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.
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.
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曲美他嗪通过直接激活Akt并促进HSF1与VEGF-A启动子结合增强压力超负荷诱导的心肌肥厚小鼠心肌血管生成
DOI：
10.1038/s41401-022-00877-8
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发表时间：
2022-10
影响因子：
8.2
通讯作者：
Zhou, Ning
中科院分区：
文献类型：
--
作者：
Shu, Hong-Yang;Peng, Yi-Zhong;Hang, Wei-Jian;Zhang, Min;Shen, Lan;Wang, Dao-Wen;Zhou, Ning
最新的临床研究表明，曲美他嗪在围手术期的治疗减轻了经皮冠状动脉介入治疗引起的不稳定型心绞痛患者的内皮功能障碍。在这项研究中，我们研究了TMZ对压力超负荷诱导的心肌肥厚小鼠心肌血管生成的影响。通过横主动脉缩窄（TAC）手术诱导小鼠心脏肥大。向TAC小鼠施用曲美他嗪（2.8mg/100 μL，i.g.）连续28天。我们表明，曲美他嗪给药可显着增加TAC小鼠左心室心肌的血管密度并消除心脏功能障碍。将特异性HSF 1抑制剂KRIBB 11（1.25 mg/100 µL，i.h.）消除了曲美他嗪在TAC小鼠中的血管生成促进作用。使用荧光素酶报告和电泳迁移率变动分析，我们证明了转录因子HSF 1结合到VEGF-A的启动子区域，并且曲美他嗪处理后HSF 1的转录活性增强。在分子对接分析中，我们发现曲美他嗪通过与Asp 292的氢键和与Trp 80的π-π键直接结合到Akt。在去甲肾上腺素处理的HUVECs中，我们发现曲美他嗪显著增加Akt的磷酸化和Akt和HSF 1的协同核转位，以及Akt和HSF 1在核中的结合。这些结果表明，曲美他嗪通过与Akt的直接相互作用和促进HSF 1的核转位，促进心肌血管生成，曲美他嗪可用于治疗高血压患者的心肌血管生成障碍。
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 µL, 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.
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