Maladaptive Expression of Metabolic Enzymes and Activity in Heart Failure

心力衰竭中代谢酶和活性的适应不良表达

• 批准号: 9126110
• 负责人: E DOUGLAS LEWANDOWSKI
• 金额: $ 69.54万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9126110
• 关键词: Acetyl Coenzyme A; Acetylation; Acute; Adult; Affect; Animals; Atrial Natriuretic Factor; Attenuated; Cardiac; Carnitine Palmitoyltransferase I; Cell Culture Techniques; Ceramides; Chronic; Code; Data; Diabetes Mellitus; Diet; Energy Metabolism; Enzymes; Failure; Fatty Acids; Fatty acid glycerol esters; Functional disorder; Gene Activation; Gene Expression; Gene Targeting; Goals; Heart; Heart Hypertrophy; Heart failure; Human; Hypertrophy; In Vitro; Kinetics; Knockout Mice; Laboratories; Ligands; Link; Lipids; Liver; Lysine; Malonyl Coenzyme A; Mediating; Messenger RNA; Metabolic; Metabolism; Mitochondria; Modification; Muscle; Myocardial; Myocardial dysfunction; Myocardium; N-palmitoylsphingosine; Nature; Neonatal; Outer Mitochondrial Membrane; PPAR alpha; Palmitates; Pathologic; Pathway interactions; Patients; Plasma; Post-Translational Protein Processing; Process; Production; Protein Isoforms; Proteins; Protocols documentation; Publishing; Rattus; Regulation; Reporting; Role; Signal Transduction; Source; Stress; Structural Genes; Testing; Triglyceride Metabolism; Triglycerides; Triolein; Up-Regulation; Viral Vector; Work; base; constriction; dietary control; enzyme activity; fatty acid oxidation; improved; indexing; long chain fatty acid; novel; overexpression; oxidation; pressure; public health relevance; research study; response; translocase; uptake

 DESCRIPTION (provided by applicant); The overall goal of this work is to elucidate and mitigate mechanisms of maladaptive metabolic remodeling that may contribute to cardiac dysfunction and the progression to decompensated hypertrophy in the pressure overloaded heart. The proposal originates from two novel findings in our laboratory: 1) that stored triglyceride (TG) in the heart is quite dynamic, but TG turnover is slow in the failing heart as is TG content, the latter finding since being confirmed in heart failure patients without diabetes. The loss of TG turnover reduces the contribution of long chain fatty acids (LCFA) from TG to mitochondrial fatty acid oxidation (FAO) and importantly, impairs TG lipolytic activation of PPARα. We have reported that while palmitate sustains this reduced TG metabolism and PPARα activation in hypertrophied hearts, oleate normalizes each of these very same parameters; 2) our lab first reported increased protein content of the liver isoform of the rate limiting enzyme in FAO, carnitine palmitoyltransferase I (CPT1) in hypertrophied hearts. We also found acute expression of the liver CPT1 (CPT1a) in healthy hearts induced two surprising results; a paradoxical reduction in FAO and elevated myocardial atrial natriuretic peptide mRNA, both classically observed responses to pathogenic stress. Preliminary data show CPT1a expression is suppressed by Mir-370 and that Mir370 content is low in hypertrophied hearts. Thus, we hypothesize that: 1) Supplying an oleate rich diet provides benefits to rat hearts following transverse aortic constriction (TAC) by a) maintaining TG turnover and PPARα target gene expression, b) influencing the formation of ceramide species, and c) thereby attenuating dysfunction and decompensation. 2) Increased CPT1a in hypertrophied hearts is a key step in the early metabolic remodeling that influences cardiac decompensation and is linked to hypertrophic signaling. 3) Increased CPT1a in hypertrophied hearts is linked to reduce FAO via changes in CPT1 acetylation and malonylation, and these changes respond to CPT1a regulation via restored Mir-370 content. Aim 1 a) determines effects of palmitate- (tripalmitin) versus oleate-rich (triolein) diets on decompensation after TAC in rat hearts, and b) determines if triolein and tripalmitin diets post-TAC affect TG turnover, PPARα target gene expression, LCFA oxidation and lipotoxic acyl-intermediates. Aim 2 determines the role of the isoform shift to CPT1a (liver) expression in the reduced LCFA oxidation and progression toward decompensation and early HF. Cardiac specific, CPT1a null mice, that are unable increase CPT1a in response to TAC, will be examined for functional and hypertrophic responses to TAC. The potential for altered FAO through exclusive changes in CPT1b (muscle isoform) content and CPT1 acetylation/malonylation, will be elucidated in the restricted absence of a CPT1a response. Aim 3 elucidates potentially maladaptive upregulation of CPT1a, due to reduced Mir-370 during TAC, and the role of CPT1a expression in acetylation and malonylation of both CPT1 isoforms. Low Mir-370 following TAC in rat hearts will be countered by acutely overexpressing Mir-370 to suppress CPT1a and downstream effects.

