Salvianolic acid A targeting the transgelin-actin complex to enhance vasoconstriction

Abstract

BackgroundSalvia miltiorrhiza is used extensively to treat cardiovascular diseases. SAA is a major bioactive component in Salvia miltiorrhiza and mediates myocardial ischemia (MI). However, the industrial production of SAA is limited due to low yields. In addition, the direct targets of SAA are unknown. Here we explore cardioprotective mechanisms and targets of SAA in the cardiovascular system.MethodsTransgelin and actin were identified as targets of SAA using a chemical biology method and were validated by Biacore analysis, microscale thermophoresis and single-molecule imaging. Studies of transgelin (−/−) knockout mice further verify the target. Cardioprotective mechanisms and targets of SAA were studied in cultured vascular smooth muscle cells and transgenic mice.FindingsIn WT mice, SAA targeted transgelin and had a protective effect on myocardium but did not have the same protective effect on transgelin (−/−) mice. SAA stabilizes the transgelin-actin complex, modulates the reorganization of the actin cytoskeleton, facilitates F-actin bundling, further enhances the contractility and blood flows of coronary arteries, and improves outcomes of myocardial ischemia. Based on the target, a more active SAA derivative offering myocardial protection, SAA-30, was obtained.InterpretationWe report on the direct targets of SAA and mechanisms of myocardial ischemia treatment. We also find that transgelin may act as a novel therapeutic target of myocardial ischemia. Furthermore, a more effective derivative of SAA provides the basis for further clinical translational research.

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“…Histological studies of human coronary arteries suggest that areas prone to atherosclerotic lesions contain more vascular SMCs, while areas less prone to atherosclerotic lesions have fewer vascular SMCs [ 4 – 6 ]. Therefore, understanding the relationship between VSMCs and AS may have important implications for the formulation of effective prevention and control measures for AS [ 7 – 9 ].…”

Cartilage Oligomeric Matrix Protein promotes epithelial-mesenchymal transition by interacting with Transgelin in Colorectal Cancer

“…TAGLN, a member of the calmodulin family, acts as an actin-binding protein that regulates cytoskeletal remodeling by promoting actin aggregation 15 . The cellular immunofluorescence experiments and SEM showed that COMP could interact with TAGLN to regulate cell remodeling and promote EMT in tumor cells.…”

“…Transgelin (TAGLN) is an actin-binding protein that regulates the dynamics of the actin cytoskeleton and promotes the aggregation of G-actin to F-actin 14 . Our previous studies have shown that excited TAGLN-actin regulates the cytoskeleton and promotes cell contraction 15 . TAGLN is recognized as a tumor suppressor in the early stage 16 , 17 .…”

Developing Small Molecules that Inhibit K-Ras/GTP Binding Based on New Affinity Measurements

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