Ceramide accumulation is known to accompany acute myocardial ischemia, but its role in the pathogenesis of ischemic heart disease is unclear. In this study, we aimed to determine how ceramides accumulate in the ischemic heart and to determine if cardiac function following ischemia can be improved by reducing ceramide accumulation. To investigate the association between ceramide accumulation and heart function, we analyzed myocardial left ventricle biopsies from subjects with chronic ischemia and found that ceramide levels were higher in biopsies from subjects with reduced heart function. Ceramides are produced by either de novo synthesis or hydrolysis of sphingomyelin catalyzed by acid and/or neutral sphingomyelinase. We used cultured HL-1 cardiomyocytes to investigate these pathways and showed that acid sphingomyelinase activity rather than neutral sphingomyelinase activity or de novo sphingolipid synthesis was important for hypoxia-induced ceramide accumulation. We also used mice with a partial deficiency in acid sphingomyelinase (Smpd1(+/-) mice) to investigate if limiting ceramide accumulation under ischemic conditions would have a beneficial effect on heart function and survival. Although we showed that cardiac ceramide accumulation was reduced in Smpd1(+/-) mice 24h after an induced myocardial infarction, this reduction was not accompanied by an improvement in heart function or survival. Our findings show that accumulation of cardiac ceramides in the post-ischemic heart is mediated by acid sphingomyelinase. However, targeting ceramide accumulation in the ischemic heart may not be a beneficial treatment strategy.

中文翻译：

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靶向酸性鞘磷脂酶可减少缺血后心脏中的心脏神经酰胺积聚。

已知神经酰胺累积会伴随急性心肌缺血，但尚不清楚其在缺血性心脏病发病机理中的作用。在这项研究中，我们旨在确定神经酰胺在缺血心脏中的蓄积方式，并确定是否可以通过减少神经酰胺积聚来改善缺血后的心脏功能。为了研究神经酰胺蓄积与心脏功能之间的关系，我们分析了慢性缺血患者的心肌左心室活检，发现心脏功能降低的患者的活检中神经酰胺水平较高。神经酰胺是通过酸和/或中性鞘磷脂酶催化的鞘磷脂的从头合成或水解产生的。我们使用培养的HL-1心肌细胞来研究这些途径，并表明酸性鞘磷脂酶活性而不是中性鞘磷脂酶活性或从头鞘脂合成对于缺氧诱导的神经酰胺积聚很重要。我们还使用了酸性鞘磷脂酶部分缺失的小鼠（Smpd1（+/-）小鼠）来研究在缺血条件下限制神经酰胺的积累是否会对心脏功能和生存产生有益的影响。尽管我们显示Smpd1（+/-）小鼠在诱发心肌梗塞后24小时心脏神经酰胺蓄积减少，但这种减少并没有伴随心脏功能或生存的改善。我们的发现表明，缺血性心脏中心脏神经酰胺的积累是由酸性鞘磷脂酶介导的。然而，