"2015","journal-title":"Circ. Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1080\/03602530802431439","article-title":"The aldo-keto reductase superfamily and its role in drug metabolism and detoxification","volume":"40","author":"Barski","year":"2008","journal-title":"Drug Metab. Rev."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e000934","DOI":"10.1161\/JAHA.114.000934","article-title":"Acrolein exposure is associated with increased cardiovascular disease risk","volume":"3","author":"DeJarnett","year":"2014","journal-title":"J. Am. Heart Assoc."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"848","DOI":"10.1016\/j.freeradbiomed.2011.01.004","article-title":"Vitamin C supplementation lowers urinary levels of 4-hydroperoxy-2-nonenal metabolites in humans","volume":"50","author":"Kuiper","year":"2011","journal-title":"Free Radic. Biol. Med."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"De Courten, B., Kurdiova, T., de Courten, M.P., Belan, V., Everaert, I., Vician, M., Teede, H., Gasperikova, D., Aldini, G., and Derave, W. (2015). Muscle Carnosine Is Associated with Cardiometabolic Risk Factors in Humans. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0138707"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Abplanalp, W., DeJarnett, N., Riggs, D.W., Conklin, D.J., McCracken, J.P., Srivastava, S., Xie, Z., Rai, S., Bhatnagar, A., and O\u2019Toole, T.E. (2017). Benzene exposure is associated with cardiovascular disease risk. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0183602"},{"key":"ref_33","unstructured":"Framingham Heart Study (2021, January 26). Cardiovascular Disease (10 Year Risk). Available online: https:\/\/framinghamheartstudy.org\/fhs-risk-functions\/cardiovascular-disease-10-year-risk\/."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1161\/CIRCRESAHA.110.222679","article-title":"Episodic exposure to fine particulate air pollution decreases circulating levels of endothelial progenitor cells","volume":"107","author":"Hellmann","year":"2010","journal-title":"Circ. Res."},{"key":"ref_35","first-page":"S23","article-title":"Evaluating assay precision","volume":"29","author":"Chesher","year":"2008","journal-title":"Clin. Biochem. Rev."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/3\/1383\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:17:29Z","timestamp":1760159849000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/3\/1383"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,1,30]]},"references-count":35,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2021,2]]}},"alternative-id":["ijms22031383"],"URL":"https:\/\/doi.org\/10.3390\/ijms22031383","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,1,30]]}}}