Novel sphingolipid metabolites in myocardial ischemia

心肌缺血中的新型鞘脂代谢物

• 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
• 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

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死亡的主要原因，影响约1％至2％ 一般人口。鞘脂，一种脂质类信号传导特性，已与 许多心脏病理。鞘脂由丝氨酸棕榈酰转移酶（一种异二聚体酶）形成 由SPTLC1和SPLTC2的亚基组成。该异二聚体结合了丝氨酸和棕榈酰辅酶A以产生 Dihydrophingosine是生成所有下游鞘脂的支架（例如，神经酰胺， 鞘磷脂，糖磷脂，1-磷酸盐等）。尽管它们在病理学中含义 所有真核细胞都需要鞘脂。 SPTLC2在心肌细胞中的耗竭导致心脏功能障碍 （Lee，Sy​​等，2012 J.Biol。Chem）。但是，以前确定了新型的心肌鞘脂池 这些脂质来自具有新型SPT亚基SPTLC3的SPTLC1的二聚化。我们以前发表了作品 表明SPTLC3在糖尿病心肌病中强烈诱导。在这里，我们表明SPTLC3也诱导了 人缺血性HF以及急性缺血和慢性缺血的小鼠模型。 SPTLC1/3的产品 我们表明的复合物是促凋亡的，在人缺血性心脏和小鼠模型中也会增加。 因此，我们建议从SPTLC1/2异二聚体衍生的规范性鞘脂，但 在某些心脏侮辱（脂肪毒性，缺血）中，SPTLC3是诱导的，改变了细胞内鞘脂组和 导致有害结果。这将提供针对治疗干预的机会 非典型，SPTLC3衍生的鞘脂，使​​体内稳态鞘脂池完整。 我们假设背后的科学前提是，可以针对鞘脂代谢 缺血性损伤。我们的假设是，缺血诱导这些非典型的鞘脂或子集，它们 促进凋亡，因此对心肌细胞有毒，而阻止其产量会减弱 缺血性损伤。这将在3个目标中进行测试：1测试SPTLC3的心肌细胞特异性耗竭是否 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 急性缺血与急性缺血中SPTLC3上调的机理，并识别下游 产生的非典型脂质的代谢途径和产生的子集；和3确定 非典型脂质诱导细胞凋亡的机制。该建议将确定非 - 缺血性心肌病中的典型鞘脂，并将为潜在的进一步研究奠定基础 将途径作为一种创新的治疗选择，以防止缺血性损伤和心力衰竭和 改善患者的结果。

项目成果

Sphingolipids in the Heart: From Cradle to Grave.

• DOI: 10.3389/fendo.2020.00652
• 发表时间: 2020
• 期刊: Frontiers in endocrinology
• 影响因子: 5.2
• 作者: Kovilakath A;Jamil M;Cowart LA
• 通讯作者: Cowart LA

Sphingolipids in Adipose: Kin or Foe?

脂肪中的鞘脂：亲人还是敌人？

• DOI: 10.1007/978-981-19-0394-6_2
• 发表时间: 2022
• 期刊: Advances in experimental medicine and biology
• 作者: Valentine,Yolander;Cowart,LAshley
• 通讯作者: Cowart,LAshley

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

• DOI: 10.15698/cst2022.02.264
• 发表时间: 2022-03
• 期刊: Cell stress
• 影响因子: 6.4
• 作者: Floros KV;Chawla AT;Johnson-Berro MO;Khatri R;Stamatouli AM;Boikos SA;Dozmorov MG;Cowart LA;Faber AC
• 通讯作者: Faber AC