Central Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China.
Research Center of Translational Medicine, Jinan Central Hospital, Shandong First Medical University, Jinan, Shandong, China.
J Cell Mol Med. 2024 Apr;28(7):e18238. doi: 10.1111/jcmm.18238.
Heart failure with preserved ejection fraction (HFpEF) accounts for approximately 50% of total heart failure patients and is characterized by peripheral circulation, cardiac remodelling and comorbidities (such as advanced age, obesity, hypertension and diabetes) with limited treatment options. Chidamide (HBI-8000) is a domestically produced benzamide-based histone deacetylase isoform-selective inhibitor used for the treatment of relapsed refractory peripheral T-cell lymphomas. Based on our in vivo studies, we propose that HBI-8000 exerts its therapeutic effects by inhibiting myocardial fibrosis and myocardial hypertrophy in HFpEF patients. At the cellular level, we found that HBI-8000 inhibits AngII-induced proliferation and activation of CFs and downregulates the expression of fibrosis-related factors. In addition, we observed that the HFpEF group and AngII stimulation significantly increased the expression of TGF-β1 as well as phosphorylated p38MAPK, JNK and ERK, whereas the expression of the above factors was significantly reduced after HBI-8000 treatment. Activation of the TGF-β1/MAPK pathway promotes the development of fibrotic remodelling, and pretreatment with SB203580 (p38MAPK inhibitor) reverses this pathological change. In conclusion, our data suggest that HBI-8000 inhibits fibrosis by modulating the TGF-β1/MAPK pathway thereby improving HFpEF. Therefore, HBI-8000 may become a new hope for the treatment of HFpEF patients.
射血分数保留的心力衰竭（HFpEF）约占心力衰竭患者总数的 50%，其特征为外周循环、心脏重构和合并症（如高龄、肥胖、高血压和糖尿病），治疗选择有限。西达本胺（HBI-8000）是一种国内生产的苯甲酰胺类组蛋白去乙酰化酶亚型选择性抑制剂，用于治疗复发/难治性外周 T 细胞淋巴瘤。基于我们的体内研究，我们提出 HBI-8000 通过抑制 HFpEF 患者的心肌纤维化和心肌肥厚发挥其治疗作用。在细胞水平上，我们发现 HBI-8000 抑制 AngII 诱导的 CFs 增殖和激活，并下调纤维化相关因子的表达。此外，我们观察到 HFpEF 组和 AngII 刺激显著增加 TGF-β1 以及磷酸化 p38MAPK、JNK 和 ERK 的表达，而 HBI-8000 治疗后上述因子的表达显著降低。TGF-β1/MAPK 通路的激活促进纤维化重塑的发展，而 p38MAPK 抑制剂 SB203580 的预处理可逆转这种病理变化。总之，我们的数据表明 HBI-8000 通过调节 TGF-β1/MAPK 通路抑制纤维化，从而改善 HFpEF。因此，HBI-8000 可能成为治疗 HFpEF 患者的新希望。
