Ba Lina, Wu Nan, Feng Xiang, Wang Ruixuan, Zhao Zhichao, Wang Rui, Liu Renling, Shi Pilong, Sun Hongli, Qi Hanping
Department of Pharmacology, Harbin Medical University, Daqing, Heilongjiang, 163319, China.
Cardiovasc Drugs Ther. 2025 Feb 20. doi: 10.1007/s10557-025-07677-2.
The purpose of this study was to investigate the protective effects of biochanin A (BCA) on cardiac hypertrophy and to elucidate the underlying molecular mechanisms. The research question was whether BCA can reverse heart dysfunction and attenuate cardiomyocyte hypertrophy induced by pressure overload and AngII, respectively, and how it interacts with the NLRP3 pyroptosis pathway to achieve these effects.
We employed an animal model of pressure overload-induced cardiac hypertrophy and an in vitro model of AngII-induced cardiomyocyte hypertrophy to assess the effects of BCA. The expression of NLRP3 and its related signaling molecules was analyzed by western blotting, and the activity of the NLRP3 pathway was measured using pyroptosis assays. The role of Cbl-b, an E3 ubiquitin ligase, in BCA-mediated NLRP3 inhibition was also investigated.
BCA was found to reverse heart dysfunction and attenuate cardiomyocyte hypertrophy induced by pressure overload and AngII. Mechanistically, BCA mitigated cardiac hypertrophy by targeting the NLRP3 pyroptosis pathway. The reduction in NLRP3 expression by BCA was predominantly mediated through the upregulation of Cbl-b, which enhanced the ubiquitination and subsequent degradation of NLRP3. Additionally, BCA facilitated the upregulation of Cbl-b expression by interacting with NF-κB, preventing NF-κB binding to the promoter region of Cbl-b and reversing its suppressive action on Cbl-b expression.
This study provides initial evidence that BCA can protect against cardiac hypertrophy. Its mechanism of action involves interacting with NF-κB to promote the expression of Cbl-b, which facilitates the ubiquitination and degradation of NLRP3, ultimately inhibiting pyroptosis. This finding suggests that BCA may be a potential therapeutic agent for the treatment of cardiac hypertrophy.
本研究旨在探讨生物活性成分A（BCA）对心脏肥大的保护作用，并阐明其潜在的分子机制。研究问题是BCA是否能分别逆转压力超负荷和血管紧张素II诱导的心脏功能障碍并减轻心肌细胞肥大，以及它如何与NLRP3焦亡途径相互作用以实现这些效果。
我们采用压力超负荷诱导的心脏肥大动物模型和血管紧张素II诱导的心肌细胞肥大体外模型来评估BCA的作用。通过蛋白质印迹法分析NLRP3及其相关信号分子的表达，并使用焦亡检测法测量NLRP3途径的活性。还研究了E3泛素连接酶Cbl-b在BCA介导的NLRP3抑制中的作用。
发现BCA可逆转压力超负荷和血管紧张素II诱导的心脏功能障碍并减轻心肌细胞肥大。从机制上讲，BCA通过靶向NLRP3焦亡途径减轻心脏肥大。BCA导致的NLRP3表达降低主要是通过Cbl-b的上调介导的，Cbl-b增强了NLRP3的泛素化及随后的降解。此外，BCA通过与核因子κB（NF-κB）相互作用促进Cbl-b表达上调，阻止NF-κB与Cbl-b启动子区域结合并逆转其对Cbl-b表达的抑制作用。
本研究提供了初步证据表明BCA可预防心脏肥大。其作用机制包括与NF-κB相互作用以促进Cbl-b的表达，这有助于NLRP3的泛素化和降解，最终抑制焦亡。这一发现表明BCA可能是治疗心脏肥大的潜在治疗药物。