 描述（由适用提供）；这项工作的总体目的是阐明和减轻适应性代谢重塑的机制，这可能导致心脏功能障碍以及在压力超负荷心脏中向代偿性肥大的发展。该提案源自我们实验室中的两个新发现：1）将甘油三酸酯（TG）存储在心脏中是动态的，但TG的周转率在失败的心脏中很慢。 TG含量，后者的发现自从没有糖尿病的心力衰竭患者被确认以来。 TG周转率的丧失降低了长链脂肪酸（LCFA）从TG到线粒体脂肪酸氧化（FAO）的贡献，并且重要的是损害PPARα的TG脂解活化。我们报告说，虽然棕榈酸酯维持这种降低的TG代谢和PPARα激活，但Oleate将这些参数中的每一个都归一化。 2）我们的实验室首先报道了fao，肉碱棕榈酰转移酶I（CPT1）在肥大的心脏中限制速率酶的肝脏同工型的蛋白质含量增加。我们还发现，健康心脏中肝CPT1（CPT1A）的急性表达引起了两个惊喜结果。粮农组织和升高的心肌心尿素肽mRNA的矛盾减少，均经典地观察到对致病应激的反应。初步数据表明，miR-370抑制了CPT1A的表达，并且MiR370含量在肥大的心脏中含量较低。这就是我们假设：1）通过a）通过a）维持TG营业额和PPARα靶基因表达，b）神经酰胺物种的影响以及c）减弱功能障碍和分解了。 2）肥厚心脏中CPT1A的增加是早期代谢重塑的关键步骤，该重塑影响心脏代谢，并与肥大信号传导有关。 3）肥大心脏中CPT1a的增加与通过CPT1乙酰化和误导化的变化相关，以减少粮农组织，这些变化通过恢复的miR-370含量对CPT1A调节做出了反应。 AIM 1 A）确定棕榈酸酯（Tripalmitin）与Oleate-rich（Triolein）饮食对大鼠心脏中TAC后代偿作用的影响，并且b）b）确定Triolein和Tripalmitin Diets是否会影响TG TG失误，PPARα靶基因表达，LCFA氧化和LIPOTOTOXIC氧化剂氧化剂。 AIM 2决定了同工型向CPT1a（肝）表达的作用在降低的LCFA氧化和向早期HF降低的LCFA氧化和进展中的作用。心脏特异性CPT1A无效的小鼠，无法响应TAC而增加CPT1A，将检查对TAC的功能和肥大反应。通过在限制缺乏CPT1A响应的情况下，将阐明粮农组织（肌肉同工型）含量和CPT1乙酰化/误导化的独家变化而改变粮农组织的潜力。 AIM 3阐明了由于TAC期间的miR-370降低以及CPT1A表达在两种CPT1同工型的乙酰化和误导化中的作用，CPT1A可能会导致CPT1A的可能性不良。急性过表达miR-370以抑制CPT1A和下游效应，将抵抗大鼠心脏中TAC之后的miR-370低miR-370。