Ectonucleotidase modulation of age-dependent vascular calcification and stiffness

外切核苷酸酶调节年龄依赖性血管钙化和僵硬度

• 批准号: 10754825
• 负责人: Nadia Razaq Sutton
• 金额: $ 24.3万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10754825
• 关键词: ADP Receptors; ATP Receptors; Acceleration; Achievement; Adenosine; Age; Age Years; Aging; Aorta; Arteries; Atherosclerosis; Biological Process; Biology; Blood Vessels; Brain; Calcium; Cardiac; Cardiovascular Diseases; Cardiovascular system; Cell surface; Cells; Clinical; Coagulation Process; Collagen; Coronary artery; Cues; Data; Deposition; Development; Disease; Elasticity; Elastin; Elderly; Endothelial Cells; Environment; Enzymes; Exposure to; Extracellular Matrix; Fibrosis; Foundations; Future; Gene Expression; Healthcare; Heart; Human; Impairment; Inflammation; Inflammatory; Kidney; Knowledge; Leukocytes; Life; Longevity; Mediating; Metabolic; Mus; Organ; Osteogenesis; Pathologic; Patients; Phenotype; Physiologic Ossification; Physiologic pulse; Physiological; Population; Predisposition; Process; Production; Proteins; Proteomics; Pulse Pressure; Purinergic P1 Receptors; Research; Research Personnel; Risk Factors; Role; Signal Transduction; Smooth Muscle Myocytes; Stress; Stress Tests; Surface; Testing; Time; Vascular Diseases; Vascular Smooth Muscle; Vascular calcification; age related; aged; calcification; care burden; coronary artery calcification; demographics; ecto-nucleotidase; experimental study; extracellular; human tissue; indexing; inflammatory marker; insight; middle age; mouse model; osteogenic; paracrine; prevent; radiological imaging; stem; transcription factor; transmission process

Abstract With increasing age, blood vessels become stiffer and more calcified. In the latter years of the human lifespan, the process of vascular aging accelerates. The reason that blood vessels lose their youthful elasticity and ability to retard the deposition of calcium precipitously later in life is poorly understood. Ectonucleotidases are found on the surface of endothelial cells which line the inner surface of blood vessels, vascular smooth muscle cells, and leukocytes. The ectonucleotidase CD39 is responsible for cleaving ATP and ADP to form AMP, and subsequently, CD73 is responsible for generating adenosine from AMP. Since ATP and ADP are pro- inflammatory and act in a paracrine fashion, I hypothesize that ectonucleotidase activity plays a role in the vascular stiffness and calcification that occurs as a consequence of age. This is supported by my preliminary data in wild type (C57BL/6) mice, which demonstrates CD73 protein levels declined with age (up to 24 months) in the heart and kidney. This is also supported by preliminary data in mice and human tissues demonstrating that loss of CD73 expression promoted expression of the transcription factor Runx2, which is critical for osteogenesis. We hypothesize that loss of ectonucleotidase expression with age could have deleterious consequences on the vessel wall, resulting in an environment which promotes vascular calcification and stiffness. Since the role of ectonucleotidases in vascular aging is unknown, we will elucidate mechanisms which mediate age-dependent vascular calcification through the following aims. Aim 1: We will determine how age-dependent decline in vascular ectonucleotidase expression renders vessels susceptible to vascular calcification and fibrosis in a murine model. Aim 2: We will determine how ectonucleotidase activity mitigates arterial fibrosis and stiffness. Aim 3: We will determine if ectonucleotidase expression plays a role in age-driven human coronary artery calcification. Achievement of these aims will elucidate the role of ectonucleotidases in age-dependent vascular calcification and stiffness in mice and humans. The mechanistic insights obtained from these experiments will define my future investigative direction and serve as a foundation for a subsequent RO1 application as an independent investigator studying vascular biology and aging.

