{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,4]],"date-time":"2026-11-04T17:18:37Z","timestamp":1793812717705,"version":"4.6.1"},"reference-count":36,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,5,10]],"date-time":"2023-05-10T00:00:00Z","timestamp":1683676800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cardiovasc. Med."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>In acute myocardial infarction and heart failure, anemia is associated with adverse clinical outcomes. Endothelial dysfunction (ED) is characterized by attenuated nitric oxide (NO)-mediated relaxation responses which is poorly studied in chronic anemia (CA). We hypothesized that CA is associated with ED due to increased oxidative stress in the endothelium.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      CA was induced by repeated blood withdrawal in male C57BL\/6J mice. Flow-Mediated Dilation (FMD) responses were assessed in CA mice using ultrasound-guided femoral transient ischemia model. Tissue organ bath was used to assess vascular responsiveness of aortic rings from CA mice, and in aortic rings incubated with red blood cells (RBCs) from anemic patients. In the aortic rings from anemic mice, the role of arginases was assessed using either an arginase inhibitor (Nor-NOHA) or genetic ablation of arginase 1 in the endothelium. Inflammatory changes in plasma of CA mice were examined by ELISA. Expression of endothelial NO synthase (eNOS), inducible NO synthase (iNOS), myeloperoxidase (MPO), 3-Nitrotyrosine levels, and 4-Hydroxynonenal (4-HNE) were assessed either by Western blotting or immunohistochemistry. The role of reactive oxygen species (ROS) in ED was assessed in the anemic mice either supplemented with N-Acetyl cysteine (NAC) or by\n                      <jats:italic>in vitro<\/jats:italic>\n                      pharmacological inhibition of MPO.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>The FMD responses were diminished with a correlation to the duration of anemia. Aortic rings from CA mice showed reduced NO-dependent relaxation compared to non-anemic mice. RBCs from anemic patients attenuated NO-dependent relaxation responses in murine aortic rings compared to non-anemic controls. CA results in increased plasma VCAM-1, ICAM-1 levels, and an increased iNOS expression in aortic vascular smooth muscle cells. Arginases inhibition or arginase1 deletion did not improve ED in anemic mice. Increased expression of MPO and 4-HNE observed in endothelial cells of aortic sections from CA mice. NAC supplementation or inhibition of MPO improved relaxation responses in CA mice.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Chronic anemia is associated with progressive endothelial dysfunction evidenced by activation of the endothelium mediated by systemic inflammation, increased iNOS activity, and ROS production in the arterial wall. ROS scavenger (NAC) supplementation or MPO inhibition are potential therapeutic options to reverse the devastating endothelial dysfunction in chronic anemia.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fcvm.2023.1099069","type":"journal-article","created":{"date-parts":[[2023,5,10]],"date-time":"2023-05-10T13:18:49Z","timestamp":1683724729000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":24,"title":["Chronic anemia is associated with systemic endothelial dysfunction"],"prefix":"10.3389","volume":"10","author":[{"given":"Ramesh","family":"Chennupati","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabella","family":"Solga","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia","family":"Wischmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Dahlmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feyza G\u00fcl","family":"Celik","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Pacht","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Asl\u0131han","family":"\u015eahin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vithya","family":"Yogathasan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammad