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Modulation of Abnormal Vasoconstriction Through 2-Hydroxyisobutyrylation of Tropomyosin 3 Lys141: Targeting Histone Deacetylase 3 as a Key Approach. | LitMetric

AI Article Synopsis

Article Abstract

Background: TPM3 (tropomyosin 3) is an actin-binding protein in vascular smooth muscle cells, where posttranslational modifications critically regulate its actin affinity, influencing cardiovascular function. Emerging evidence suggests that Khib (2-hydroxyisobutyrylation) plays a significant role in the cardiovascular system. Histone deacetylase 3 (HDAC3) serves as an "eraser" of Khib marks. However, the impact of TPM3 de-2-hydroxyisobutyrylation on vascular contraction remains unclear.

Methods And Results: In this study, we employed mouse models and in vitro experiments to elucidate the mechanism by which phenylephrine-induced HDAC3 activation drives vasoconstriction via de-2-hydroxyisobutyrylation 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 vivo vascular tension assays using mouse aortic rings revealed that treatment with the Khib donor, ethyl 2-hydroxyisobutyrate, induces endothelium-independent vasodilation and ameliorates hypertensive vascular dysfunction. Molecular docking and kinetic simulations identified Lys141 of TPM3 as the primary site targeted by HDAC3-mediated de-2-hydroxyisobutyrylation. This was further validated by adenoviral transfection of isolated blood vessels with a Lys141-mutated TPM3 construct, which abolished the effects of HDAC3 on TPM3 Khib modification and vascular contractility.

Conclusions: These findings underscore the critical role of TPM3 de-2-hydroxyisobutyrylation in vasoconstriction and suggest that modulating this posttranslational modification could provide a novel therapeutic strategy for hypertensive vascular dysfunction.

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http://dx.doi.org/10.1161/JAHA.124.037400DOI Listing

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