Novel sphingolipid metabolites in myocardial ischemia

心肌缺血中的新型鞘脂代谢物

• 批准号: 10428358
• 负责人: Lauren Ashley Cowart
• 金额: $ 38.81万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-07 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10428358
• 关键词: Ablation; Acute; Acyl Coenzyme A; Address; Affect; Alleles; Amino Acids; Anabolism; Apoptosis; Apoptotic; Attenuated; Autophagocytosis; Biochemical; Carbon; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cell model; Cell physiology; Cells; Ceramides; Cessation of life; Characteristics; Chronic; Coenzyme A; Complex; Coupled; Cytosol; Data; Diabetic mouse; Dihydrosphingosine; Dimerization; Disease; Enzymes; Eukaryotic Cell; Event; Foundations; General Population; Generations; Genetic Transcription; Glycosphingolipids; Heart; Heart Injuries; Heart failure; Homeostasis; Human; In Vitro; Infarction; Inflammation; Ischemia; Lead; Lipids; Mass Spectrum Analysis; Messenger RNA; Metabolic Pathway; Metabolism; Modeling; Mouse Strains; Mus; Myocardial; Myocardial Ischemia; Myocardial dysfunction; Myocardium; Outcome; Palmitates; Palmitoyl Coenzyme A; Pathologic; Pathology; Pathway interactions; Patient-Focused Outcomes; Patients; Physical condensation; Physiological; Play; Post-Transcriptional Regulation; Production; Property; Proteins; Publishing; Reaction; Regulation; Research; Role; Route; Scheme; Serine; Signal Transduction; Single Nucleotide Polymorphism; Sphingolipids; Sphingomyelins; Stress; Structure; TP53 gene; Techniques; Testing; Therapeutic; Therapeutic Intervention; Transcriptional Regulation; Up-Regulation; Vertebral column; Work; base; cell type; diabetic cardiomyopathy; fibrogenesis; functional group; genomic locus; heart function; human model; improved; in vivo; innovation; inorganic phosphate; insight; ischemic cardiomyopathy; ischemic injury; mouse model; novel; preference; prevent; programs; response; scaffold; serine palmitoyltransferase; sphingosine 1-phosphate; tool; transcription factor

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.

项目摘要 缺血性心肌病是世界上主要的死亡原因，发病率约为1%至2% 在普通人群中。鞘磷脂是一类具有信号特性的脂类，已被认为与 大量的心脏病变。鞘脂是由丝氨酸棕榈酰转移酶形成的，它是一种异二聚体酶。 由Sptlc1和Spltc2亚基组成。这种杂二聚体结合丝氨酸和棕榈酰辅酶A生成 二氢鞘氨醇，用作生成所有下游鞘脂(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意义， 鞘磷脂是所有真核细胞所必需的；心肌细胞中Sptlc2的缺失导致心脏功能障碍 (Lee，Sy等人)2012 J.Biol.化学)。然而，之前发现了一种新的心肌鞘脂池 这些脂质是由Sptlc1与新的SPT亚基Sptlc3二聚化而成的。我们之前曾发表过一篇文章 表明Sptlc3在糖尿病心肌病中有强烈的诱导作用。在这里，我们证明了Sptlc3也是在 在人类缺血性心力衰竭和小鼠急性和慢性缺血模型中。Sptlc1/3的产品 我们发现的促进细胞凋亡的复合体在人类缺血心脏和小鼠模型中也增加了。 因此，我们认为由Sptlc1/2杂二聚体衍生的典型神经鞘糖脂是动态平衡的，但是 在一些心脏损伤(脂毒性、缺血)中，Sptlc3被诱导，改变了细胞内的鞘磷脂和 导致了有害的后果。这将为针对以下目标的治疗干预提供机会 非典型的Sptlc3衍生的鞘脂，保持动态平衡的鞘脂池完好无损。 我们假设背后的科学前提是鞘磷脂新陈代谢可以靶向预防 缺血性损伤。我们的假设是，缺血诱导了这些非典型的鞘脂或其子集，这是 促进细胞凋亡，从而对心肌细胞产生毒性，而阻止其产生将减弱 缺血性损伤。这将在三个目标中进行测试：1-测试心肌细胞特异性Sptlc3的耗竭 将减轻急性或慢性缺血小鼠的缺血性损伤和/或心力衰竭，2-确定 急、慢性脑缺血Sptlc3表达上调的机制(S)及其下游辨证 代谢途径和由此产生的非典型脂类的子集；以及3-确定 非典型脂质诱导细胞凋亡的机制(S)。这项提案将确立非政府组织的作用 规范的鞘磷脂在缺血性心肌病中的作用，并将为进一步研究其潜力奠定基础 靶向该通路作为预防缺血性损伤和心力衰竭的创新治疗选择 改善患者的预后。