{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T19:10:00Z","timestamp":1792091400100,"version":"4.4.0"},"reference-count":38,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2025,10,17]],"date-time":"2025-10-17T00:00:00Z","timestamp":1760659200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,10,17]],"date-time":"2025-10-17T00:00:00Z","timestamp":1760659200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Kaohsiung J of Med Scie"],"published-print":{"date-parts":[[2026,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Sacubitril\/valsartan (Sac\/Val) has emerged as an effective compound with myocardium\u2010protective functions in experimental and clinical trials for heart failure. This study investigated the function of Sac\/Val in hypertensive heart disease (HHD) and explored the underlying mechanism. Spontaneous hypertensive rats (SHRs) were used as an animal model of HHD. Sac\/Val administration ameliorated pathological injury, fibrosis, cell apoptosis, inflammatory cytokine production, and oxidative stress in the myocardial tissues of HHD rats. Similar findings were observed in\u00a0vitro, where Sac\/Val treatment reduced inflammation, oxidative stress, and fibrosis\u2010related markers in Ang II\u2010challenged H9C2 cells. Calcium\/calmodulin\u2010dependent protein kinase kinase 2 (CAMKK2) was identified as a target of Sac\/Val which was downregulated\u00a0in HHD models, and CAMKK2 protein levels were restored by Sac\/Val treatment. Lentiviral vector\u2010induced CAMKK2 knockdown reduced the phosphorylation levels of AMPK\u03b1, AKT, and GSK\u20103\u03b2, thereby negating the treatment effects of Sac\/Val. Further treatment with AICAR, an AMPK agonist, significantly reactivated the AMPK\/AKT\/GSK\u20103\u03b2 cascade and alleviated inflammatory injury in both models. Collectively, this study suggests that Sac\/Val ameliorates inflammation and oxidative stress in HHD by restoring the CAMKK2 protein and activating the AMPK\/AKT\/GSK\u20103\u03b2 cascade.<\/jats:p>","DOI":"10.1002\/kjm2.70127","type":"journal-article","created":{"date-parts":[[2025,10,17]],"date-time":"2025-10-17T11:15:25Z","timestamp":1760699725000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Sacubitril\/Valsartan Ameliorates Inflammation and Oxidative Stress in Hypertensive Heart Disease by Upregulating\n                    <scp>CAMKK2<\/scp>\n                    Protein and Modulating the\n                    <scp>AMPK<\/scp>\n                    \/\n                    <scp>AKT<\/scp>\n                    \/\n                    <scp>GSK<\/scp>\n                    \u20103\u03b2 Axis"],"prefix":"10.1002","volume":"42","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-7386-5329","authenticated-orcid":false,"given":"Yan\u2010Jun","family":"Yang","sequence":"first","affiliation":[{"name":"Department of General Practice Tiyuzhongxin Street Community Health Service Center in Nankai District of Tianjin  Tianjin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiu\u2010Sheng","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine Tianjin Shuige Hospital  Tianjin China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,10,17]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccl.2021.12.011"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcvm.2023.1205475"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11906-020-1017-9"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41569-024-01062-6"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.hfc.2019.09.001"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.122.19373"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13098-022-00944-4"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12933-021-01270-1"},{"issue":"11","key":"e_1_2_8_10_1","first-page":"733","article-title":"Sacubitril\/Valsartan: Practice Changing Guideline in the Management of Congestive Heart Failure","volume":"27","author":"Karim M. A.","year":"2017","journal-title":"Journal of the College of Physicians and Surgeons\u2013Pakistan"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1409077"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehw128"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2017.04.025"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehab499"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1042\/EBC20240011"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceca.2023.102820"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00011-023-01756-6"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11010-024-05117-7"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2024.04.011"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13098-024-01284-1"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/suab098"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1002\/clc.23717"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.117.006617"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1093\/ajh\/hpv015"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2023.175754"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehx525"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.119.015640"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.3892\/mmr.2021.12315"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tem.2016.06.001"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2016.00352"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.26508\/lsa.201900619"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1042\/BSR20181767"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1093\/abbs\/gmab099"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehab503"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms231911025"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2005.06.005"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-019-1406-7"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnagi.2022.1015453"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2022.892460"}],"container-title":["The Kaohsiung Journal of Medical Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/kjm2.70127","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/kjm2.70127","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/kjm2.70127","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,3]],"date-time":"2026-04-03T02:37:08Z","timestamp":1775183828000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/kjm2.70127"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,17]]},"references-count":38,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2026,4]]}},"alternative-id":["10.1002\/kjm2.70127"],"URL":"https:\/\/doi.org\/10.1002\/kjm2.70127","archive":["Portico"],"relation":{},"ISSN":["1607-551X","2410-8650"],"issn-type":[{"value":"1607-551X","type":"print"},{"value":"2410-8650","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,17]]},"assertion":[{"value":"2025-03-12","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-09-26","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-10-17","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70127"}}