Zhou Hongyan, Kee Hae Jin, Wan Le, Asfaha Yodita, Fischer Fabian, Kassack Matthias U, Kurz Thomas, Kim Seong Hoon, Kee Seung-Jung, Hong Young Joon, Jeong Myung Ho
Heart Research Center of Chonnam National University Hospital, Gwangju, Korea.
Hypertension Heart Failure Research Center, Chonnam National University Hospital, Gwangju, Korea.
Korean Circ J. 2025 Mar;55(3):231-247. doi: 10.4070/kcj.2024.0093. Epub 2024 Oct 11.
Heart failure is a potentially fatal event caused by diverse cardiovascular diseases, leading to high morbidity and mortality. Histone deacetylase (HDAC) inhibitors positively influence cardiac hypertrophy, fibrosis, hypertension, myocardial infarction, and heart failure, causing some side effects. We aimed to investigate the effect of the novel HDAC inhibitor YAK577 on the heart failure mouse model and its underlying mechanism.
New hydroxamic acid YAK577 was prepared via methyl-2,3-diphenylpropanoate synthesis using carboxylic acids. We used a micro-osmotic pump, including isoproterenol (ISO; 80 mg/kg/day), to induce a heart failure with reduced ejection fraction. Cardiac hypertrophy was assessed by heart weight to body weight ratio and cross-sectional area. The left ventricular (LV) function was assessed by echocardiography. Fibrosis was evaluated using picrosirius red staining. Overexpression and knockdown experiments were performed to investigate the association between HDAC8 and matrix metalloproteinase 12 (MMP12).
YAK577 treatment restored ISO-induced reduction in LV fractional shortening and ejection fraction (n=9-11). YAK577 significantly downregulated cardiac hypertrophy marker genes (natriuretic peptide B, , and myosin heavy chain 7, ) and cardiomyocyte size in vitro but not in vivo. YAK577 ameliorated cardiac fibrosis and fibrosis-related genes in vivo and in vitro. Additionally, YAK577 reduced elevated HDAC8 and MMP12 mRNA and protein expressions in ISO-infused mice, H9c2 cells, and rat neonatal cardiomyocytes. HDAC8 overexpression stimulated and mRNA levels, while HDAC8 knockdown downregulated these genes.
YAK577 acts as a novel heart failure drug through the HDAC8/MMP12 pathway.
心力衰竭是由多种心血管疾病引起的潜在致命事件，导致高发病率和死亡率。组蛋白脱乙酰酶（HDAC）抑制剂对心脏肥大、纤维化、高血压、心肌梗死和心力衰竭有积极影响，但会引起一些副作用。我们旨在研究新型HDAC抑制剂YAK577对心力衰竭小鼠模型的影响及其潜在机制。
通过使用羧酸的2,3-二苯基丙酸甲酯合成制备新型异羟肟酸YAK577。我们使用微渗透泵，包括异丙肾上腺素（ISO；80mg/kg/天），来诱导射血分数降低的心力衰竭。通过心脏重量与体重比和横截面积评估心脏肥大。通过超声心动图评估左心室（LV）功能。使用苦味酸天狼星红染色评估纤维化。进行过表达和敲低实验以研究HDAC8与基质金属蛋白酶12（MMP12）之间的关联。
YAK577治疗恢复了ISO诱导的LV缩短分数和射血分数的降低（n = 9 - 11）。YAK577在体外显著下调心脏肥大标记基因（利钠肽B、肌球蛋白重链7）和心肌细胞大小，但在体内没有。YAK577在体内和体外改善了心脏纤维化和纤维化相关基因。此外，YAK577降低了ISO注入小鼠、H9c2细胞和大鼠新生心肌细胞中升高的HDAC8和MMP12 mRNA及蛋白表达。HDAC8过表达刺激和mRNA水平，而HDAC8敲低下调这些基因。
YAK577通过HDAC8/MMP12途径作为一种新型心力衰竭药物发挥作用。
