{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T08:06:29Z","timestamp":1784621189452,"version":"3.55.0"},"reference-count":49,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2025,7,15]],"date-time":"2025-07-15T00:00:00Z","timestamp":1752537600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Warner\/Fermaturo and A. T. Still University Board of Trustees Research Grant","award":["560-940"],"award-info":[{"award-number":["560-940"]}]},{"name":"A. T. Still University","award":["560-940"],"award-info":[{"award-number":["560-940"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Alzheimer\u2019s disease (AD) is associated with an abnormal accumulation of amyloid \u03b2 (A\u03b2) fibrils in the brain parenchyma and cerebrovasculature, which leads to cognitive impairment and cerebrovascular dysfunction. Cerebrovascular endothelial cells play a crucial role in regulating cerebral blood flow, vascular permeability, and neurovascular function. Reactive oxygen species (ROS), particularly those generated by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (NOX2), contribute to vascular dysfunction and amyloid deposition in the Alzheimer\u2019s disease (AD) brain. However, the role of the NOX4 isoform in AD pathogenesis remains to be examined. In the present study, we found that NOX4 among the NOX isoforms is predominantly expressed in bEnd.3 mouse brain endothelial cells. Treatment with A\u03b240 significantly enhanced the release of H2O2 and NO, and increased the endothelial cell viability. To test the involvement of NOX4 in A\u03b240-induced H2O2 production, we utilized pharmacological inhibitors of NOX isoforms. A\u03b240-induced H2O2 production was attenuated in the presence of the pan-NOX inhibitor, apocynin, or the NOX1\/4-selective inhibitors, setanaxib and GKT136901. Since only the NOX4 isoform is expressed in bEnd.3 cells, these results indicate that NOX4 is responsible for the release of H2O2 stimulated by A\u03b240. Taken together, the present study demonstrated that A\u03b240 peptide exerts beneficial effects in bEnd.3 endothelial cells via the NOX4-dependent mechanism.<\/jats:p>","DOI":"10.3390\/ijms26146759","type":"journal-article","created":{"date-parts":[[2025,7,15]],"date-time":"2025-07-15T09:45:52Z","timestamp":1752572752000},"page":"6759","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["A\u03b240 Improves Cerebrovascular Endothelial Function via NOX4-Dependent Hydrogen Peroxide Release"],"prefix":"10.3390","volume":"26","author":[{"given":"Elizabeth","family":"Heller","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Kirksville College of Osteopathic Medicine, A.T. Still University of Health Sciences, Kirksville, MO 63501, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lindsey","family":"McGurran","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Kirksville College of Osteopathic Medicine, A.T. Still University of Health Sciences, Kirksville, MO 63501, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph K.","family":"Brown","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Kirksville College of Osteopathic Medicine, A.T. Still University of Health Sciences, Kirksville, MO 63501, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathleen","family":"Love","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Kirksville College of Osteopathic Medicine, A.T. Still University of Health Sciences, Kirksville, MO 63501, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Hobbs","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Kirksville College of Osteopathic Medicine, A.T. Still University of Health Sciences, Kirksville, MO 63501, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeong Sook","family":"Kim-Han","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Kirksville College of Osteopathic Medicine, A.T. Still University of Health Sciences, Kirksville, MO 63501, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Byung Hee","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Kirksville College of Osteopathic Medicine, A.T. 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