SIRT6 and vascular endothelial homeostasis

SIRT6 与血管内皮稳态

• 批准号: 10529926
• 负责人: ZHENG-GEN JIN
• 金额: $ 56.44万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10529926
• 关键词: Adipose tissue; Atherosclerosis; Blood Circulation; Blood Vessels; CD36 gene; Cardiac; Cardiovascular Diseases; Cardiovascular system; Cells; Chronic; Coronary; Coronary Vessels; DNA Repair; Development; Diabetes Mellitus; Disease; EFRAC; Endothelial Cells; Endothelium; Energy Metabolism; Epidemic; Epigenetic Process; Failure; Family; Fatty Acids; Functional disorder; Gene Expression Regulation; Genes; Genetic Transcription; Genome; Genome Stability; Goals; HDAC4 gene; Heart; Heart Hypertrophy; Heart failure; High Prevalence; Histone Acetylation; Histone Deacetylase; Homeostasis; Human; In Vitro; Inflammation; Knock-out; Left; Link; Lipids; Lysine; Mediator of activation protein; Metabolic; Metabolic Diseases; Metabolic syndrome; Molecular; Morbidity - disease rate; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Organ; PPAR gamma; Pathogenesis; Pathway interactions; Patients; Persons; Pharmacology; Phenotype; Play; Predisposition; Prevalence; Regulation; Reporting; Risk Factors; Role; Sampling; Sirtuins; Stress; Testing; Tissues; Transcriptional Regulation; Transgenic Mice; Transportation; United States; Vascular Endothelium; Ventricular; blood glucose regulation; diabetic; effective therapy; endothelial dysfunction; energy balance; epigenetic marker; experimental study; fatty acid transport; fighting; in vivo; lipid metabolism; lipid transport; longevity gene; loss of function; mortality; mouse model; neglect; non-diabetic; novel; novel therapeutic intervention; overexpression; pre-clinical; preservation; public health relevance; resistance gene; therapeutic candidate; treatment strategy; uptake

The major goal of the project is to elucidate the molecular mechanisms underlying cardiac microvascular fatty acid transport dysfunctions and its involvement in heart failure with preserved ejection fraction (HFpEF) under diabetic conditions. Diabetes mellitus, one of the major leading chronic morbidities worldwide, is continually increasing with a high prevalence in the United States and throughout the world. Cardiovascular complications are mainly responsible for the high morbidity and mortality in people with diabetes. Type 2 diabetes (T2D) is one of key risk factors for the development of HFpEF, and the prevalence of HFpEF is rising in parallel with global surging of T2D. However, the molecular mechanisms linking diabetes to HFpEF are poorly understood, and currently there are no effective treatments available for HFpEF. Endothelium, a cell layer lining of blood vessels, is an independent organ that functions as a barrier for the nutrient shuttling. The neglected role of endothelium in controlling the metabolic homeostasis is beginning to evolve. However, the role of coronary microvascular endothelial fatty acid shuttling in diabetic heart and the underlying molecular mechanisms remain elusive. Sirtuin 6 (SIRT6), a well-recognized longevity gene, regulates genome stabilization, DNA repair, inflammation and metabolic homoeostasis. SIRT6 is a histone deacetylase that targets the acetylation of histone 3 lysine 9, an epigenetic marker for active gene transcription. Recent studies indicate that SIRT6 deficiency is associated with metabolic disease, and SIRT6 has been proposed as a potential therapeutic candidate fighting the metabolic syndrome epidemic. In parallel, emerging evidence from our group suggests that SIRT6 plays a crucial role in regulation of cardiac endothelial homeostasis. Specifically, we have recently found that SIRT6 modulates coronary microvascular endothelial fatty acid transport and cardiac lipid metabolism under the nondiabetic and diabetic conditions, which is implicated in the pathogenesis of T2D-induced HFpEF. As such we propose that an alternation of SIRT6 expression and function in coronary microvascular endothelial cells under diabetic conditions could cause cardiac microvascular endothelial fatty acid transport abnormality and cardiac metabolic disarrangement, which may cause diabetes-associated diastolic dysfunction. We will use the combination of in vitro and in vivo experiments to test this novel hypothesis. Results from proposed studies would help to understand molecular basis of endothelial FA transport, and facilitate the development of new therapeutic approaches, such as enhancing SIRT6 expression and activity, to limit diabetes-associated HFpEF, a deadly disease without any effective therapy.

该项目的主要目标是阐明心脏微血管脂肪的分子机制。 酸转运功能障碍及其在射血分数保留心力衰竭中的作用 糖尿病的情况。糖尿病是世界范围内主要的慢性疾病之一，它不断地 在美国和全世界都有很高的流行率。心血管并发症 是糖尿病患者高发病率和高死亡率的主要原因。2型糖尿病(T2D)是一种 HFpEF发展的关键风险因素，并且HFpEF的患病率与全球同步上升 T2D的涌动。然而，将糖尿病与HFpEF联系起来的分子机制却知之甚少。 目前还没有有效的治疗HFpEF的方法。内皮，血管的细胞层， 是一个独立的器官，起着营养物质穿梭的屏障的作用。血管内皮细胞被忽视的作用 在控制新陈代谢方面，动态平衡开始演变。然而，冠状动脉微血管的作用 内皮脂肪酸在糖尿病心脏中的穿梭和潜在的分子机制仍然难以捉摸。先生们 6(SIRT6)，一个公认的长寿基因，调节基因组稳定，DNA修复，炎症和 代谢动态平衡。SIRT6是一种组蛋白脱乙酰酶，其靶向是组蛋白3赖氨酸9的乙酰化，以及 激活基因转录的表观遗传标记。最近的研究表明，SIRT6缺乏与 代谢性疾病，SIRT6已被认为是对抗代谢疾病的潜在候选治疗药物 综合症流行。同时，来自我们小组的新证据表明，SIRT6在 心脏内皮细胞内稳态的调节。具体地说，我们最近发现SIRT6调节 非糖尿病和非糖尿病患者冠脉微血管内皮细胞脂肪酸转运和心脏脂质代谢 糖尿病状态，这与T2D诱导的HFpEF的发病机制有关。因此，我们建议一个 糖尿病时冠状动脉微血管内皮细胞SIRT6表达和功能的变化 条件可导致心脏微血管内皮细胞脂肪酸运输异常和心脏代谢 排列紊乱，这可能导致糖尿病相关的舒张期功能障碍。我们将使用中的组合 体外和体内实验来验证这一新的假设。拟议研究的结果将有助于 了解内皮FA转运的分子基础，促进新疗法的开发 一些方法，如增强SIRT6的表达和活性，以限制糖尿病相关的HFpEF，这是一种致命的 没有任何有效治疗的疾病。