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Published on: January 22, 2017
4'‑O‑methylbavachalcone inhibits succinate induced cardiomyocyte hypertrophy via the NFATc4 pathway
Han Sun1, Guanghao Zhu1, Shuang Ling1
1Institute of Interdisciplinary Medical Science, Shanghai University of Traditional Chinese Medicine, Pudong New Area, Shanghai 201203, P.R. China.
Insights
4'-O-methylbavachadone (MeBavaC) inhibits pathological cardiac hypertrophy by blocking the succinate receptor 1 (SUCNR1) pathway. This natural compound prevents cardiomyocyte hypertrophy and may offer a new therapeutic target for heart conditions.
Area of Science:
- Cardiovascular Biology
- Pharmacology
- Traditional Chinese Medicine
Background:
- Pathological cardiac hypertrophy is a major risk factor for severe cardiac complications like heart failure and sudden death.
- Succinate, a metabolic intermediate, exacerbates cardiac hypertrophy via its receptor, succinate receptor 1 (SUCNR1).
- Traditional Chinese Medicine (TCM) offers potential therapeutic agents for cardiac conditions.
Purpose of the Study:
- To investigate the efficacy of 4'-O-methylbavachadone (MeBavaC), a TCM compound, in ameliorating succinate-induced cardiomyocyte hypertrophy.
- To elucidate the molecular mechanisms underlying MeBavaC's effects, particularly its interaction with the SUCNR1 pathway and NFATc4 signaling.
Main Methods:
- Immunofluorescence staining, reverse transcription-quantitative PCR, and western blotting were used to assess cellular changes.
- Molecular docking analysis was employed to predict the binding interactions between MeBavaC, succinate, and SUCNR1.
- Cardiomyocyte hypertrophy models were induced by succinate exposure.
Main Results:
- Succinate promoted cardiomyocyte hypertrophy by activating the calcineurin/NFATc4 and ERK1/2 signaling pathways.
- MeBavaC significantly inhibited succinate-induced cardiomyocyte hypertrophy.
- MeBavaC suppressed the nuclear translocation of NFATc4 and the activation of ERK1/2 signaling.
- Molecular docking confirmed MeBavaC's stable binding to SUCNR1, inhibiting the succinate-SUCNR1 interaction.
Conclusions:
- MeBavaC effectively suppresses cardiomyocyte hypertrophy by blocking SUCNR1 receptor activity.
- The mechanism involves the inhibition of NFATc4 and ERK1/2 signaling pathways.
- MeBavaC shows promise as a potential therapeutic agent for treating cardiac hypertrophy.
Abstract:
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.
