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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 <b>13-E</b> was designed and synthesized by appending <i>p</i>-hydroxythiobenzamide (TBZ), an H₂S-releasing donor, to an analog of our previously discovered cardioprotective natural product XJP, 7,8-dihydroxy-3-methyl-isochromanone-4. This hybrid <b>13-E</b> exhibited excellent H₂S-generating ability and low cellular toxicity. The <b>13-E</b> protected against cardiomyocyte hypertrophy In Vitro and reduced the induction of <i>Anp</i> and <i>Bnp</i>. More importantly, <b>13-E</b> could reduce TAC-induced cardiac hypertrophy In Vivo, alleviate cardiac interstitial fibrosis and restore cardiac function. Unbiased transcriptomic analysis showed that <b>13-E</b> regulated the AMPK signaling pathway and influenced fatty acid metabolic processes, which may be attributed to its cardioprotective activities.