{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T07:47:38Z","timestamp":1793260058070,"version":"4.5.0"},"reference-count":64,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"11","license":[{"start":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T00:00:00Z","timestamp":1779408000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2026,5,22]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>Presently, we investigated hypothesized roles and mechanisms of cell type\u2013specific, selective activation of different vascular NOX (NADPH oxidase) isoforms in obesity and metabolic syndrome.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>Wild-type, NOX1\/2\/4 global knockout mice, endothelial\/VSMC-specific NOX1 knockout mice, or vascular endothelial-speicifc NOX1 knockin mice were exposed to high-fat diet feeding prior to phenotypical analyses of obesity and metabolic syndrome, as well as of exercise capacity, skeletal muscle mitochondrial function, and novel genetic signatures.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>\n                      Expression of NOX1 was significantly upregulated in wild-type mice fed a high-fat diet. Global knockout of NOX1 (NOX1\n                      <jats:sup>\u2212\/y<\/jats:sup>\n                      ), rather than of NOX2\/NOX4, markedly abrogated high-fat feeding\u2013induced body weight\/fat mass gain, preadipocyte differentiation, fatty liver, glucose intolerance, and insulin\/leptin resistance. Intriguingly, endothelial-specific NOX1 knockout (Cdh5cre [cadherin 5 (vascular endothelial cadherin) promoter\u2013driven Cre recombinase (endothelial-specific Cre expression)]-NOX1CKO), rather than vascular smooth muscle-specific NOX1 knockout (Myh11cre [myosin heavy chain 11 promoter\u2013driven Cre recombinase (smooth muscle\u2013specific Cre expression)]-NOX1CKO), substantially alleviated obesity and metabolic syndrome. Consistently, endothelial-specific NOX1 knockin mice (Cdh5cre-NOX1CKI) fed a high-fat diet displayed exaggerated metabolic disorders. Endothelial cell\u2013specific knockout\/knockin of NOX1 was confirmed using endothelial cell washout experiments. Food\/water intakes were not different from corresponding controls in high-fat fed NOX1\n                      <jats:sup>\u2212\/y<\/jats:sup>\n                      , Cdh5cre-NOX1CKO, or Cdh5cre-NOX1CKI mice, indicating no difference in energy intake. Instead, spontaneous activity, exercise capacity, mitochondrial oxygen consumption\/ATP production, skeletal muscle mitochondrial function (ROS production and swelling activity), and mitochondrial cristae structure were all substantially improved in NOX1\n                      <jats:sup>\u2212\/y<\/jats:sup>\n                      or Cdh5cre-NOX1CKO mice, indicating augmented energy expenditure attributed to preserved skeletal muscle mitochondrial function. Supportively, Cdh5cre-NOX1CKI mice displayed deteriorated exercise capacity and skeletal muscle mitochondrial dysfunction. Endothelium-dependent vasorelaxation was restored in high-fat fed NOX1\n                      <jats:sup>\u2212\/y<\/jats:sup>\n                      or Cdh5cre-NOX1CKO mice, confirming improved endothelial function. RNA-sequencing identified 4 genes (\n                      <jats:italic toggle=\"yes\">Cntnap4<\/jats:italic>\n                      [contactin-associated protein-like 4],\n                      <jats:italic toggle=\"yes\">Sgsm1<\/jats:italic>\n                      ,\n                      <jats:italic toggle=\"yes\">Tll2<\/jats:italic>\n                      , and\n                      <jats:italic toggle=\"yes\">Syt9<\/jats:italic>\n                      ) and 7 genes (\n                      <jats:italic toggle=\"yes\">Odf3l2<\/jats:italic>\n                      ,\n                      <jats:italic toggle=\"yes\">Col9a1<\/jats:italic>\n                      [collagen type IX alpha 1 chain],\n                      <jats:italic toggle=\"yes\">Cldn23<\/jats:italic>\n                      ,\n                      <jats:italic toggle=\"yes\">Atp5g2<\/jats:italic>\n                      ,\n                      <jats:italic toggle=\"yes\">Nkx6-3<\/jats:italic>\n                      ,\n                      <jats:italic toggle=\"yes\">Ntsr2<\/jats:italic>\n                      , and\n                      <jats:italic toggle=\"yes\">Zfp69<\/jats:italic>\n                      ) significantly downregulated\/upregulated in high-fat fed Cdh5cre-NOX1CKO mice, among which Cntnap4 and Col9a1 linked to muscular disorders. Importantly, we observed marked upregulation of NOX1 in isolated coronary arteries from human patients with obesity.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>Taken together, our data for the first time establish a novel and paradigm-shifting concept that endothelial NOX1 drives systematic metabolic phenotypes, via impairment in skeletal muscle mitochondrial dysfunction with novel genetic signatures. Tissue-specific targeting of endothelial NOX1 and novel candidate genes may prove to be robustly effective in treating obesity and metabolic syndrome.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circresaha.125.326768","type":"journal-article","created":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T09:00:16Z","timestamp":1776934816000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":4,"title":["Endothelial NOX1 Drives Obesity via Skeletal Muscle Mitochondrial Dysfunction"],"prefix":"10.1161","volume":"138","author":[{"given":"Kai","family":"Huang","sequence":"first","affiliation":[{"name":"Division of Molecular Medicine, Department of Anesthesiology and Perioperative Medicine, Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles (K.H., Y.H., Yuhan Zhang, Yixuan Zhang, N.W.H., 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