Nitroxyl (HNO), one-electron reduced and protonated sibling of nitric oxide (NO), is a potential regulator of cardiovascular functions. It produces positive inotropic, lusitropic, myocardial anti-hypertrophic and vasodilator properties. Despite of these favorable actions, the significance and the possible mechanisms of HNO in diabetic hearts have yet to be fully elucidated. H9c2 cells or primary neonatal mouse cardiomyocytes were incubated with normal glucose (NG) or high glucose (HG). Male C57BL/6 mice received intraperitoneal injection of streptozotocin (STZ) to induce diabetes. Here, we demonstrated that the baseline fluorescence signals of HNO in H9c2 cells were reinforced by both HNO donor Angeli's salt (AS), and the mixture of hydrogen sulfide (H₂S) donor sodium hydrogen sulfide (NaHS) and NO donor sodium nitroprusside (SNP), but decreased by HG. Pretreatment with AS significantly reduced HG-induced cell vitality injury, apoptosis, reactive oxygen species (ROS) generation, and hypertrophy in H9c2 cells. This effect was mediated by induction of caveolin-3 (Cav-3)/endothelial nitric oxide (NO) synthase (eNOS) complex. Disruption of Cav-3/eNOS by pharmacological manipulation or small interfering RNA (siRNA) abolished the protective effects of AS in HG-incubated H9c2 cells. In STZ-induced diabetic mice, administration of AS ameliorated the development of diabetic cardiomyopathy, as evidenced by improved cardiac function and reduced cardiac hypertrophy, apoptosis, oxidative stress and myocardial fibrosis without affecting hyperglycemia. This study shed light on how interaction of NO and H₂S regulates cardiac pathology and provide new route to treat diabetic cardiomyopathy with HNO.

Nitroxyl (HNO) 是一氧化氮 (NO) 的单电子还原和质子化同胞，是心血管功能的潜在调节剂。它产生正性肌力，lusitropic，心肌抗肥大和血管扩张特性。尽管有这些有利的作用，但 HNO 在糖尿病心脏中的意义和可能的机制尚未完全阐明。H9c2 细胞或原代新生小鼠心肌细胞与正常葡萄糖 (NG) 或高葡萄糖 (HG) 一起孵育。雄性 C57BL/6 小鼠腹腔注射链脲佐菌素 (STZ) 以诱导糖尿病。在这里，我们证明了 H9c2 细胞中 HNO 的基线荧光信号被 HNO 供体 Angeli 盐 (AS) 和硫化氢混合物 (H ₂S) 供体硫化氢钠 (NaHS) 和 NO 供体硝普钠 (SNP)，但因 HG 而减少。用 AS 预处理显着降低了 H9c2 细胞中 HG 诱导的细胞活力损伤、细胞凋亡、活性氧 (ROS) 生成和肥大。这种作用是由caveolin-3 (Cav-3)/内皮一氧化氮(NO) 合酶(eNOS) 复合物的诱导介导的。通过药理学操作或小干扰 RNA (siRNA) 破坏 Cav-3/eNOS 消除了 AS 在 HG 孵育的 H9c2 细胞中的保护作用。在 STZ 诱导的糖尿病小鼠中，施用 AS 改善了糖尿病性心肌病的发展，这可以通过改善心脏功能和减少心脏肥大、细胞凋亡、氧化应激和心肌纤维化而不影响高血糖来证明。这项研究揭示了 NO 和 H 如何相互作用₂ S 调节心脏病理学并提供用 HNO 治疗糖尿病心肌病的新途径。