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: 8775693
• 负责人: E DOUGLAS LEWANDOWSKI
• 金额: $ 53.83万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 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 2015-12-10
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8775693
• 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; Fatty acid glycerol esters; Female; Fiber; Gender; Gender Role; Genetic; Health; Heart; Heart Hypertrophy; Heart failure; 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; Sex Characteristics; Signal Transduction; Skin; Sphingosine; Stress; Testing; Therapeutic; Time; Tissues; Transgenic Mice; Treatment Protocols; Ventricular; base; fatty acid metabolism; fatty acid oxidation; 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（应用程序提供）：尽管没有继承肌细胞收缩力差异，但性别影响心力衰竭的发病机理。人类和动物在病理生理压力期间都表现出脂质动力学的性别差异。然而，性别的作用是改变心脏脂质的改变，在心脏代偿发病中的作用在很大程度上尚不清楚。这项研究的重点是性别，饮食脂肪和压力超负荷的压力所引起的机制，这改变了线粒体氧化与长链脂肪酸（LCFA）的细胞储存之间的平衡，以影响肌丝生物化学和活性。我们将检查性别和雌激素对响应压力超负荷的心脏脂质动力学重塑的影响，重点是心脏功能的主动和被动成分；由于代谢信号传导，活性成分是肉瘤蛋白质内的生化变化，并且被动成分是由于脂质浸润而引起的心肌刚度。初步数据表明脂质积累会产生心肌僵硬，并且性别会影响心脏脂质动力学和酰基衍生物。我们报道了降低的三酰甘油三酸酯（TAG）周转率以及TAG对肥大心脏中线粒体氧化的贡献，发现酰基衍生物会影响肌丝磷酸化和对Ca2+的敏感性。 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表达）和摄取（FATP1过表达）揭示了心脏脂质动力学的性别特异性变化，从而影响心肌依从性和肌节活动。目的是：1）检查男性，女性和过度切除的女性，非转基因（NTG）和MHC-Pppar的脂质利用/储存动力学的性别和雌激素依赖性差异； 2）测试LCFA的吸收，性别和雌激素如何通过确定a）脂质动态和后果影响对压力过载的反应，对心肌2-D菌株，组织僵硬和收缩性以及脊酰胺物种以及脊辛生物的产生以及对肌丝磷酸化，氧化和ca-氧化度的影响，并将其产生的后果产生，氧化和ca）的产生，氧化和ca-氧化不良，并在氧化，氧化性，氧化度和转移性中，并呈现出良好的并呈现的效果。 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.这些目标是阐明影响心脏功能的心脏脂质动力学的机制，从而确定了早期诊断和性别特定治疗方案的策略，以减轻心肌病的发展。