摘要 随着年龄的增长，血管变得更加僵硬和钙化。在人类寿命的最后几年， 血管老化的过程会加快。血管失去年轻弹性的原因是 人们对其在晚年突然延缓钙沉积的能力知之甚少。胞外核苷酸酶是 发现于排列在血管内表面的内皮细胞表面，血管平滑肌 细胞和白细胞。胞外核苷酸酶CD39负责裂解ATP和ADP形成AMP，以及 随后，CD73负责从AMP产生腺苷。由于ATP和ADP是亲- 炎症性和旁分泌方式，我假设ECN活性在 血管僵硬和钙化是年龄的结果。这得到了我初步的支持 野生型(C57BL/6)小鼠的数据显示，CD73蛋白水平随着年龄的增长而下降(长达24个月) 在心脏和肾脏。在小鼠和人体组织中显示的初步数据也支持这一点 CD73表达的丧失促进了转录因子Runx2的表达，Runx2是 成骨作用。我们假设，随着年龄的增长，ECN表达的丧失可能是有害的。 对血管壁的影响，导致环境促进血管钙化和 僵硬。由于胞外核苷酸酶在血管老化中的作用尚不清楚，我们将阐明其机制。 它通过以下目的来调节年龄相关的血管钙化。目标1：我们将确定如何 血管外膜核苷酸酶表达的增龄性下降使血管易患血管病变 小鼠模型中的钙化和纤维化。目标2：我们将确定ECN活性如何减轻 动脉纤维化和僵硬。目的3：我们将确定ECN的表达是否在年龄驱动中起作用 人体冠状动脉钙化。这些目标的实现将阐明外源核糖核酸酶在 小鼠和人的年龄依赖性血管钙化和僵硬。获得的机械洞察力 这些实验将明确我未来的研究方向，并为后续的研究奠定基础 RO1申请成为研究血管生物学和衰老的独立研究员。

项目成果

Challenges of the Transcatheter Approach to Mitral Valve Replacement in Women Contemplating Pregnancy.

打算怀孕的女性经导管二尖瓣置换术面临的挑战。

• DOI: 10.1161/circinterventions.120.010227
• 发表时间: 2020
• 期刊: Circulation. Cardiovascular interventions
• 作者: Warnes,CaroleA;Sutton,NadiaR
• 通讯作者: Sutton,NadiaR

Coronary Artery Disease Evaluation and Management Considerations for High Risk Occupations: Commercial Vehicle Drivers and Pilots.

高风险职业的冠状动脉疾病评估和管理注意事项：商用车辆驾驶员和飞行员。

• DOI: 10.1161/circinterventions.120.009950
• 发表时间: 2021
• 期刊: Circulation. Cardiovascular interventions
• 作者: Sutton,NadiaR;Banerjee,Shrilla;Cooper,MatthewM;Arbab-Zadeh,Armin;Kim,Judy;Arain,MansoorA;Rao,SunilV;Blumenthal,RogerS
• 通讯作者: Blumenthal,RogerS

Race, Ethnicity, and 60-Day Outcomes After Hospitalization With COVID-19.

• DOI: 10.1016/j.jamda.2021.08.023
• 发表时间: 2021-11
• 期刊: Journal of the American Medical Directors Association
• 影响因子: 7.6
• 作者: Robinson-Lane SG;Sutton NR;Chubb H;Yeow RY;Mazzara N;DeMarco K;Kim T;Chopra V
• 通讯作者: Chopra V

Sex-Related Differences in the Bleeding Trade-Off for Patients Undergoing Percutaneous Coronary Intervention.

接受经皮冠状动脉介入治疗的患者出血权衡中与性别相关的差异。

• DOI: 10.1161/circinterventions.121.011299
• 发表时间: 2021
• 期刊: Circulation. Cardiovascular interventions
• 作者: Sutton,NadiaR;Hughes,ErinnK
• 通讯作者: Hughes,ErinnK

Comparative Safety of Bioabsorbable Polymer Everolimus-Eluting, Durable Polymer Everolimus-Eluting, and Durable Polymer Zotarolimus-Eluting Stents in Contemporary Clinical Practice.

生物可吸收聚合物依维莫司洗脱支架、耐用聚合物依维莫司洗脱支架和耐用聚合物佐他莫司洗脱支架在当代临床实践中的安全性比较。

• DOI: 10.1161/circinterventions.120.009850
• 发表时间: 2021
• 期刊: Circulation. Cardiovascular interventions
• 作者: Sutton,NadiaR;Seth,Milan;Madder,RyanD;Sukul,Devraj;Dixon,SimonR;Cannon,LouisA;Gurm,HitinderS
• 通讯作者: Gurm,HitinderS