{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T16:24:00Z","timestamp":1790871840014,"version":"4.1.0"},"reference-count":53,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2022,2]]},"abstract":"<jats:sec>\n            <jats:title>Background:<\/jats:title>\n            <jats:p>High salt intake is the leading dietary risk factor for cardiovascular diseases. Although clinical evidence suggests that high salt intake is associated with nonalcoholic fatty liver disease, which is an independent risk factor for cardiovascular diseases, it remains elusive whether salt-induced hepatic damage leads to the development of cardiovascular diseases.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods:<\/jats:title>\n            <jats:p>Mice were fed with normal or high-salt diet for 8 weeks to determine the effect of salt loading on liver histological changes and blood pressure, and salt withdrawal and metformin treatment were also conducted on some high-salt diet\u2013fed mice. Adeno-associated virus 8, global knockout, or tissue-specific knockout mice were used to manipulate the expression of some target genes in vivo, including SIRT3 (sirtuin 3), NRF2 (NF-E2-related factor 2), and AMPK (AMP-activated protein kinase).<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results:<\/jats:title>\n            <jats:p>Mice fed with a high-salt diet displayed obvious hepatic steatosis and inflammation, accompanied with hypertension and cardiac dysfunction. All these pathological changes persisted after salt withdrawal, displaying a memory phenomenon. Gene expression analysis and phenotypes of SIRT3 knockout mice revealed that reduced expression of SIRT3 was a chief culprit responsible for the persistent inflammation in the liver, and recovering SIRT3 expression in the liver effectively inhibits the sustained hepatic inflammation and cardiovascular damage. Mechanistical studies reveal that high salt increases acetylated histone 3 lysine 27 (H3K27ac) on SIRT3 promoter in hepatocytes, thus inhibiting the binding of NRF2, and results in the sustained inhibition of SIRT3 expression. Treatment with metformin activated AMPK, which inhibited salt-induced hepatic inflammatory memory and cardiovascular damage by lowering the H3K27ac level on SIRT3 promoter, and increased NRF2 binding ability to activate SIRT3 expression.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>This study demonstrates that SIRT3 inhibition caused by histone modification is the key factor for the persistent hepatic steatosis and inflammation that contributes to cardiovascular damage under high salt loading. Avoidance of excessive salt intake and active intervention of epigenetic modification may help to stave off the persistent inflammatory status that underlies high-salt\u2013induced cardiovascular damage in clinical practice.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circulationaha.121.055600","type":"journal-article","created":{"date-parts":[[2022,1,31]],"date-time":"2022-01-31T19:00:31Z","timestamp":1643655631000},"page":"375-391","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":98,"title":["Salt-Induced Hepatic Inflammatory Memory Contributes to Cardiovascular Damage Through Epigenetic Modulation of SIRT3"],"prefix":"10.1161","volume":"145","author":[{"given":"Peng","family":"Gao","sequence":"first","affiliation":[{"name":"Department of Hypertension and Endocrinology, Center for Hypertension and Metabolic Diseases, Daping Hospital, Chongqing Institute of Hypertension (P.G., M.Y., L.L., X.W., Q. Zhou, H.Z., Z.L., L.W., F.S., D.L., Z.Y., Z.Z.), Army Medical University, Chongqing China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mei","family":"You","sequence":"additional","affiliation":[{"name":"Department of Hypertension and Endocrinology, Center for Hypertension and Metabolic Diseases, Daping Hospital, Chongqing Institute of Hypertension (P.G., M.Y., L.L., X.W., Q. Zhou, H.Z., Z.L., L.W., F.S., D.L., Z.Y., Z.Z.), Army Medical University, Chongqing China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Hypertension and Endocrinology, Center for Hypertension and Metabolic Diseases, Daping Hospital, Chongqing Institute of Hypertension (P.G., M.Y., L.L., X.W., Q. Zhou, H.Z., Z.L., L.W., F.S., D.L., Z.Y., Z.Z.), Army Medical University, Chongqing China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qin","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, The Second Affiliated Hospital, Chongqing Medical University, China (Q. Zhang, X.F., M.W., G.Y.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xia","family":"Fang","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Translational Research Key Laboratory for Diabetes, Xinqiao Hospital (H.Z.), Army Medical University, Chongqing China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao","family":"Wei","sequence":"additional","affiliation":[{"name":"Department of Hypertension and Endocrinology, Center for Hypertension and Metabolic Diseases, Daping Hospital, Chongqing Institute of Hypertension (P.G., M.Y., L.L., X.W., Q. Zhou, H.Z., Z.L., L.W., F.S., D.L., Z.Y., Z.Z.), Army Medical University, Chongqing China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Hypertension and Endocrinology, Center for Hypertension and Metabolic Diseases, Daping Hospital, Chongqing Institute of Hypertension (P.G., M.Y., L.L., X.W., Q. Zhou, H.Z., Z.L., L.W., F.S., D.L., Z.Y., Z.Z.), Army Medical University, Chongqing China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hexuan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Translational Research Key Laboratory for Diabetes, Xinqiao Hospital (H.Z.), Army Medical University, Chongqing China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miao","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, The Second Affiliated Hospital, Chongqing Medical University, China (Q. Zhang, X.F., M.W., G.Y.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zongshi","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Hypertension and Endocrinology, Center for Hypertension and Metabolic Diseases, Daping Hospital, Chongqing Institute of Hypertension (P.G., M.Y., L.L., X.W., Q. 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