Sodium tanshinone IIA sulfonate ameliorates experimental coronary no-reflow phenomenon through down-regulation of FGL2.
OBJECTIVE
The effects of sodium tanshinone IIA sulfonate (STS) on coronary no-reflow (CNR) relevant to microvascular obstruction (MVO) remain unknown. Studies had shown that fibrinogen-like protein 2 (FGL2) expressed in microvascular endothelial cells (MECs) is a key mediator in MVO. Thus, we aimed to elucidate the roles of STS in CNR and relations between STS and FGL2.


METHODS
Myocardial ischemia/reperfusion was selected to represent CNR model. The no-reflow zone and infarct area were assessed using Thioflavin S and TTC staining, and cardiac functional parameters were detected using echocardiography. Western blot was used to detected FGL2 level, fibrin level, protease-activated receptor-1 (PAR-1) activation and inflammation cells infiltration. FGL2 and inflammation cells were also identified by IHC. Microthrombus was detected by Carstairs' and MSB staining. We also detected the roles of STS on FGL2 expression, thrombin generation, phospho-Akt and NF-κB levels in MECs.


RESULTS
Upon treatment with STS in CNR model, the no-reflow and infarct areas decreased significantly and cardiac function improved. The FGL2 expression was inhibited by STS in vivo as well as in vitro with thrombin generation inhibition. In addition, STS up-regulates Akt phosphorylation and suppressed NF-κB expression in activated MECs. Furthermore, fibrin deposition, PAR-1 activation and inflammatory response were inhibited with STS administration in CNR model.


CONCLUSIONS
Our results displayed a novel pharmacological action of STS on CNR. STS is able to ameliorate CNR through inhibition of FGL2 expression mediated by Akt and NF-κB pathways as well as prevention of MVO by suppressing fibrin deposition and inflammation.
Department of Geriatrics, Institute of Geriatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Rui
R
Long
Department of Geriatrics, Institute of Geriatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Ya
Y
You
Department of Geriatrics, Institute of Geriatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Wenzhu
W
Li
Department of Geriatrics, Institute of Geriatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Nan
N
Jin
Department of Geriatrics, Institute of Geriatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Shiyuan
S
Huang
Department of Geriatrics, Institute of Geriatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Ting
T
Li
Department of Cardiology, Institute of Cardiovascular Disease, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address: liukun@hust.edu.cn.
Kun
K
Liu
Department of Geriatrics, Institute of Geriatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address: zhaohuiwang@hust.edu.cn.
Zhaohui
Z
Wang
D000818:Animals; D003326:Coronary Circulation / Q000187:drug effects* / Q000235:genetics; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects* / Q000235:genetics; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D005337:Fibrin / Q000378:metabolism; D005340:Fibrinogen / Q000096:biosynthesis* / Q000235:genetics; D008297:Male; D054318:No-Reflow Phenomenon / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010616:Phenanthrenes / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044463:Receptor, PAR-1 / Q000235:genetics / Q000378:metabolism; D015427:Reperfusion Injury / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction
D010616:Phenanthrenes; D044463:Receptor, PAR-1; C585327:fibrinogen-like protein 2, rat; C024894:tanshinone II A sodium sulfonate; D005337:Fibrin; D005340:Fibrinogen; D051057:Proto-Oncogene Proteins c-akt
Coronary no-reflow; Fibrinogen-like protein 2; In situ microthrombus; Microvascular obstruction; Sodium tanshinone IIA sulfonate