{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T18:21:45Z","timestamp":1787768505368,"version":"build-2784847793"},"reference-count":50,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"9","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["ATVB"],"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>\n                      Endothelial dysfunction is critical for the pathogenesis of atherosclerosis, particularly in arterial regions exposed to disturbed flow (DF). ADCY4 (adenylate cyclase 4) catalyzes the production of cAMP (cyclic adenosine monophosphate), a ubiquitous second messenger that regulates cellular and physiological processes. This study investigated\n                      <jats:italic toggle=\"yes\">ADCY4<\/jats:italic>\n                      as a shear-stress-responsive gene in endothelial cells (ECs) for the regulation of vascular endothelial inflammation during atherogenesis.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>\n                      Integrated analysis of RNA sequencing data sets from human vascular ECs exposed to unidirectional flow or DF, and single-cell RNA-seq data from mouse partial ligation carotid arteries, was performed. ADCY4 expression was quantified in cultured ECs under various flow conditions. Nanoparticles carrying\n                      <jats:italic toggle=\"yes\">Cdh5<\/jats:italic>\n                      promoter-driven CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats\/CRISPR-associated protein 9) and\n                      <jats:italic toggle=\"yes\">Adcy4<\/jats:italic>\n                      -specific guide RNA plasmids were used to achieve EC-specific\n                      <jats:italic toggle=\"yes\">Adcy4<\/jats:italic>\n                      knockout in\n                      <jats:italic toggle=\"yes\">ApoE<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic toggle=\"yes\">\u2212\/\u2212<\/jats:italic>\n                      <\/jats:sup>\n                      mice for atherogenesis studies.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      ADCY4 was upregulated in ECs under unidirectional flow but downregulated under DF. We identified that KLF2 (Kr\u00fcppel-like factor 2) directly bound to the\n                      <jats:italic toggle=\"yes\">ADCY4<\/jats:italic>\n                      promoter and transcriptionally enhanced its expression in human aortic ECs.\n                      <jats:italic toggle=\"yes\">ADCY4<\/jats:italic>\n                      knockdown in ECs under unidirectional flow increased proinflammatory gene expression and monocyte adhesion, whereas\n                      <jats:italic toggle=\"yes\">ADCY4<\/jats:italic>\n                      overexpression under DF produced opposite changes. Further studies showed ADCY4 attenuated endothelial inflammation by inhibiting NF-\u03baB (nuclear factor \u03baB) signaling. We performed partial carotid ligation in the high-fat diet-fed\n                      <jats:italic toggle=\"yes\">ApoE<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic toggle=\"yes\">\u2212\/\u2212<\/jats:italic>\n                      <\/jats:sup>\n                      mouse atherosclerosis model, demonstrating that EC-specific\n                      <jats:italic toggle=\"yes\">Adcy4<\/jats:italic>\n                      knockout increased vascular endothelial inflammation and monocyte infiltration, thus promoting atherosclerotic plaque formation. Aggravated atherogenesis was also observed in EC-\n                      <jats:italic toggle=\"yes\">Adcy4<\/jats:italic>\n                      knockout high-fat diet-fed\n                      <jats:italic toggle=\"yes\">ApoE<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic toggle=\"yes\">\u2212<\/jats:italic>\n                      <\/jats:sup>\n                      <jats:sup>\n                        <jats:italic toggle=\"yes\">\/\u2212<\/jats:italic>\n                      <\/jats:sup>\n                      mice, with increased atherosclerotic lesions in en face aortas and aortic arches. Finally, semaglutide increased ADCY4 expression in human aortic ECs under DF and reduced vascular endothelial inflammation, monocyte accumulation, and atherosclerotic plaque formation. These beneficial effects were substantially impaired when EC ADCY4 was absent.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>ADCY4 regulation of the cAMP\/PKA (protein kinase A)-NF-\u03baB pathway in the endothelium advances our understanding of vascular inflammation in atherogenesis and provides opportunities for therapeutic intervention of atherosclerotic cardiovascular disease.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/atvbaha.126.324797","type":"journal-article","created":{"date-parts":[[2026,8,6]],"date-time":"2026-08-06T09:00:23Z","timestamp":1786006823000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Endothelial Shear-Stress-Responsive Gene Adenylate Cyclase 4 Suppresses Atherosclerosis by Inhibiting cAMP\/PKA-NF-\u03baB Mediated Vascular Inflammation"],"prefix":"10.1161","volume":"46","author":[{"given":"Wenzhen","family":"Bao","sequence":"first","affiliation":[{"name":"State Key Laboratory of Cardiovascular Diseases and Medical Innovation Center, Shanghai Heart Failure Research Center, Department of Cardiology, Department of Cardiovascular Surgery, Shanghai East Hospital, School of Medicine, Tongji University, China (W.B., J.X., W.N., P.P., W.W., Z.H., L.H., H.L., W.P., X.G., L.Z., X.C., J.L., Y.Z.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianfei","family":"Xu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cardiovascular Diseases and Medical Innovation Center, Shanghai Heart Failure Research Center, Department of Cardiology, Department of Cardiovascular Surgery, Shanghai East Hospital, School of Medicine, Tongji University, China (W.B., J.X., W.N., P.P., W.W., Z.H., L.H., H.L., W.P., X.G., L.Z., X.C., J.L., Y.Z.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjian","family":"Nian","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cardiovascular Diseases and Medical Innovation Center, Shanghai Heart Failure Research Center, Department of Cardiology, Department of Cardiovascular Surgery, Shanghai East Hospital, School of Medicine, Tongji University, China (W.B., J.X., W.N., P.P., W.W., Z.H., L.H., H.L., W.P., X.G., L.Z., X.C., J.L., Y.Z.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peilin","family":"Pang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cardiovascular Diseases and Medical Innovation Center, Shanghai Heart Failure Research Center, Department of Cardiology, Department of Cardiovascular Surgery, Shanghai East Hospital, School of Medicine, Tongji University, China (W.B., J.X., W.N., P.P., W.W., Z.H., L.H., H.L., W.P., X.G., L.Z., X.C., J.L., 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