Transendothelial transport and CD36 in the dysregulated lipid trafficking of failing hearts

衰竭心脏脂质运输失调中的跨内皮转运和 CD36

• 批准号: 10338438
• 负责人: E DOUGLAS LEWANDOWSKI
• 金额: $ 70.24万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-15 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10338438
• 关键词: Acyl Coenzyme A; Address; Affect; Albumins; Antisense Oligonucleotides; Awareness; Blood Circulation; Blood Vessels; CD36 gene; Cardiac; Cardiac Myocytes; Cardiotoxicity; Cells; Ceramides; Cessation of life; Chronic; Chylomicrons; Coenzyme A Ligases; Data; Defect; Dependence; Detection; Endothelial Cells; Endothelium; Energy Metabolism; Enzymes; Esterification; Event; Fatty Acids; Fatty acid glycerol esters; Female; Heart; Heart Diseases; Heart failure; Human; Impairment; Kinetics; Knockout Mice; Link; Lipids; Lipoproteins; Mediating; Metabolic; Metabolism; Molecular; Mus; Myocardial; Myocardium; Outcome; Pathogenesis; Pathologic; Pathway interactions; Physiological; Physiological Processes; Predisposition; Process; Production; Publishing; Research; Role; Sarcolemma; Sex Differences; Source; Stress; Transport Process; Triglycerides; constriction; defined contribution; experimental study; fatty acid metabolism; fatty acid oxidation; functional decline; heart function; heart metabolism; improved; in vivo; lipid metabolism; lipid transport; long chain fatty acid; male; mouse model; overexpression; oxidation; physical process; pressure; response; sex; stable isotope; therapeutic target; trafficking; uptake

Project Summary: The proposed research explores mechanisms of dysregulated lipid metabolism in failing hearts within the dynamic processes of long chain fatty acid (LCFA) delivery from the circulation to metabolism in the cardiomyocyte (CM). We will explore the roles of LCFA delivery by endothelial cells (EC) to CMs and rates of LCFA uptake by CMs in adverse metabolic remodeling in a mouse model of heart failure that recapitulates key metabolic defects in failing human hearts. Hearts rely on LCFA oxidation, up to 70% of fuels, to meet ATP demand. LCFA are also esterified into the neutral triglyceride (TG) pool and into physiologically active acyl- derivatives. In failing hearts, LCFA oxidation is reduced and the lipid profile becomes toxic. We have shown a reduction in the central LCFA metabolite, acyl-CoA, in failing hearts is detrimental, and increased acyl CoA production by ACSL1 improves metabolic state and mitigates functional decline. 13C NMR of hearts revealed an exponential component of 13C LCFA entry into TG that reflects LCFA uptake rate and is sensitive to activity of the LCFA transporter, CD36. LCFA uptake is also accelerated by metabolic trapping via esterification of LCFA to acyl-CoA by ACSL1, a process that is sex-dependent. Experiments on mice with cell- specific, CD36 deletion in ECs (EC-CD36 KO) and CMs (CM-CD36 KO) will support the objective to study the separate roles of LCFA delivery by ECs to CMs and uptake by CMs on LCFA metabolism within competing pathways, including deleterious ceramide formation in failing hearts. Potential differences in LCFA uptake and metabolism between two primary physiological sources, albumin-bound LCFA and lipoprotein-bound TG, will be studied. The hypothesis is: a) the contributions of EC CD36-dependent and independent transendothelial transport of LCFAs into CMs of normal and diseased hearts determine the metabolic fate of LCFAs, separate from CM CD36 activity, and depend on the LCFA source; b) there are sex-dependent differences in both CD36 transport of LCFA and trapping of LCFAs into CMs via esterification that contribute to the lipotoxic profile of failing hearts. Specific aims are: 1. Elucidate EC CD36 contributions to transendothelial transport of LCFA uptake kinetics and metabolic fate in normal and failing hearts of male vs. female EC-CD36 KO mice. 2. Distinguish CM-CD36 from EC contributions to LCFA uptake kinetics and metabolic fate in hearts of normal and failing heats of male vs. female CM-CD36 KO mice. 3. Elucidate reciprocal effects of CD36 transport and metabolic trapping by ACSL1 on LCFA use in normal and failing hearts, by silencing of CD36 in hearts having low overexpression of ACSL1 (MHC-ACSL1 J3) and in hearts from crossed, MHC-ASCL1xEC-CD36 KO and MHC-ASCL1xCM-CD36 KO mice. 4. Distinguish contributions of EC-CD36 and CM-CD36 to LCFA uptake rates and metabolism from albumin-bound vs. chylomicron-bound sources in normal and failing hearts of wild type, EC-CD36 KO, and CM-CD36 KO mice. Outcomes will provide unique information on molecular events modulating lipid content as new targets to resolve metabolic imbalances in failing hearts.

