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.

项目总结