{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T01:20:56Z","timestamp":1793064056236,"version":"4.5.0"},"reference-count":48,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2025,1,7]]},"abstract":"<jats:sec xml:lang=\"en\">\n            <jats:title>Background<\/jats:title>\n            <jats:p xml:lang=\"en\">TPM3 (tropomyosin 3) is an actin\u2010binding protein in vascular smooth muscle cells, where posttranslational modifications critically regulate its actin affinity, influencing cardiovascular function. Emerging evidence suggests that Khib (2\u2010hydroxyisobutyrylation) plays a significant role in the cardiovascular system. Histone deacetylase 3 (HDAC3) serves as an \u201ceraser\u201d of Khib marks. However, the impact of TPM3 de\u20102\u2010hydroxyisobutyrylation on vascular contraction remains unclear.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Methods and Results<\/jats:title>\n            <jats:p xml:lang=\"en\">In this study, we employed mouse models and in\u00a0vitro experiments to elucidate the mechanism by which phenylephrine\u2010induced HDAC3 activation drives vasoconstriction via de\u20102\u2010hydroxyisobutyrylation of TPM3. Our findings demonstrate that phenylephrine triggers HDAC3 nuclear export and promotes its interaction with TPM3, resulting in decreased Khib modification and enhanced vasoconstriction. Coimmunoprecipitation experiments confirmed that phenylephrine reduces Khib levels on TPM3 in mouse aorta. Additionally, ex\u00a0vivo vascular tension assays using mouse aortic rings revealed that treatment with the Khib donor, ethyl 2\u2010hydroxyisobutyrate, induces endothelium\u2010independent vasodilation and ameliorates hypertensive vascular dysfunction. Molecular docking and kinetic simulations identified Lys141 of TPM3 as the primary site targeted by HDAC3\u2010mediated de\u20102\u2010hydroxyisobutyrylation. This was further validated by adenoviral transfection of isolated blood vessels with a Lys141\u2010mutated TPM3 construct, which abolished the effects of HDAC3 on TPM3 Khib modification and vascular contractility.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p xml:lang=\"en\">These findings underscore the critical role of TPM3 de\u20102\u2010hydroxyisobutyrylation in vasoconstriction and suggest that modulating this posttranslational modification could provide a novel therapeutic strategy for hypertensive vascular dysfunction.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/jaha.124.037400","type":"journal-article","created":{"date-parts":[[2024,12,25]],"date-time":"2024-12-25T03:53:09Z","timestamp":1735098789000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":3,"title":["Modulation of Abnormal Vasoconstriction Through 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