项目摘要： 拟议的研究探讨了心脏失败的脂质代谢失调的机制 长链脂肪酸（LCFA）从循环中递送到代谢的动态过程 心肌细胞（CM）。我们将探讨内皮细胞（EC）到CMS的LCFA传递的作用 CMS在不良代谢重塑的心力衰竭模型中摄取LCFA 人类心脏失败的代谢缺陷。心脏依靠LCFA氧化（多达70％的燃料）来满足ATP 要求。 LCFA也被酯化到中性甘油三酸酯（TG）池中，并进入生理活性的酰基 衍生物。在失败的心脏中，LCFA氧化减少，脂质谱变得有毒。我们已经显示了一个 降低中央LCFA代谢物，酰基-COA，心脏失败是有害的，酰基增加 ACSL1生产COA可改善代谢状态，并减轻功能下降。 13c nmr的心 揭示了13C LCFA进入TG的指数成分，它反映了LCFA摄取率，并且是敏感的 LCFA转运蛋白的活性，CD36。 LCFA摄取也通过代谢诱捕加速 通过ACSL1将LCFA酯化为酰基-COA，这是性别依赖性的过程。用细胞进行小鼠的实验 ECS（EC-CD36 KO）和CMS（CM-CD36 KO）中的特定CD36缺失将支持研究目标 ECS向CMS传递LCFA的角色，CMS在LCFA代谢中摄取 途径，包括在失败的心脏中形成有害的神经酰胺。 LCFA摄取的潜在差异和 两种主要生理来源之间的代谢，白蛋白结合的LCFA和脂蛋白结合的TG将 被研究。假设是：a）EC CD36依赖性和独立的跨内皮的贡献 将LCFA运输到正常心脏和患病心脏的CMS中，确定LCFA的代谢命运，分开 来自CM CD36活性，并取决于LCFA源； b）两种CD36都有性别依赖性差异 LCFA的运输和将LCFA捕获到CMS中，通过酯化有助于脂肪毒性。 失败的心。具体目的是：1。阐明EC CD36对LCFA的跨内皮运输的贡献 男性与女性EC-CD36 KO小鼠的摄取动力学和代谢命运。 2。 将CM-CD36与EC对LCFA摄取动力学和代谢命运的贡献区分开 以及雄性与雌性CM-CD36 KO小鼠的热量失败。 3。阐明CD36转运和 ACSL1代谢诱捕在正常和失败心脏中使用的LCFA使用，通过将CD36沉默 ACSL1（MHC-ACSL1 J3）的低过表达和Crossed的心脏，MHC-ASCL1XEC-CD36 KO和 MHC-ASCL1XCM-CD36 KO小鼠。 4。区分EC-CD36和CM-CD36对LCFA摄取的贡献 在野生的正常和失败的心脏中，白蛋白结合与乳糜微粒的来源的发生率和代谢 类型，EC-CD36 KO和CM-CD36 KO小鼠。结果将提供有关分子事件的独特信息 将脂质含量调节为新目标，以解决心脏失败的代谢失衡。