The Role of Arylsulfatase in Vascular Calcification

芳基硫酸酯酶在血管钙化中的作用

• 批准号: 10658067
• 负责人: PAUL STEFAN DE VRIES
• 金额: $ 70.92万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10658067
• 关键词: Affect; African American; Agatston Score; Aorta; Arteries; Arylsulfatases; Atherosclerosis; Autophagocytosis; Biological; Biological Assay; Blood Vessels; Bone Morphogenetic Proteins; Calcium; Cardiovascular Diseases; Cells; Clinical; Cohort Studies; Coronary; Coronary Arteriosclerosis; Coronary artery; Data; Deposition; Development; Disease; Electronic Health Record; Esters; Event; Extracellular Matrix; Family; Genetic; Genetic Determinism; Genetic Polymorphism; Homologous Gene; Human; Human Genetics; Human Genome; In Vitro; Individual; Link; Measures; Mediating; Messenger RNA; Molecular; Morbidity - disease rate; Mus; Myocardial Infarction; Outcome; Participant; Pathway interactions; Peripheral arterial disease; Phenotype; Play; Prevention; Protein Family; Proteins; Risk; Risk Factors; Role; Series; Signal Pathway; Signaling Protein; Single Nucleotide Polymorphism; Smooth Muscle Myocytes; Stroke; Sulfatases; Sulfate; Testing; Thoracic aorta; Tissues; Trans-Omics for Precision Medicine; Variant; Vascular Diseases; Vascular Smooth Muscle; Vascular calcification; X Chromosome; abdominal aorta; aortic valve; biobank; calcification; calcium phosphate; cardiovascular disorder risk; cardiovascular risk factor; coronary artery calcification; coronary artery calcium; density; experimental study; genetic analysis; genetic association; genetic variant; genome wide association study; genomic locus; high risk; improved; in vitro Model; in vivo; in vivo Model; indexing; insight; member; mortality; mouse model; novel; osteogenic; overexpression; prevent; success; transcription factor

Project Summary Vascular calcification is a hallmark of atherosclerotic cardiovascular diseases such as myocardial infarction and stroke, which are the leading causes of morbidity and mortality in the world. Although coronary artery calcification (CAC) is a strong independent risk factor for cardiovascular disease, the genetic determinants of CAC and the molecular mechanisms of vascular calcification remain incompletely elucidated. In a multi-cohort study with more than 22,000 participants, we identified single nucleotide polymorphisms in the arylsulfatase E (ARSE) locus that are associated with coronary artery calcification. In an in vitro model of calcification, our preliminary experiments demonstrated that inhibition of ARSE or a related protein sulfatase 1 (SULF1) prevented the calcification of coronary and aortic vascular smooth muscle cells (VSMCs). Furthermore, we found that SULF1-deficient mice are protected from developing vascular calcification. Based on our preliminary evidence, combining a human genome-wide association study, in vitro VSMC experiments, and an in vivo murine model of vascular calcification, we have identified ARSE and SULF1 to be novel activators of vascular calcification. The overall objective of this proposal is to understand the molecular mechanisms by which these sulfatases promote vascular calcification and atherosclerosis. First, using a series of VSMC functional assays, we propose to determine the specific role of ARSE and SULF1 in promoting VSMC osteogenic phenotype switch and calcification. We will also ascertain whether the sulfatases induce the development of vascular calcification and atherosclerosis in vivo using mouse models. Second, we have uncovered an important role for ARSE and SULF1 in regulating autophagy and bone morphogenetic protein (BMP) signaling. We will determine if the effects of ARSE and SULF1 on VSMC-mediated vascular calcification is dependent on their effects on autophagy and/or BMP signaling. Lastly, we will examine the associations of the ARSE index variant with a range of electronic health record phenotypes, as well as with additional vascular calcification phenotypes including aortic calcium volume and density, aortic valve calcification and mitral annular calcification. Furthermore, we will conduct the first genome-wide association study to identify novel genetic determinants of coronary calcification density. The experiments proposed will provide important mechanistic insights into the function of sulfatases in the vasculature and into the underlying molecular and genetic mechanisms of vascular calcification and atherosclerosis.

项目摘要 血管钙化是心肌梗死等动脉粥样硬化性心血管疾病的标志 和中风，它们是世界上发病率和死亡率的主要原因。虽然冠状动脉 钙化（CAC）是心血管疾病的一个强有力的独立危险因素， CAC和血管钙化的分子机制仍不完全阐明。在多队列中 我们对超过22，000名参与者进行了一项研究，发现了芳基硫酸酯酶E的单核苷酸多态性 （ARSE）位点与冠状动脉钙化相关。在体外钙化模型中，我们 初步实验表明，抑制ARSE或相关蛋白硫酸酯酶1（SULF 1）， 防止冠状动脉和主动脉血管平滑肌细胞（VSMC）钙化。而且我们 发现SULF 1缺陷小鼠不会发生血管钙化。根据我们初步的 证据，结合人类全基因组关联研究，体外VSMC实验和体内 在小鼠血管钙化模型中，我们已经鉴定了ARSE和SULF 1是血管钙化的新激活剂， 钙化这项建议的总体目标是了解这些分子机制， 硫酸酯酶促进血管钙化和动脉粥样硬化。首先，使用一系列VSMC功能测定， 我们建议确定ARSE和SULF 1在促进VSMC成骨表型中的特定作用， 转换和钙化。我们还将确定硫酸酯酶是否诱导血管的发展， 钙化和动脉粥样硬化。其次，我们发现了一个重要的作用， ARSE和SULF 1在调节自噬和骨形态发生蛋白（BMP）信号传导中的作用。我们将 确定ARSE和SULF 1对VSMC介导的血管钙化的影响是否依赖于它们的 对自噬和/或BMP信号传导的影响。最后，我们将检查ARSE索引变量的关联 具有一系列电子健康记录表型，以及额外的血管钙化 表型包括主动脉钙体积和密度、主动脉瓣钙化和二尖瓣环钙化 钙化此外，我们将进行第一次全基因组关联研究，以确定新的遗传 冠状动脉钙化密度的决定因素。提出的实验将提供重要的机理 深入了解硫酸酯酶在血管系统中的功能，以及潜在的分子和遗传学 血管钙化和动脉粥样硬化的机制。