Gender Effects on Remodeling of Lipid and Sarcomere Dynamics in Hypertrophy

性别对肥大中脂质和肌节动力学重塑的影响

• 批准号: 9197390
• 负责人: E DOUGLAS LEWANDOWSKI
• 金额: $ 23.19万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-15 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9197390
• 关键词: Address; Affect; Animals; Benign; Biochemical; Biochemistry; Caloric Restriction; Cardiac; Cardiac Myocytes; Cardiomyopathies; Carrier Proteins; Ceramides; Chronic; Data; Development; Diagnostic; Diet; Dietary Fats; Drops; Early Diagnosis; Enzymes; Equation; Equilibrium; Estrogens; Exhibits; Fatty Acids; Female; Fiber; Gender; Gender Role; Genetic; Health; Heart; Heart Hypertrophy; Heart failure; High Fat Diet; Human; Hypertrophy; Infiltration; Kinetics; Laboratories; Left; Left Ventricular Function; Link; Lipase; Lipids; Magnetic Resonance Imaging; Measurement; Mechanical Stress; Mechanics; Metabolic; Microfilaments; Mitochondria; Mus; Muscle Cells; Myocardial; Myocardial dysfunction; Myocardium; Outcome; Ovariectomy; Pathogenesis; Pathology; Peroxisome Proliferator-Activated Receptors; Phosphorylation; Predisposition; Preparation; Production; Property; Proteins; Proteomics; Protocols documentation; Publishing; Rattus; Receptor Activation; Reporting; Research; Resistance; Risk; Sarcomeres; Signal Transduction; Skin; Sphingosine; Stress; Testing; Therapeutic; Time; Tissues; Transgenic Mice; Treatment Protocols; Ventricular; base; fatty acid metabolism; fatty acid oxidation; gender difference; gender disparity; heart function; in vivo; interest; lipid metabolism; long chain fatty acid; male; overexpression; oxidation; pressure; protein activation; research study; response; stable isotope; two-dimensional; uptake

DESCRIPTION (provided by applicant): Gender influences the pathogenesis of heart failure, despite no inherent differences in myocyte contractility. Both humans and animals show gender differences in lipid dynamics during pathophysiological stress. Yet, the role of gender, as a determinant of altered cardiac lipid, in the pathogenesis of cardiac decompensation is largely unknown. This research focuses on mechanisms invoked by gender, dietary fat, and stress via pressure overload, that alter the balance between mitochondrial oxidation and cellular storage of long chain fatty acids (LCFA) to affect myofilament biochemistry and activity. We will examine gender and estrogen effects on the remodeling of cardiac lipid dynamics in response to pressure overload, focusing on both active and passive components of heart function; the active component being biochemical changes within sarcomeric proteins, due to metabolic signaling, and the passive component being myocardial stiffness due to lipid infiltration. Preliminary data suggest lipid accumulation produces myocardial stiffness, and that gender influences cardiac lipid dynamics and acyl derivatives. We reported reduced triacylglyceride (TAG) turnover and contributions of TAG to mitochondrial oxidation in hypertrophied hearts and find that acyl-derivatives affect myofilament phosphorylation and sensitivity to Ca2+. We plan to combine in vivo measurements of cardiac function and lipid content, with stable isotope kinetics of metabolic flux and myofilament proteomics to address a two-fold hypothesis that: 1) Gender differences, due to estrogen, affect metabolic reprogramming in cardiac hypertrophy with shifts in lipid utilization/storage affecting cardiac function, and 2) that dietary fat, storage (PPAR� ovr expression) and uptake (FATP1 overexpression) reveal gender-specific changes in cardiac lipid dynamics, affecting myocardial compliance and sarcomere activity. Aims are: 1) Examine gender and estrogen-dependent differences in lipid utilization/storage dynamics in hearts of male, female, and overiectomized female, non-transgenic (NTG) and MHC-PPAR� low-overexpressing (strain 404-4) mice; 2) Test how LCFA uptake, gender and estrogen contribute to the response to pressure overload by determining a) lipid dynamics and consequential effects on myocardial 2-D strains, tissue stiffness and contractility and b) ceramide species and sphingosine production and consequential effects on myofilament phosphorylation, oxidation and Ca-responsiveness in hearts of non-transgenic mice and transgenic mice overexpressing FATP1; 3) Determine the potential for gender-based adaptations in TAG dynamics and LCFA oxidation rates in response to pressure overload, to affect a) myocardial 2-D strains and stiffness through mechanical effects of lipid accumulation and b) sarcomere activity through phosphorylation effects of LCFA-derived intermediates, ceramides and sphingosine, on myofilament sensitivity in MHC-PPAR� hearts. The objectives are to elucidate mechanisms for reprogramming cardiac lipid dynamics that affect heart function, thereby identifying strategies for early diagnosis and gender specific-treatment protocols to mitigate the development of cardiomyopathy.

描述（由申请人提供）：尽管人类和动物在病理生理应激期间的脂质动态方面没有固有差异，但性别影响心力衰竭的发病机制。脂质在心脏代偿失调的发病机制中很大程度上是未知的，这项研究的重点是性别、膳食脂肪和压力超载引起的压力，这些机制改变了线粒体氧化和长链脂肪的细胞储存之间的平衡。我们将研究性别和雌激素对压力超负荷时心脏脂质重塑的动态影响，重点关注心脏功能的主动和被动成分；蛋白质，由于代谢信号，而被动成分是由于脂质渗透引起的心肌僵硬，初步数据表明脂质积累会产生心肌僵硬，并且性别影响心脏脂质动态和酰基。我们报道了甘油三酯 (TAG) 周转率的降低以及 TAG 对肥大心脏中线粒体氧化的贡献，并发现酰基衍生物影响肌丝磷酸化和对 Ca2+ 的敏感性，我们计划将心脏功能和脂质含量的体内测量与稳定相结合。代谢流的同位素动力学和肌丝蛋白质组学解决了两个假设：1）雌激素导致的性别差异影响心脏肥大中的代谢重编程以及影响心脏功能的脂质利用/储存的变化，以及 2) 膳食脂肪、储存（PPAR�ovr 表达）和摄取（FATP1 过表达）揭示了心脏脂质动态的性别特异性变化，影响心肌顺应性和目的是：1) 检查男性、女性和过度切除的女性、非转基因心脏中脂质利用/储存动态的性别和雌激素依赖性差异。 (NTG) 和 MHC-PPAR 低过表达（品系 404-4）小鼠；2) 通过确定 a) 脂质动态和对心肌 2-D 的影响，测试 LCFA 摄取、性别和雌激素如何影响压力超负荷反应b) 神经酰胺种类和鞘氨醇的产生以及对肌丝磷酸化、氧化和非转基因小鼠和过表达 FATP1 的转基因小鼠心脏中的 Ca 反应性；3) 确定 TAG 动态和 LCFA 氧化速率中基于性别的适应对压力超负荷的影响，以影响 a) 心肌 2-D 应变和硬度b) 通过 LCFA 衍生中间体、神经酰胺和磷酸化作用的肌小节活性鞘氨醇对 MHC-PPAR 心脏肌丝敏感性的影响 目的是阐明影响心脏功能的心脏脂质动态重编程机制，从而确定早期诊断策略和性别特异性治疗方案，以减轻心肌病的发展。