Hypoxia-activated dual donors of H2S and NO alleviate myocardial injury in coronary heart disease via synergistic mechanisms.

Coronary heart disease (CHD) and related hypoxic cardiac disorders involve a detrimental interplay between hypoxia and inflammation, which often fail to address effectively by traditional therapies. Here, we report the design and synthesis of a hypoxia-activated dual donor of hydrogen sulfide (H2S) and nitric oxide (NO), termed prodrug NS-1, which selectively releases therapeutic levels of two gases under hypoxic conditions. NS-1, which is stable under normoxia, exhibits high hypoxia responsiveness and target delivery to hypoxic tissues, minimizing systemic off-target effects. Both in vitro and in vivo evaluations demonstrate that NS-1 shows a remarkable capacity to substantially mitigate myocardial injury, attributing to the synergistic interplay between H2S and NO. Mechanistic studies reveal that this synergy orchestrates a concerted action, encompassing potent vasodilatory, anti-inflammatory, and cytoprotective effects, thereby conferring substantial cardioprotection. In a murine CHD model, NS-1 attenuated cardiac hypertrophy, collagen deposition, and oxidative stress, outperforming conventional NO donors. This study offers a novel approach to disrupt the hypoxia-inflammation cycle and promote tissue repair.