Laboratory of Pharmacology & Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China; Guangzhou Hospital of Integrated Traditional and West Medicine, Guangzhou 510801, China.
Laboratory of Pharmacology & Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
Phytomedicine. 2024 Oct;133:155894. doi: 10.1016/j.phymed.2024.155894. Epub 2024 Jul 20.
According to recent research, treating heart failure (HF) by inhibiting G protein-coupled receptor kinase 2 (GRK2) to improve myocardial energy metabolism has been identified as a potential approach. Cinnamaldehyde (CIN), a phenylpropyl aldehyde compound, has been demonstrated to exhibit beneficial effects in cardiovascular diseases. However, whether CIN inhibits GRK2 to ameliorate myocardial energy metabolism in HF is still unclear.
This study examines the effects of CIN on GRK2 and myocardial energy metabolism to elucidate its underlying mechanism to treat HF.
The isoproterenol (ISO) induced HF model in vivo and in vitro were constructed using Sprague-Dawley (SD) rats and primary neonatal rat cardiomyocytes (NRCMs). Based on this, the effects of CIN on myocardial energy metabolism and GRK2 were investigated. Additionally, validation experiments were conducted after interfering and over-expressing GRK2 in ISO-induced NRCMs to verify the regulatory effect of CIN on GRK2. Furthermore, binding capacity between GRK2 and CIN was explored by Cellular Thermal Shift Assay (CETSA) and Microscale Thermophoresis (MST).
In vivo and in vitro, CIN significantly improved HF as demonstrated by reversing abnormal changes in myocardial injury markers, inhibiting myocardial hypertrophy and decreasing myocardial fibrosis. Additionally, CIN promoted myocardial fatty acid metabolism to ameliorate myocardial energy metabolism disorder by activating AMPK/PGC-1α signaling pathway. Moreover, CIN reversed the inhibition of myocardial fatty acid metabolism and AMPK/PGC-1α signaling pathway by GRK2 over-expression in ISO-induced NRCMs. Meanwhile, CIN had no better impact on the stimulation of cardiac fatty acid metabolism and the AMPK/PGC-1α signaling pathway in ISO-induced NRCMs when GRK2 was disrupted. Noticeably, CETSA and MST confirmed that CIN binds to GRK2 directly. The binding of CIN and GRK2 promoted the ubiquitination degradation of GRK2 mediated by murine double mimute 2.
This study demonstrates that CIN exerts a protective intervention in HF by targeting GRK2 and promoting its ubiquitination degradation to activate AMPK/PGC-1α signaling pathway, ultimately improving myocardial fatty acid metabolism.
最近的研究表明，通过抑制 G 蛋白偶联受体激酶 2（GRK2）来改善心肌能量代谢，从而治疗心力衰竭（HF），这可能是一种治疗方法。肉桂醛（CIN）是一种苯丙醛化合物，已被证明对心血管疾病有有益作用。然而，CIN 是否通过抑制 GRK2 来改善 HF 中的心肌能量代谢尚不清楚。
本研究旨在探讨 CIN 对 GRK2 和心肌能量代谢的影响，以阐明其治疗 HF 的潜在机制。
使用 Sprague-Dawley（SD）大鼠和原代乳鼠心肌细胞（NRCMs）构建异丙肾上腺素（ISO）诱导的 HF 体内和体外模型。在此基础上，研究了 CIN 对心肌能量代谢和 GRK2 的影响。此外，在 ISO 诱导的 NRCMs 中干扰和过表达 GRK2 后进行验证实验，以验证 CIN 对 GRK2 的调节作用。此外，通过细胞热转移分析（CETSA）和微量热泳动（MST）探索了 GRK2 和 CIN 之间的结合能力。
体内和体外实验均表明，CIN 显著改善了 HF，表现为逆转心肌损伤标志物的异常变化、抑制心肌肥大和减少心肌纤维化。此外，CIN 通过激活 AMPK/PGC-1α 信号通路促进心肌脂肪酸代谢，改善心肌能量代谢紊乱。此外，CIN 逆转了 ISO 诱导的 NRCMs 中 GRK2 过表达对心肌脂肪酸代谢和 AMPK/PGC-1α 信号通路的抑制作用。同时，当 GRK2 被破坏时，CIN 对 ISO 诱导的 NRCMs 中心脏脂肪酸代谢和 AMPK/PGC-1α 信号通路的刺激作用没有改善。值得注意的是，CETSA 和 MST 证实 CIN 直接与 GRK2 结合。CIN 与 GRK2 的结合促进了鼠双模拟 2 介导的 GRK2 的泛素化降解。
本研究表明，CIN 通过靶向 GRK2 并促进其泛素化降解来激活 AMPK/PGC-1α 信号通路，从而改善心肌脂肪酸代谢，对 HF 发挥保护干预作用。
