Latest clinical research shows that trimetazidine therapy during the perioperative period relieves endothelial dysfunction in patients with unstable angina induced by percutaneous coronary intervention.In this study we investigated the effects of TMZ on myocardial angiogenesis in pressure overload-induced cardiac hypertrophy mice.Cardiac hypertrophy was induced in mice by transverse aortic constriction(TAC)surgery.TAC mice were administered trimetazidine(2.8 mg/100 μL,i.g.)for 28 consecutive days.We showed that trimetazidine administration significantly increased blood vessel density in the left ventricular myocardium and abrogated cardiac dysfunction in TAC mice.Co-administration of a specific HSF1 inhibitor KRIBB11(1.25 mg/100 uL,i.h.)abrogated the angiogenesis-promoting effects of trimetazidine in TAC mice.Using luciferase reporter and electrophoretic mobility shift assays we demonstrated that the transcription factor HSF1 bound to the promoter region of VEGF-A,and the transcriptional activity of HSF1 was enhanced upon trimetazidine treatment.In molecular docking analysis we found that trimetazidine directly bound to Akt via a hydrogen bond with Asp292 and a pi-pi bond with Trp80.In norepinephrine-treated HUVECs,we showed that trimetazidine significantly increased the phosphorylation of Akt and the synergistic nuclear translocation of Akt and HSF1,as well as the binding of Akt and HSF1 in the nucleus.These results suggest that trimetazidine enhances myocardial angiogenesis through a direct interaction with Akt and promotion of nuclear translocation of HSF1,and that trimetazidine may be used for the treatment of myocardial angiogenic disorders in hypertensive patients.

Hong-yang Shu;Yi-zhong Peng;Wei-jian Hang;Min Zhang;Lan Shen;Dao-wen Wang;Ning Zhou

Division of Cardiology,Department of Internal Medicine,Tongji Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan 430030,China;Hubei Key Laboratory of Genetics and Molecular Mechanism of Cardiologic Disorders,Huazhong University of Science and Technology,Wuhan 430030,China;Department of Orthopedics,Union Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan 430030,China;Department of Cardiology,Shanghai Chest Hospital Shanghai Jiaotong University,Shanghai 200030,China

中国药理学报（英文版）

[1]Hong-yang Shu;Yi-zhong Peng;Wei-jian Hang;Min Zhang;Lan Shen;Dao-wen Wang;Ning Zhou-.Trimetazidine enhances myocardial angiogenesis in pressure overload-induced cardiac hypertrophy mice through directly activating Akt and promoting the binding of HSF1 to VEGF-A promoter)[J].中国药理学报（英文版）,2022(10):2550-2561

Trimetazidine,KRIBB11,Asp292,Trp80

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