Rabiul","family":"Hosen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norbert","family":"Gerdes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Malte","family":"Kelm","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Jung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,5,10]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"595","DOI":"10.1253\/circj.CJ-08-1169","article-title":"Endothelial dysfunction: the first step toward coronary arteriosclerosis","volume":"73","author":"Vanhoutte","year":"2009","journal-title":"Circ J"},{"key":"B2","doi-asserted-by":"publisher","first-page":"840","DOI":"10.1161\/01.RES.87.10.840","article-title":"Endothelial dysfunction in cardiovascular diseases: the role of oxidant stress","volume":"87","author":"Cai","year":"2000","journal-title":"Circ Res"},{"key":"B3","doi-asserted-by":"publisher","first-page":"4","DOI":"10.2174\/157016112798829760","article-title":"The role of nitric oxide on endothelial function","volume":"10","author":"Tousoulis","year":"2012","journal-title":"Curr Vasc Pharmacol"},{"key":"B4","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1161\/CIRCRESAHA.107.155028","article-title":"Diabetes-induced coronary vascular dysfunction involves increased arginase activity","volume":"102","author":"Romero","year":"2008","journal-title":"Circ Res"},{"key":"B5","doi-asserted-by":"publisher","first-page":"2000","DOI":"10.1161\/01.CIR.0000092948.04444.C7","article-title":"Arginase reciprocally regulates nitric oxide synthase activity and contributes to endothelial dysfunction in aging blood vessels","volume":"108","author":"Berkowitz","year":"2003","journal-title":"Circulation"},{"key":"B6","doi-asserted-by":"publisher","first-page":"149","DOI":"10.3389\/fimmu.2013.00149","article-title":"Arginase: the emerging therapeutic target for vascular oxidative stress and inflammation","volume":"4","author":"Yang","year":"2013","journal-title":"Front Immunol"},{"key":"B7","doi-asserted-by":"publisher","first-page":"H777","DOI":"10.1152\/ajpheart.00831.2010","article-title":"Arginase 1 contributes to diminished coronary arteriolar dilation in patients with diabetes","volume":"300","author":"Beleznai","year":"2011","journal-title":"Am J Physiol Heart Circ Physiol"},{"key":"B8","doi-asserted-by":"publisher","first-page":"334","DOI":"10.1093\/cvr\/cvt036","article-title":"Arginase as a potential target in the treatment of cardiovascular disease: reversal of arginine steal?","volume":"98","author":"Pernow","year":"2013","journal-title":"Cardiovasc Res"},{"key":"B9","doi-asserted-by":"publisher","first-page":"692","DOI":"10.1161\/CIRCRESAHA.107.157727","article-title":"Inducible no synthase dependent S-nitrosylation and activation of Arginase1 contribute to age-related endothelial dysfunction","volume":"101","author":"Santhanam","year":"2007","journal-title":"Circ Res"},{"key":"B10","doi-asserted-by":"publisher","first-page":"594","DOI":"10.3858\/emm.2012.44.10.068","article-title":"Increased arginase ii activity contributes to endothelial dysfunction through endothelial nitric oxide synthase uncoupling in aged mice","volume":"44","author":"Shin","year":"2012","journal-title":"Exp Mol Med"},{"key":"B11","doi-asserted-by":"publisher","first-page":"3","DOI":"10.4097\/kjae.2011.61.1.3","article-title":"Endothelial arginase ii and atherosclerosis","volume":"61","author":"Ryoo","year":"2011","journal-title":"Korean J Anesthesiol"},{"key":"B12","doi-asserted-by":"publisher","first-page":"3579","DOI":"10.2174\/13816128113196660748","article-title":"Enos uncoupling in cardiovascular diseases\u2013the role of oxidative stress and inflammation","volume":"20","author":"Karbach","year":"2014","journal-title":"Curr Pharm Des"},{"key":"B13","doi-asserted-by":"publisher","first-page":"168","DOI":"10.1016\/j.vph.2012.02.004","article-title":"Nitric oxide synthase uncoupling: a therapeutic target in cardiovascular diseases","volume":"57","author":"Roe","year":"2012","journal-title":"Vascul