Sphingolipids in Diabetic Cardiomyopathy

糖尿病心肌病中的鞘脂

• 批准号: 8914028
• 负责人: Lauren Ashley Cowart
• 金额: $ 36.81万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-18 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8914028
• 关键词: Acids; Address; Affect; American; Anabolism; Apoptosis; Attenuated; Autophagocytosis; Biochemical; Biochemistry; Biology; Cardiac; Cardiac Myocytes; Cardiology; Cardiomyopathies; Catheterization; Cell Nucleus; Cell physiology; Cells; Ceramides; Characteristics; Clinical; Complement; Data; Diabetes Mellitus; Diet; Disease; Echocardiography; Enzymes; Fatty Acids; Functional disorder; Generations; Geometry; Goals; Health; Heart; Heart failure; Hypertrophy; Individual; Injury; Insulin Resistance; Left Ventricular Hypertrophy; Light; Lipids; Measures; Mediating; Mediator of activation protein; Metabolic; Metabolic Pathway; Metabolism; Mitochondria; Modeling; Molecular; Mus; Myocardial dysfunction; Myocardium; Nature; Nuclear; Obesity; Outcome; Pathway interactions; Plasma; Play; Process; Protein Isoforms; Publications; Publishing; Regulation; Risk Factors; Role; Scheme; Signal Transduction; Sphingolipids; Testing; Tissues; Toxic effect; Up-Regulation; Work; base; diabetic; diabetic cardiomyopathy; dihydroceramide desaturase; enzyme pathway; feeding; heart disease risk; high risk; improved; in vivo; insight; lipid metabolism; mitochondrial dysfunction; novel; prevent; response; saturated fat; translational approach

DESCRIPTION (provided by applicant):: Diabetics are at increased risk of heart disease from several factors including geometric and functional changes that occur independently of other risk factor; this is termed 'diabetic cardiomyopathy'. Mechanisms of this disease are not completely understood, but data increasingly support the notion that aberrant lipid metabolism contributes to this disease process. Among these metabolic changes are perturbations in sphingolipid synthesis; others and we have shown that blocking sphingolipid synthesis ameliorates many facets of diabetic cardiomyopathy. Sphingolipid metabolism comprises numerous enzymes, pathways, and products; teasing apart specific sphingolipids that mediate a specific process has proven challenging. Moreover, mechanisms by which these processes occur have been difficult to determine. We recently published that a specific enzyme of sphingolipid synthesis, Ceramide Synthase 5 (CerS5), mediated lipid- induced cardiomyocyte hypertrophy and autophagy. In a high saturated-fat feeding model in mice, which caused insulin resistance and obesity, sphingolipid biosynthesis was perturbed in heart. We observed sphingolipid-dependent cell hypertrophy, autophagy, and most importantly, cardiac dysfunction. New preliminary data implicate sphingolipids in mitochondrial damage and mitophagy, and also shed light on molecular mechanisms by which CerS5 causes autophagy. We have observed 1-nuclear accumulation of CerS5 and its product C14-ceramide, 2-CerS5-dependent accumulation of p53 in the nucleus, and 3- sphingolipid-dependent loss of mitochondrial reserve, and increase in mitophagy. Here we propose to dissect mechanisms for DbCM based on these initial findings, and using a combination of strategies including in vivo determinations o diastolic dysfunction in mice lacking CerS5, components of the mitophagy pathway, components of the macroautophagy pathway. As evidenced by our recent publications (Russo et al. 2012, J. Clin. Invest.; Russo et al 2013, J. Biol. Chem.), we are highly suited to address these questions that lie at the interface of sphingolipid biochemistry and cardiology. To facilitat this highly translational work we have enlisted cardiology and metabolism experts to complement our expertise in sphingolipid biochemistry, signaling, and analysis. These studies will reveal roles of these cell processes in diabetic cardiomyopathy, address the controversy surrounding the nature of autophagy in cardiac injury, specifically whether it is adaptive or deleterious, provide insights into sphingolipid-dependent mitochondrial dysfunction, which is especially important in the diabetic context, and finally reveal cell, biochemical, and molecular mechanisms of sphingolipid-dependent lipotoxicity in the heart.

描述（由申请人提供）：：糖尿病患者因几种因素而患心脏病的风险增加，包括独立于其他风险因素的几何和功能变化；这被称为“糖尿病性心肌病”。这种疾病的机制尚不完全清楚，但越来越多的数据支持异常脂质代谢有助于这种疾病过程的观点。这些代谢变化包括鞘脂合成的紊乱；其他人和我们已经表明，阻断鞘脂合成可以改善糖尿病心肌病的许多方面。鞘脂代谢包括许多酶、途径和产物；事实证明，分离介导特定过程的特定鞘脂具有挑战性。此外，这些过程发生的机制一直难以确定。我们最近发表了鞘脂合成的一种特殊酶，神经酰胺合成酶5 (CerS5)，介导脂质诱导的心肌细胞肥大和自噬。在小鼠高饱和脂肪喂养模型中，引起胰岛素抵抗和肥胖，心脏鞘脂生物合成受到干扰。我们观察到鞘脂依赖性细胞肥大，自噬，最重要的是，心功能障碍。新的初步数据提示鞘脂参与线粒体损伤和线粒体自噬，并揭示了CerS5引起自噬的分子机制。我们观察到1- CerS5及其产物c14 -神经酰胺在细胞核内积累，2-CerS5依赖于p53在细胞核内积累，3-鞘脂依赖于线粒体储备丧失，线粒体自噬增加。在此，我们建议基于这些初步发现来分析DbCM的机制，并结合多种策略，包括缺乏CerS5的小鼠舒张功能障碍的体内测定，线粒体自噬途径的成分，巨噬途径的成分。正如我们最近的出版物(Russo et al. 2012， J. clinin；投资。Russo et al . 2013, [j]。化学)，我们非常适合解决这些位于神经脂生物化学和心脏病学界面的问题。为了促进这项高度转化的工作，我们招募了心脏病学和代谢专家来补充我们在鞘脂生物化学，信号传导和分析方面的专业知识。这些研究将揭示这些细胞过程在糖尿病心肌病中的作用，解决围绕心脏损伤中自噬性质的争议，特别是它是适应性的还是有害的，提供对鞘脂依赖性线粒体功能障碍的见解，这在糖尿病背景下尤为重要，并最终揭示鞘脂依赖性心脏脂肪毒性的细胞，生化和分子机制。