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However, unexpected side effects of cardiovascular nature reported for bardoxolone methyl in patients with type 2 diabetes mellitus and stage 4 chronic kidney disease (the BEACON trial) still have not been fully explained. Here, we aimed to characterize the effects of bardoxolone methyl compared with other Nrf2 activators\u2014dimethyl fumarate and L-sulforaphane\u2014on human microvascular endothelium. Endothelial toxicity, bioenergetics, mitochondrial membrane potential, endothelin-1 (ET-1) release, endothelial permeability, Nrf2 expression, and ROS production were assessed in human microvascular endothelial cells (HMEC-1) incubated for 3 and 24 hours with 100\u2009nM\u20135\u2009\u03bcM of either bardoxolone methyl, dimethyl fumarate, or L-sulforaphane. Three-hour incubation with bardoxolone methyl (100\u2009nM\u20135\u2009\u03bcM), although not toxic to endothelial cells, significantly affected endothelial bioenergetics by decreasing mitochondrial membrane potential (\n                    <jats:inline-formula>\n                      <a:math xmlns:a=\"http:\/\/www.w3.org\/1998\/Math\/MathML\" id=\"M1\">\n                        <a:mtext>concentrations<\/a:mtext>\n                        <a:mo>\u2265<\/a:mo>\n                        <a:mn>3<\/a:mn>\n                        <a:mtext>\u2009<\/a:mtext>\n                        <a:mi>\u03bc<\/a:mi>\n                        <a:mtext>M<\/a:mtext>\n                      <\/a:math>\n                    <\/jats:inline-formula>\n                    ), decreasing spare respiratory capacity (\n                    <jats:inline-formula>\n                      <c:math xmlns:c=\"http:\/\/www.w3.org\/1998\/Math\/MathML\" id=\"M2\">\n                        <c:mtext>concentrations<\/c:mtext>\n                        <c:mo>\u2265<\/c:mo>\n                        <c:mn>1<\/c:mn>\n                        <c:mtext>\u2009<\/c:mtext>\n                        <c:mi>\u03bc<\/c:mi>\n                        <c:mtext>M<\/c:mtext>\n                      <\/c:math>\n                    <\/jats:inline-formula>\n                    ), and increasing proton leak (\n                    <jats:inline-formula>\n                      <e:math xmlns:e=\"http:\/\/www.w3.org\/1998\/Math\/MathML\" id=\"M3\">\n                        <e:mtext>concentrations<\/e:mtext>\n                        <e:mo>\u2265<\/e:mo>\n                        <e:mn>500<\/e:mn>\n                        <e:mtext>\u2009<\/e:mtext>\n                        <e:mtext>nM<\/e:mtext>\n                      <\/e:math>\n                    <\/jats:inline-formula>\n                    ), while dimethyl fumarate and L-sulforaphane did not exert such actions. Bardoxolone methyl at\n                    <jats:inline-formula>\n                      <g:math xmlns:g=\"http:\/\/www.w3.org\/1998\/Math\/MathML\" id=\"M4\">\n                        <g:mtext>concentrations<\/g:mtext>\n                        <g:mo>\u2265<\/g:mo>\n                        <g:mn>3<\/g:mn>\n                        <g:mtext>\u2009<\/g:mtext>\n                        <g:mi>\u03bc<\/g:mi>\n                        <g:mtext>M<\/g:mtext>\n                      <\/g:math>\n                    <\/jats:inline-formula>\n                    also decreased cellular viability and induced necrosis and apoptosis in the endothelium upon 24-hour incubation. In turn, endothelin-1 decreased permeability in endothelial cells in picomolar range, while bardoxolone methyl decreased ET-1 release and increased endothelial permeability even after short-term (3 hours) incubation. In conclusion, despite that all three Nrf2 activators exerted some beneficial effects on the endothelium, as evidenced by a decrease in ROS production, bardoxolone methyl, the most potent Nrf2 activator among the tested compounds, displayed a distinct endothelial profile of activity comprising detrimental effects on mitochondria and cellular viability and suppression of endothelial ET-1 release possibly interfering with ET-1\u2013dependent local regulation of endothelial permeability.\n                  <\/jats:p>","DOI":"10.1155\/2020\/4678252","type":"journal-article","created":{"date-parts":[[2020,10,16]],"date-time":"2020-10-16T01:20:09Z","timestamp":1602811209000},"page":"1-16","source":"Crossref","is-referenced-by-count":27,"title":["Bardoxolone Methyl Displays Detrimental Effects on Endothelial Bioenergetics, Suppresses Endothelial ET-1 Release, and Increases Endothelial Permeability in Human Microvascular Endothelium"],"prefix":"10.1155","volume":"2020","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6356-6453","authenticated-orcid":true,"given":"Ewa","family":"Szczesny-Malysiak","sequence":"first","affiliation":[{"name":"Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Bobrzynskiego 14, 30-348 Krakow, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Stojak","sequence":"additional","affiliation":[{"name":"Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Bobrzynskiego 14, 30-348 Krakow, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberto","family":"Campagna","sequence":"additional","affiliation":[{"name":"Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Bobrzynskiego 14, 30-348 Krakow, Poland"},{"name":"Department of Clinical Sciences, Polytechnic University of Marche, Via Ranieri 65, 60131 Ancona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marek","family":"Grosicki","sequence":"additional","affiliation":[{"name":"Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Bobrzynskiego 14, 30-348 Krakow, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marek","family":"Jamrozik","sequence":"additional","affiliation":[{"name":"Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Bobrzynskiego 14, 30-348 Krakow, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0106-4172","authenticated-orcid":true,"given":"Patrycja","family":"Kaczara","sequence":"additional","affiliation":[{"name":"Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Bobrzynskiego 14, 30-348 Krakow, 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