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（由申请人提供）;这项工作的总体目标是阐明和减轻适应不良代谢重塑的机制，这种机制可能导致心脏功能障碍和压力超负荷心脏失代偿性肥大的进展。该建议源于我们实验室的两个新发现：1）心脏中储存的甘油三酯（TG）是相当动态的，但在衰竭的心脏中TG周转缓慢， TG含量，后一项发现在无糖尿病的心力衰竭患者中得到证实。TG周转的损失减少了TG中长链脂肪酸（LCFA）对线粒体脂肪酸氧化（FAO）的贡献，重要的是，损害了PPARα的TG脂解激活。我们已经报道，虽然棕榈酸盐维持了肥厚心脏中TG代谢和PPARα活化的降低，但油酸盐使这些相同参数中的每一个正常化; 2）我们的实验室首次报道了在肥厚心脏中FAO限速酶-肉毒碱棕榈酰转移酶I（CPT 1）的肝脏同种型的蛋白质含量增加。我们还发现，健康心脏中肝脏CPT 1（CPT 1a）的急性表达诱导了两个令人惊讶的结果; FAO的矛盾减少和心肌心房利钠肽mRNA的升高，这两种反应都是对致病性应激的经典观察。初步数据显示，CPT 1a的表达受到Mir-370的抑制，并且在肥大的心脏中，Mir 370的含量很低。因此，我们假设：1）提供富含油酸的饮食通过a）维持TG周转和PPARα靶基因表达，B）影响神经酰胺物质的形成，和c）从而减轻功能障碍和代偿失调，为横向主动脉缩窄（TAC）后的大鼠心脏提供益处。2)肥厚心脏中CPT 1a的增加是影响心脏失代偿的早期代谢重塑的关键步骤，并与肥厚信号有关。3)肥厚心脏中CPT 1a的增加与通过CPT 1乙酰化和丙二酰化的变化减少FAO有关，这些变化通过恢复Mir-370含量响应CPT 1a调节。目的1 a）确定棕榈酸酯（三棕榈精）与富含油酸酯（三油酸甘油酯）饮食对大鼠心脏中TAC后失代偿的影响，和B）确定三油酸甘油酯和三棕榈精饮食在TAC后是否影响TG转换、PPARα靶基因表达、LCFA氧化和脂毒性酰基中间体。目的2确定亚型向CPT 1a（肝脏）表达的转变在LCFA氧化减少和向失代偿和早期HF进展中的作用。将检查不能响应于TAC而增加CPT 1a的心脏特异性CPT 1a缺失小鼠对TAC的功能性和肥大性响应。通过CPT 1b（肌肉同种型）含量和CPT 1乙酰化/丙二酰化的独家变化改变FAO的可能性，将在有限的CPT 1a反应的情况下阐明。目的3阐明了潜在的适应不良上调CPT 1a，由于减少米尔-370在TAC，和CPT 1a表达的作用，在乙酰化和丙二酰化的CPT 1亚型。在大鼠心脏中TAC后的低Mir-370将通过急性过表达Mir-370来抑制CPT 1a和下游效应来抵消。