Novel sphingolipid metabolites in myocardial ischemia

项目摘要 缺血性心肌病是世界上主要的死亡原因，约占1%至2%。 普通大众的。鞘脂是一类具有信号传导特性的脂质， 多种心脏病鞘脂由丝氨酸棕榈酰转移酶形成， 由亚基Sptlc 1和Spltc 2组成。这种异二聚体结合丝氨酸和棕榈酰辅酶A， 二氢鞘氨醇，其用作产生所有下游鞘脂（例如神经酰胺， 鞘磷脂、鞘糖脂、鞘氨醇-1-磷酸等）。尽管它们在病理学上有牵连， 所有真核细胞都需要鞘脂;心肌细胞中Sptlc 2的缺失导致心脏功能障碍 (Lee，SY等人，2012 J. Biol. Chem）。然而，以前发现了一种新的心肌鞘脂库， 这些脂质来自Sptlc 1与新的SPT亚基Sptlc 3的二聚化。我们以前发表的工作 表明Sptlc 3在糖尿病性心肌病中被强烈诱导。在这里，我们表明Sptlc 3也被诱导， 人缺血性HF以及急性和慢性缺血的小鼠模型。Sptlc 1/3的产品 复合物，我们表明是促凋亡的，也增加了人类缺血性心脏和小鼠模型。 因此，我们认为Sptlc 1/2异源二聚体衍生的典型鞘脂是稳态的，但 在某些心脏损伤（脂毒性、局部缺血）中，Sptlc 3被诱导，改变细胞内鞘脂组， 导致有害的结果。这将为治疗干预提供机会， 非典型的Sptlc 3衍生的鞘脂，保持体内平衡鞘脂池完整。 我们的假设背后的科学前提是，鞘脂代谢可以有针对性地预防 缺血性损伤我们的假设是，缺血诱导这些非典型鞘脂，或其子集， 促进细胞凋亡，从而对心肌细胞有毒，阻断它们的产生将减弱 缺血性损伤这将在3个目标中进行测试：1-测试心肌细胞特异性Sptlc 3耗竭是否 将减弱小鼠急性或慢性缺血中的缺血性损伤和/或心力衰竭，2-为了确定 Sptlc 3在急性与慢性缺血中上调的机制，并确定其下游调节机制。 代谢途径和所产生的非典型脂质的子集;以及3-确定 非典型脂质诱导细胞凋亡的机制。这项建议将确立非政府组织的作用， 为进一步研究鞘脂在缺血性心肌病中的作用奠定基础。 靶向该途径作为预防缺血性损伤和心力衰竭的创新治疗选择， 改善患者预后。

Project Summary Ischemic cardiomyopathy is the leading cause of death in the world and affects approximately 1% to 2% of the general population. Sphingolipids, a lipid class bearing signaling properties, have been implicated in numerous cardiac pathologies. Sphingolipids are formed by serine palmitoyltransferase, a heterodimeric enzyme comprised of the subunits Sptlc1 and Spltc2. This heterodimer combines serine and palmitoyl-CoA to generate dihydrosphingosine, which serves as a scaffold for generation of all downstream sphingolipids (e.g. ceramides, sphingomyelins, glycosphingolipids, sphingosine-1-phosphate, etc.). Despite their implication in pathology, sphingolipids are required by all eukaryotic cells; depletion of Sptlc2 in cardiomyocytes led to cardiac dysfunction (Lee, SY et al. 2012 J. Biol. Chem). However, previously identified a novel pool of myocardial sphingolipids These lipids arise from a dimerization of Sptlc1 with a novel SPT subunit, Sptlc3. We previously published work showing that Sptlc3 is strongly induced in diabetic cardiomyopathy. Here we show that Sptlc3 is also induced in human ischemic HF and in mouse models of both acute and chronic ischemia. The products of the Sptlc1/3 complex, which we showed are pro-apoptotic, also increase in human ischemic heart and mouse models. Therefore, we propose that the canonical sphingolipids derived from Sptlc1/2 heterodimer are homeostatic, but in some cardiac insults (lipotoxicity, ischemia) Sptlc3 is induced, changing the intracellular sphingolipidome and leading to deleterious outcomes. This would present the opportunity for therapeutic intervention directed toward atypical, Sptlc3-derived sphingolipids, leaving the homeostatic sphingolipid pool intact. The scientific premise behind our hypothesis is that sphingolipid metabolism could be targeted to prevent ischemic injury. Our hypothesis is that ischemia induces these atypical sphingolipids, or a subset thereof, which promote apoptosis and are thereby toxic to cardiomyocytes, and that blocking their production will attenuate ischemic injury. This will be tested in 3 aims: 1-to test whether cardiomyocyte-specific depletion of Sptlc3 will attenuate ischemic injury and/or heart failure in acute or chronic ischemia in mice, 2-to determine the mechanism(s) of Sptlc3 upregulation in acute vs. chronic ischemia and identify the downstream metabolic pathways and resulting subset of atypical lipids that are produced; and 3-to determine the mechanism(s) by which the atypical lipids induce apoptosis. This proposal will establish the role of non- canonical sphingolipids in ischemic cardiomyopathy and will lay the foundation for further research on potential targeting of the pathway as an innovative therapeutic option to prevent ischemic injury and heart failure and improve patient outcome.