Pharmacol"},{"key":"B14","doi-asserted-by":"publisher","first-page":"3129","DOI":"10.1021\/bi9016632","article-title":"Peroxynitrite induces destruction of the tetrahydrobiopterin and heme in endothelial nitric oxide synthase: transition from reversible to irreversible enzyme inhibition","volume":"49","author":"Chen","year":"2010","journal-title":"Biochemistry"},{"key":"B15","doi-asserted-by":"publisher","first-page":"1448","DOI":"10.1161\/ATVBAHA.119.312725","article-title":"Inhibition of mpo (myeloperoxidase) attenuates endothelial dysfunction in mouse models of vascular inflammation and atherosclerosis","volume":"39","author":"Cheng","year":"2019","journal-title":"Arterioscler Thromb Vasc Biol"},{"key":"B16","doi-asserted-by":"publisher","first-page":"1331","DOI":"10.1093\/eurheartj\/ehp116","article-title":"Prevalence, incidence, and prognostic value of anaemia in patients after an acute myocardial infarction: data from the optimaal trial","volume":"30","author":"Anker","year":"2009","journal-title":"Eur Heart J"},{"key":"B17","doi-asserted-by":"publisher","first-page":"337","DOI":"10.1161\/CIRCOUTCOMES.110.957050","article-title":"Incidence, correlates, and outcomes of acute, hospital-acquired Anemia in patients with acute myocardial infarction","volume":"3","author":"Salisbury","year":"2010","journal-title":"Circ Cardiovasc Qual Outcomes"},{"key":"B18","doi-asserted-by":"publisher","first-page":"e007175","DOI":"10.1161\/CIRCINTERVENTIONS.118.007175","article-title":"Association of Anemia with outcomes among st-segment-elevation myocardial infarction patients receiving primary percutaneous coronary intervention","volume":"11","author":"Moghaddam","year":"2018","journal-title":"Circ Cardiovasc Interv"},{"key":"B19","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1007\/s00395-020-0799-x","article-title":"Anaemia is associated with severe rbc dysfunction and a reduced circulating No pool: vascular and cardiac enos are crucial for the adaptation to anaemia","volume":"115","author":"Wischmann","year":"2020","journal-title":"Basic Res Cardiol"},{"key":"B20","doi-asserted-by":"publisher","first-page":"2651","DOI":"10.1161\/ATVBAHA.114.304699","article-title":"Measurement of endothelium-dependent vasodilation in mice\u2013brief report","volume":"34","author":"Schuler","year":"2014","journal-title":"Arterioscler Thromb Vasc Biol"},{"key":"B21","doi-asserted-by":"publisher","first-page":"336","DOI":"10.3389\/fphar.2019.00336","article-title":"Endothelial-dependent and independent vascular relaxation effect of tetrahydropalmatine on rat aorta","volume":"10","author":"Zhou","year":"2019","journal-title":"Front Pharmacol"},{"key":"B22","doi-asserted-by":"publisher","first-page":"769","DOI":"10.1016\/j.jacc.2018.05.052","article-title":"Erythrocytes from patients with type 2 diabetes induce endothelial dysfunction via arginase I","volume":"72","author":"Zhou","year":"2018","journal-title":"J Am Coll Cardiol"},{"key":"B23","doi-asserted-by":"publisher","first-page":"1215","DOI":"10.3390\/ijms19041215","article-title":"Mechanisms of diabetes-induced endothelial cell senescence: role of arginase 1","volume":"19","author":"Shosha","year":"2018","journal-title":"Int J Mol Sci"},{"key":"B24","doi-asserted-by":"publisher","first-page":"292","DOI":"10.1038\/nrcardio.2017.224","article-title":"Nitric oxide signalling in cardiovascular health and disease","volume":"15","author":"Farah","year":"2018","journal-title":"Nat Rev Cardiol"},{"key":"B25","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1016\/j.mam.2004.09.003","article-title":"The role of nitric oxide in cardiovascular diseases","volume":"26","author":"Naseem","year":"2005","journal-title":"Mol Aspects Med"},{"key":"B26","doi-asserted-by":"publisher","first-page":"e0184076","DOI":"10.1371\/journal.pone.0184076","article-title":"Associations between endothelial dysfunction and clinical and laboratory parameters in children and adolescents with sickle