Novel sphingolipid metabolites in myocardial ischemia

心肌缺血中的新型鞘脂代谢物

基本信息

批准号：
10641983
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
项目类别：
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/10641983
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 alteration 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 Induction of Apoptosis Infarction Inflammation Ischemia Lipids LoxP-flanked allele 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 Scheme Serine Signal Transduction Single Nucleotide Polymorphism Sphingolipids Sphingomyelins Stress Structure TP53 gene Techniques Testing Therapeutic Therapeutic Intervention 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

项目摘要

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.

项目概要缺血性心肌病是世界上死亡的主要原因，影响约 1% 至 2% 普通民众的。鞘脂是一种具有信号传导特性的脂质类，与许多心脏病。鞘脂由丝氨酸棕榈酰转移酶（一种异二聚酶）形成由 Spltc1 和 Spltc2 亚基组成。这种异二聚体结合了丝氨酸和棕榈酰辅酶A以生成二氢鞘氨醇，作为生成所有下游鞘脂（例如神经酰胺、鞘磷脂、鞘糖脂、1-磷酸鞘氨醇等）。尽管它们在病理学上有影响，所有真核细胞都需要鞘脂；心肌细胞中 Sptlc2 的耗竭导致心功能障碍（Lee, SY 等人，2012 年《生物化学杂志》）。然而，之前发现了一种新的心肌鞘脂池这些脂质源自 Sptlc1 与新型 SPT 亚基 Sptlc3 的二聚化。我们之前发表过作品表明 Sptlc3 在糖尿病心肌病中被强烈诱导。在这里我们表明 Sptlc3 也在人类缺血性心力衰竭以及急性和慢性缺血的小鼠模型。 Sptlc1/3的产品我们证明该复合物具有促凋亡作用，在人类缺血性心脏和小鼠模型中也有所增加。因此，我们提出源自 Sptlc1/2 异二聚体的经典鞘脂是稳态的，但是在某些心脏损伤（脂毒性、缺血）中，Sptlc3 被诱导，改变细胞内鞘脂组并导致有害的结果。这将为针对以下方面的治疗干预提供机会：非典型的 Sptlc3 衍生的鞘脂，使稳态鞘脂库保持完整。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。我们的假设是缺血会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，阻止其产生会减弱缺血性损伤。这将在 3 个目标中进行测试： 1-测试是否心肌细胞特异性耗尽 Sptlc3 将减轻小鼠急性或慢性缺血的缺血性损伤和/或心力衰竭，2-确定 Sptlc3 在急性与慢性缺血中上调的机制并确定下游代谢途径和产生的非典型脂质的子集； 3-确定非典型脂质诱导细胞凋亡的机制。该提案将确立非典型的鞘脂在缺血性心肌病中的作用，将为进一步研究潜在的基础奠定基础将该途径作为预防缺血性损伤和心力衰竭的创新治疗选择，改善患者的治疗效果。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

MYCN upregulates the transsulfuration pathway to suppress the ferroptotic vulnerability in MYCN-amplified neuroblastoma.

MYCN 上调转硫途径以抑制 MYCN 扩增的神经母细胞瘤中的铁死亡脆弱性。

DOI：
发表时间：
2022-02
期刊：
影响因子：
6.4
作者：
Floros, Konstantinos V;Chawla, Ayesha T;Johnson;Khatri, Rishabh;Stamatouli, Angeliki M;Boikos, Sosipatros A;Dozmorov, Mikhail G;Cowart, L Ashley;Faber, Anthony C
通讯作者：
Faber, Anthony C

Sphingolipids in Adipose: Kin or Foe?

脂肪中的鞘脂：亲人还是敌人？