Key Laboratory of Cardiovascular and Cerebrovascular Medicine, Nanjing Medical University, Nanjing 211166, China.
State Key Laboratory of Natural Medicines, Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China.
Molecules. 2022 Jun 27;27(13):4114. doi: 10.3390/molecules27134114.
Cardiac pathological hypertrophy is associated with undesirable epigenetic changes and causes maladaptive cardiac remodeling and heart failure, leading to high mortality rates. Specific drugs for the treatment of cardiac hypertrophy are still in urgent need. In the present study, a hydrogen-sulfide-releasing hybrid was designed and synthesized by appending -hydroxythiobenzamide (TBZ), an HS-releasing donor, to an analog of our previously discovered cardioprotective natural product XJP, 7,8-dihydroxy-3-methyl-isochromanone-4. This hybrid exhibited excellent HS-generating ability and low cellular toxicity. The protected against cardiomyocyte hypertrophy In Vitro and reduced the induction of and . More importantly, could reduce TAC-induced cardiac hypertrophy In Vivo, alleviate cardiac interstitial fibrosis and restore cardiac function. Unbiased transcriptomic analysis showed that regulated the AMPK signaling pathway and influenced fatty acid metabolic processes, which may be attributed to its cardioprotective activities.
心脏病理性肥大与不良的表观遗传变化有关，导致适应性心脏重构和心力衰竭，从而导致高死亡率。仍然急需专门用于治疗心脏肥大的药物。在本研究中，设计并合成了一种释放氢硫化物的混合分子，方法是将氢硫化物供体 - 羟硫代苯甲酰胺（TBZ）连接到我们之前发现的具有心脏保护作用的天然产物 XJP 的类似物 7,8-二羟基-3-甲基-异色满酮-4 上。该混合分子具有出色的氢硫化物生成能力和低细胞毒性。该分子在体外可防止心肌细胞肥大，并减少 和 的诱导。更重要的是，该分子可以减少 TAC 诱导的体内心脏肥大，减轻心脏间质纤维化并恢复心脏功能。无偏转录组分析表明，该分子调节 AMPK 信号通路并影响脂肪酸代谢过程，这可能与其心脏保护活性有关。
