Aims Growing evidence correlate the accrual of the sphingolipid ceramide in plasma and cardiac tissue with heart failure (HF). Regulation of sphingolipid metabolism in the heart and the pathological impact of its derangement remain poorly understood. Recently, we discovered that Nogo-B, a membrane protein of endoplasmic reticulum, abundant in the vascular wall, down-regulates the sphingolipid de novo biosynthesis, via serine palmitoyltransferase (SPT), first and rate liming enzyme, to impact vascular functions and blood pressure. Nogo-A, a splice isoform of Nogo, is transiently expressed in cardiomyocyte (CM) following pressure overload. Cardiac Nogo is upregulated in dilated and ischemic cardiomyopathies in animals and humans. However, its biological function in the heart remains unknown. Methods and Results We discovered that Nogo-A is a negative regulator of SPT activity and refrains ceramide de novo biosynthesis in CM exposed to hemodynamic stress, hence limiting ceramide accrual. At 7 days following transverse aortic constriction (TAC), SPT activity was significantly upregulated in CM lacking Nogo-A and correlated with ceramide accrual, particularly very long chain ceramides, which are the most abundant in CM, resulting in the suppression of “beneficial” autophagy. At 3 months post-TAC, mice lacking Nogo-A in CM showed worse pathological cardiac hypertrophy and dysfunction, with ca.50% mortality rate. Conclusions Mechanistically, Nogo-A refrains ceramides from accrual, therefore preserves the “beneficial” autophagy, mitochondrial function, and metabolic gene expression, limiting the progression to HF under sustained stress.

中文翻译：

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Nogo-A 减少神经酰胺从头生物合成以预防心力衰竭


目的 越来越多的证据表明血浆和心脏组织中鞘脂神经酰胺的积累与心力衰竭 (HF) 相关。心脏中鞘脂代谢的调节及其紊乱的病理影响仍然知之甚少。最近，我们发现 Nogo-B 是一种内质网膜蛋白，在血管壁中含量丰富，可通过丝氨酸棕榈酰转移酶 (SPT)（首要的石灰酶）下调鞘脂从头生物合成，从而影响血管功能和血液压力。 Nogo-A 是 Nogo 的剪接亚型，在压力超负荷后在心肌细胞 (CM) 中短暂表达。 Cardiac Nogo 在动物和人类的扩张型和缺血性心肌病中表达上调。然而，其在心脏中的生物学功能仍不清楚。方法和结果我们发现，Nogo-A 是 SPT 活性的负调节剂，可抑制暴露于血流动力学应激的 CM 中的神经酰胺从头生物合成，从而限制神经酰胺的累积。在横主动脉缩窄 (TAC) 后 7 天，缺乏 Nogo-A 的 CM 中 SPT 活性显着上调，并与神经酰胺累积相关，特别是超长链神经酰胺，其在 CM 中含量最丰富，从而抑制“有益”神经酰胺自噬。 TAC 后 3 个月，CM 中缺乏 Nogo-A 的小鼠表现出更严重的病理性心脏肥大和功能障碍，死亡率约为 50%。结论 从机制上讲，Nogo-A 抑制神经酰胺累积，因此保留了“有益的”自噬、线粒体功能和代谢基因表达，限制了持续应激下向 HF 的进展。