{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,4]],"date-time":"2026-03-04T16:59:32Z","timestamp":1772643572257,"version":"3.50.1"},"reference-count":31,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"17","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2019,9,3]]},"abstract":"<jats:sec xml:lang=\"en\">\n            <jats:title>Background<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              Elevated levels of ceramide, a sphingolipid known to cause a transition from nitric oxide (NO)\u2013 to hydrogen peroxide\u2013dependent flow\u2010induced dilation (\n              <jats:styled-content style=\"fixed-case\">FID<\/jats:styled-content>\n              ) in human arterioles, correlate with adverse cardiac events. However, elevations of ceramide are associated with changed concentrations of other sphingolipid metabolites. The effects of sphingolipid metabolites generated through manipulation of this lipid pathway on microvascular function are unknown. We examined the hypothesis that inhibition or activation of the ceramide pathway would determine the mediator of\n              <jats:styled-content style=\"fixed-case\">FID<\/jats:styled-content>\n              .\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Methods and Results<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              Using videomicroscopy, internal diameter changes were measured in human arterioles collected from discarded adipose tissue during surgery. Inhibition of neutral ceramidase, an enzyme responsible for the hydrolysis of ceramide, favored hydrogen peroxide\u2013dependent\n              <jats:styled-content style=\"fixed-case\">FID<\/jats:styled-content>\n              in arterioles from healthy patients. Using adenoviral technology, overexpression of neutral ceramidase in microvessels from diseased patients resulted in restoration of\n              <jats:styled-content style=\"fixed-case\">NO<\/jats:styled-content>\n              \u2010dependent\n              <jats:styled-content style=\"fixed-case\">FID<\/jats:styled-content>\n              . Exogenous sphingosine\u20101\u2010phosphate, a sphingolipid with opposing effects of ceramide, also restored\n              <jats:styled-content style=\"fixed-case\">NO<\/jats:styled-content>\n              as the mediator of\n              <jats:styled-content style=\"fixed-case\">FID<\/jats:styled-content>\n              in diseased arterioles. Likewise, exogenous adiponectin, a known activator of neutral ceramidase, or, activation of adiponectin receptors, favored\n              <jats:styled-content style=\"fixed-case\">NO<\/jats:styled-content>\n              \u2010dependent dilation in arterioles collected from patients with coronary artery disease.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              Sphingolipid metabolites play a critical role in determining the mediator of\n              <jats:styled-content style=\"fixed-case\">FID<\/jats:styled-content>\n              in human resistance arterioles. Manipulating the sphingolipid balance towards ceramide versus sphingosine\u20101\u2010phosphate favors microvascular dysfunction versus restoration of\n              <jats:styled-content style=\"fixed-case\">NO<\/jats:styled-content>\n              \u2010mediated\n              <jats:styled-content style=\"fixed-case\">FID<\/jats:styled-content>\n              , respectively. Multiple targets exist within this biolipid pathway to treat microvascular dysfunction and potentially improve patient outcomes.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/jaha.119.013153","type":"journal-article","created":{"date-parts":[[2019,8,29]],"date-time":"2019-08-29T09:01:56Z","timestamp":1567069316000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":26,"title":["Manipulation of the Sphingolipid Rheostat Influences the Mediator of Flow\u2010Induced Dilation in the Human Microvasculature"],"prefix":"10.1161","volume":"8","author":[{"given":"Mary E.","family":"Schulz","sequence":"first","affiliation":[{"name":"Department of Anesthesiology Medical College of Wisconsin Milwaukee WI"},{"name":"Cardiovascular Center Medical College of Wisconsin Milwaukee WI"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Boran","family":"Katunaric","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology Medical College of Wisconsin Milwaukee WI"},{"name":"Cardiovascular Center Medical College of Wisconsin Milwaukee WI"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joseph C.","family":"Hockenberry","sequence":"additional","affiliation":[{"name":"Cardiovascular Center Medical College of Wisconsin Milwaukee WI"},{"name":"Division of Cardiology Department of Medicine Medical College of Wisconsin Milwaukee WI"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David D.","family":"Gutterman","sequence":"additional","affiliation":[{"name":"Cardiovascular Center Medical College of Wisconsin Milwaukee WI"},{"name":"Division of Cardiology Department of Medicine Medical College of Wisconsin Milwaukee WI"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julie K.","family":"Freed","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology Medical College of Wisconsin Milwaukee WI"},{"name":"Cardiovascular Center Medical College of Wisconsin Milwaukee WI"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"276","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.115.305364"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00819.2006"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.116.307497"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.115.303881"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature13475"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2277"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.114.302439"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000054200.44505.AB"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1194\/jlr.C088377"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrm.2017.107"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrm2329"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-11-0365"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrc1411"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2002-021883"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1253\/circj.69.1154"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11892-005-0019-y"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.HYP.0000083488.67550.B8"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M307878200"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature21714"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature08991"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.R200007200"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.biocel.2016.02.018"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1124\/pr.107.07113"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1159\/000315104"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1161\/hc3501.095214"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrc3398"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1054\/drup.2001.0225"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrd4099"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2006.02.023"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2008.20.8983"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.275.5.3462"}],"container-title":["Journal of the American Heart Association"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/JAHA.119.013153","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,13]],"date-time":"2024-05-13T11:35:34Z","timestamp":1715600134000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/JAHA.119.013153"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,9,3]]},"references-count":31,"journal-issue":{"issue":"17","published-print":{"date-parts":[[2019,9,3]]}},"alternative-id":["10.1161\/JAHA.119.013153"],"URL":"https:\/\/doi.org\/10.1161\/jaha.119.013153","relation":{},"ISSN":["2047-9980"],"issn-type":[{"value":"2047-9980","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,9,3]]},"assertion":[{"value":"2019-05-02","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-07-25","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-08-29","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e013153"}}