cell Anemia","volume":"12","author":"Teixeira","year":"2017","journal-title":"PLoS One"},{"key":"B27","doi-asserted-by":"publisher","first-page":"e38089","DOI":"10.1371\/journal.pone.0038089","article-title":"Vascular endothelial dysfunction in beta-thalassemia occurs despite increased enos expression and preserved vascular smooth muscle cell reactivity to no","volume":"7","author":"Stoyanova","year":"2012","journal-title":"PLoS One"},{"key":"B28","doi-asserted-by":"publisher","first-page":"3088","DOI":"10.1182\/blood-2006-08-039438","article-title":"Hemolysis in sickle cell mice causes pulmonary hypertension due to global impairment in nitric oxide bioavailability","volume":"109","author":"Hsu","year":"2007","journal-title":"Blood"},{"key":"B29","doi-asserted-by":"publisher","first-page":"551441","DOI":"10.3389\/fimmu.2020.551441","article-title":"Association between nitric oxide, oxidative stress, eryptosis, red blood cell microparticles, and vascular function in sickle cell Anemia","volume":"11","author":"Nader","year":"2020","journal-title":"Front Immunol"},{"key":"B30","doi-asserted-by":"publisher","first-page":"589","DOI":"10.3389\/fimmu.2014.00589","article-title":"Arginase in the vascular endothelium: friend or foe?","volume":"5","author":"Lucas","year":"2014","journal-title":"Front Immunol"},{"key":"B31","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1016\/j.atherosclerosis.2012.10.062","article-title":"Increased inos activity in vascular smooth muscle cells from diabetic rats: potential role of Ca(2+)\/calmodulin-dependent protein kinase ii delta 2 (camkiidelta(2))","volume":"226","author":"Di Pietro","year":"2013","journal-title":"Atherosclerosis"},{"key":"B32","doi-asserted-by":"publisher","first-page":"1232","DOI":"10.1016\/j.freeradbiomed.2007.12.025","article-title":"Regulation of smooth muscle by inducible nitric oxide synthase and nadph oxidase in vascular proliferative diseases","volume":"44","author":"Ginnan","year":"2008","journal-title":"Free Radic Biol Med"},{"key":"B33","doi-asserted-by":"publisher","first-page":"7092151","DOI":"10.1155\/2019\/7092151","article-title":"Vascular inflammation and oxidative stress: major triggers for cardiovascular disease","volume":"2019","author":"Steven","year":"2019","journal-title":"Oxid Med Cell Longev"},{"key":"B34","doi-asserted-by":"publisher","first-page":"567","DOI":"10.1016\/j.jacbts.2021.05.004","article-title":"Implications of iron deficiency in stemi patients and in a murine model of myocardial infarction","volume":"6","author":"Inserte","year":"2021","journal-title":"JACC Basic Transl Sci"},{"key":"B35","doi-asserted-by":"publisher","first-page":"752939","DOI":"10.3389\/fcvm.2021.752939","article-title":"N-Acetylcysteine for cardiac protection during coronary artery reperfusion: a systematic review and meta-analysis of randomized controlled trials","volume":"8","author":"Khan","year":"2021","journal-title":"Front Cardiovasc Med"},{"key":"B36","doi-asserted-by":"publisher","first-page":"1384","DOI":"10.1161\/HYPERTENSIONAHA.109.138305","article-title":"Endothelial nitric oxide synthase uncoupling and perivascular adipose oxidative stress and inflammation contribute to vascular dysfunction in a rodent model of metabolic syndrome","volume":"54","author":"Marchesi","year":"2009","journal-title":"Hypertension"}],"container-title":["Frontiers in Cardiovascular Medicine"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcvm.2023.1099069\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,5,10]],"date-time":"2023-05-10T13:18:52Z","timestamp":1683724732000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcvm.2023.1099069\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,5,10]]},"references-count":36,"alternative-id":["10.3389\/fcvm.2023.1099069"],"URL":"https:\/\/doi.org\/10.3389\/fcvm.2023.1099069","relation":{},"ISSN":["2297-055X"],"issn-type":[{"value":"2297-055X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,5,10]]},"article-number":"1099069"}}