Sun Han, Zhu Guanghao, Ling Shuang, Liu Jun, Xu Jin-Wen
Institute of Interdisciplinary Medical Science, Shanghai University of Traditional Chinese Medicine, Pudong New Area, Shanghai 201203, P.R. China.
Exp Ther Med. 2023 Mar 6;25(4):172. doi: 10.3892/etm.2023.11871. eCollection 2023 Apr.
Pathological cardiac hypertrophy is an independent risk factor for complications such as arrhythmia, myocardial infarction, sudden mortality and heart failure. Succinate, an intermediate product of the Krebs cycle, is released into the bloodstream by cells; its levels increase with exacerbations of hypertension, myocardial and other tissue damage and metabolic disease. Succinate may also be involved in several metabolic pathways and mediates numerous pathological effects through its receptor, succinate receptor 1 (SUCNR1; previously known as GPR91). Succinate-induced activation of SUCNR1 has been reported to be related to cardiac hypertrophy, making SUCNR1 a potential target for treating cardiac hypertrophy. Traditional Chinese medicine (TCM) and its active ingredients have served important roles in improving cardiac functions and treating heart failure. The present study investigated whether 4'-O-methylbavachadone (MeBavaC), an active ingredient of the herbal remedy Fructus Psoraleae, which is often used in TCM and has protective effect on myocardial injury and hypertrophy induced by adriamycin, ischemia-reperfusion and sepsis, could ameliorate succinate-induced cardiomyocyte hypertrophy by inhibiting the NFATc4 pathway. Using immunofluorescence staining, reverse transcription-quantitative PCR, western blotting and molecular docking analysis, it was determined that succinate activated the calcineurin/NFATc4 and ERK1/2 pathways to promote cardiomyocyte hypertrophy. MeBavaC inhibited cardiomyocyte hypertrophy, nuclear translocation of NFATc4 and ERK1/2 signaling activation in succinate-induced cardiomyocytes. Molecular docking analysis revealed that MeBavaC interacts with SUCNR1 to form a relatively stable binding and inhibits the succinate-SUCNR1 interaction. The results demonstrated that MeBavaC suppressed cardiomyocyte hypertrophy by blocking SUCNR1 receptor activity and inhibiting NFATc4 and ERK1/2 signaling, which will contribute to the preclinical development of this compound.
病理性心脏肥大是心律失常、心肌梗死、猝死和心力衰竭等并发症的独立危险因素。琥珀酸是三羧酸循环的中间产物，由细胞释放到血液中；其水平随着高血压、心肌及其他组织损伤和代谢疾病的加重而升高。琥珀酸还可能参与多种代谢途径，并通过其受体琥珀酸受体1（SUCNR1；以前称为GPR91）介导多种病理效应。据报道，琥珀酸诱导的SUCNR1激活与心脏肥大有关，使SUCNR1成为治疗心脏肥大的潜在靶点。中药及其活性成分在改善心脏功能和治疗心力衰竭方面发挥了重要作用。本研究调查了补骨脂（常用于中药，对阿霉素、缺血再灌注和脓毒症诱导的心肌损伤和肥大具有保护作用）的活性成分4'-O-甲基补骨脂查耳酮（MeBavaC）是否能通过抑制NFATc4途径改善琥珀酸诱导的心肌细胞肥大。通过免疫荧光染色、逆转录定量PCR、蛋白质印迹和分子对接分析，确定琥珀酸激活钙调神经磷酸酶/NFATc4和ERK1/2途径以促进心肌细胞肥大。MeBavaC抑制琥珀酸诱导的心肌细胞肥大、NFATc4的核转位和ERK1/2信号激活。分子对接分析表明，MeBavaC与SUCNR1相互作用形成相对稳定的结合，并抑制琥珀酸与SUCNR1的相互作用。结果表明，MeBavaC通过阻断SUCNR1受体活性和抑制NFATc4及ERK1/2信号传导来抑制心肌细胞肥大，这将有助于该化合物的临床前开发。
