Enhancer of zeste homolog 2-mediated epigenetic activation of acid sphingomyelinase in endothelial dysfunction during obesity

肥胖期间内皮功能障碍中 zeste 同源物 2 介导的酸性鞘磷脂酶表观遗传激活的增强剂

• 批准号: 10443790
• 负责人: Xiang Li
• 金额: $ 44.71万
• 依托单位: UNIVERSITY OF HOUSTON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10443790
• 关键词: 7-ketocholesterol; Abbreviations; Adhesions; Applications Grants; Arteries; Atherosclerosis; Blood Vessels; CASP1 gene; Cardiovascular system; Carotid Arteries; Cell membrane; Cells; Ceramide Signaling Pathway; Ceramides; DNA; DNA Methylation; DNA Modification Methylases; Defect; Development; Diabetes Mellitus; Endothelial Cells; Endothelium; Enhancers; Enzymes; Epigenetic Process; Gene Expression; Genes; High Fat Diet; Homologous Gene; Human; Hydrolysis; Hyperlipidemia; Hypertension; Immunohistochemistry; Impairment; Inflammasome; Inflammatory Response; Injury; Interleukin-1 beta; Interleukin-18; Knock-out; Knockout Mice; Lead; Lesion; Mediating; Membrane; Metabolic; Metabolism; Molecular; Morbidity - disease rate; Mus; Nonesterified Fatty Acids; Nucleotides; Obesity; Oxidation-Reduction; Palmitates; Pathogenesis; Pathologic; Pathway interactions; Patients; Pattern; Phenotype; Prevention; Production; Proteins; Reactive Oxygen Species; Regulation; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Smooth Muscle; Smooth Muscle Myocytes; Sphingolipids; Sphingomyelins; Testing; Time; Transcriptional Regulation; Umbilical vein; Vascular Diseases; Vasodilation; acid sphingomyelinase; arterial stiffness; base; cardiovascular risk factor; endothelial dysfunction; endothelial stem cell; epigenetic regulation; histone methylation; histone methyltransferase; insight; marenostrin; monocyte; mortality; novel; obesity development; receptor; therapeutic target; treatment strategy; vascular injury

Project Summary Endothelial dysfunction is an early defect in obesity, which is a major contributor to increased cardiovascular morbidity and mortality such as arterial stiffness, atherosclerosis, and hypertension. Recent studies have demonstrated a critical role of acid sphingomyelinase (ASM)-ceramide signaling in instigation of Nlrp3 inflammasomes and endothelial dysfunction during obesity and diabetes. The present proposal seeks to explore a novel mechanism mediating transcriptional control of ASM gene expression in ECs and determine how dysregulated ASM expression and activity promote vascular injury in obesity. Enhancer of zeste homolog 2 (Ezh2) is a histone methyltransferase that normally suppresses methylated genes, serving as a crucial epigenetic regulatory mechanism in gene expression. In preliminary studies, we found that loss of Ezh2 function increased ASM expression and ceramide levels in the intima leading to neointimal lesions in the carotid arteries of mice fed high fat diet (HFD). Such Ezh2-mediated suppression of ASM gene expression and ceramide signaling were also confirmed in cultured ECs. Based on these observations, we propose a hypothesis that loss of endothelial Ezh2 function upregulates ASM gene expression and augments ceramide production under hyperlipidemic conditions, which trigger Nlrp3 inflammasome activation and produce endothelial injury resulting in subsequent neointimal lesions on the carotid arterial wall. To test this hypothesis, the following Specific Aims are proposed. Specific Aim 1 will determine whether endothelial ASM activation due to loss of Ezh2 function contributes to endothelial dysfunction or injury at the early stage of obesity using endothelium-specific Ezh2 knockout mice (Ezh2ecKO) and their wild type littermates. Specific Aim 2 attempts to test how Ezh2-regulated ASM activation leads to endothelial dysfunction or injury by studying the role of ceramide and ceramide-enriched membrane rafts, Nlrp3 inflammasome activation, pyroptosis, endothelium- dependent vasodilation, inter-endothelial junction disruption, and adaptive endothelial progenitor cell landing or differentiation. In Specific Aim 3, we will explore the molecular mechanisms by which loss of Ezh2 function activates ASM with a main focus on the roles of histone and DNA methylation in cultured ECs from Ezh2ecKO mice and their wild type littermates. The findings will provide new insights into the pathogenesis of endothelial dysfunction and identify Ezh2-ASM pathway as therapeutic target for prevention or treatment of vaculopathy associated with obesity.

项目总结