Salvianolic acid A targeting the transgelin-actin complex to enhance vasoconstrictionResearch in context
Weilong Zhong,
Bo Sun,
Wenqing Gao,
Yuan Qin,
Heng Zhang,
Longcong Huai,
Yuanhao Tang,
Yuan Liang,
Lingfei He,
Xiaoyun Zhang,
Honglian Tao,
Shuang Chen,
Wei Yang,
Lan Yang,
Yanrong Liu,
Huijuan Liu,
Honggang Zhou,
Tao Sun,
Cheng Yang
Affiliations
Weilong Zhong
State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin 300000, China; Tianjin Key Laboratory of Molecular Drug Research, Tianjin International Joint Academy of Biomedicine, Tianjin 300000, China
Bo Sun
Tianjin Key Laboratory of Molecular Drug Research, Tianjin International Joint Academy of Biomedicine, Tianjin 300000, China
Wenqing Gao
Heart Center, Tianjin Third Central Hospital, Tianjin 300170, China
Yuan Qin
State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin 300000, China; Tianjin Key Laboratory of Molecular Drug Research, Tianjin International Joint Academy of Biomedicine, Tianjin 300000, China
Heng Zhang
State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin 300000, China; Tianjin Key Laboratory of Molecular Drug Research, Tianjin International Joint Academy of Biomedicine, Tianjin 300000, China
Longcong Huai
State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin 300000, China
Yuanhao Tang
State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin 300000, China
Yuan Liang
State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin 300000, China
Lingfei He
State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin 300000, China
Xiaoyun Zhang
State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin 300000, China
Honglian Tao
State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin 300000, China
Shuang Chen
Tianjin Key Laboratory of Molecular Drug Research, Tianjin International Joint Academy of Biomedicine, Tianjin 300000, China
Wei Yang
Tianjin Key Laboratory of Molecular Drug Research, Tianjin International Joint Academy of Biomedicine, Tianjin 300000, China
Lan Yang
Tianjin Key Laboratory of Molecular Drug Research, Tianjin International Joint Academy of Biomedicine, Tianjin 300000, China
Yanrong Liu
Tianjin Key Laboratory of Molecular Drug Research, Tianjin International Joint Academy of Biomedicine, Tianjin 300000, China
Huijuan Liu
State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin 300000, China; Tianjin Key Laboratory of Molecular Drug Research, Tianjin International Joint Academy of Biomedicine, Tianjin 300000, China
Honggang Zhou
State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin 300000, China; Tianjin Key Laboratory of Molecular Drug Research, Tianjin International Joint Academy of Biomedicine, Tianjin 300000, China; Corresponding authors at: State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin 300350, China.
Tao Sun
State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin 300000, China; Tianjin Key Laboratory of Molecular Drug Research, Tianjin International Joint Academy of Biomedicine, Tianjin 300000, China; Corresponding authors at: State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin 300350, China.
Cheng Yang
State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin 300000, China; Tianjin Key Laboratory of Molecular Drug Research, Tianjin International Joint Academy of Biomedicine, Tianjin 300000, China; Corresponding authors at: State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin 300350, China.
Background: Salvia 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. Methods: Transgelin 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. Findings: In 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. Interpretation: We 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. Keywords: Transgelin, Actin, SAA, Vascular smooth muscle cell, Myocardial ischemia
