Effects of Aging on Experimental Atherosclerosis in Nonhuman Primates

衰老对非人灵长类动物实验性动脉粥样硬化的影响

• 批准号: 7732169
• 负责人: Edward Lakatta
• 金额: $ 21.26万
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7732169
• 关键词: Age; Aging; Arterial Fatty Streak; Atherogenic Diet; Atherosclerosis; Biochemical Markers; Blood; Blood Chemical Analysis; Blood Pressure; Blood Vessels; Body Weight; CCL2 gene; Carotid Arteries; Cholesterol; Collection; Coronary; Data; Deposition; Development; Diet; Elderly; Fatty acid glycerol esters; Gene Proteins; Genetic Transcription; Glucose; HDL-triglyceride; Harvest; Hip region structure; In Vitro; Left; Link; Low-Density Lipoproteins; Magnetic Resonance Imaging; Matrix Metalloproteinases; Measurement; Measures; Medial; Molecular; Monkeys; Physiologic pulse; Plasma; Pulse taking; Smooth Muscle Myocytes; Temperature; Thick; Thoracic aorta; Tissues; Translations; Ultrasonography; Upper arm; Vascular remodeling; age effect; age related; ascending aorta; atherogenesis; cysteine rich protein; feeding; human TGFB1 protein; left coronary artery; nonhuman primate; noninvasive diagnosis; oxidized low density lipoprotein; protein expression; rectal; tonometry

We had quarterly measured over two year period: blood pressure via arm cuff, body weight, rectal temperature, and morphometric measurements including waist and hip circumferences, and blood pressure. Following collection of baseline data, 16 monkeys had been assigned to an atherogenic diet and 7 monkeys to a control diet. We have obtained measures of vascular stiffness: Doppler pulse wave velocity and applanation tonometry; morphologic characterization of atherosclerosis: CE-MRI; and blood chemistry measures: Glucose, cholesterol, triglycerides, HDL, LDL, ox-LDL, CRP, MMPs, TIMPs, MTMMPs, MCP-1, TGF-beta1. After sacrifice, we harvested arterial tissue, including aorta: ascending and descending thoracic, aorta arches; carotid arteries: right and left; coronary arteries: left descending coronary, right coronary. These tissues will be analyzed in the levels of transcription, translation, distribution for the previously mentioned biomolecules. In addition, we have isolated arterial endothelial and smooth muscle cells from these monkeys for in vitro studies. Results shows that pulse wave velocity (PWV) determined by ultrasound examination, and the intimal and medial thickness (IMT) determined by MRI, dynamically increased in monkeys with advancing age and high cholesterol diets. Histochemical observation and morphological analysis indicate that age increases intimal thickness and medial thickness along with atherosclerotic lesions in these domestic monkeys fed normal diets. Interestingly, age effects fat deposition within arterial walls in these domestic monkeys with high cholesterol diets. We will further define the molecular and cellular mechanisms of atherogenesis during aging via combinational analysis of parameters from blood biochemistryl, echo, MRI, histopathological, and gene and protein expression of the aforementioned molecules.

我们在两年内每季度测量一次：通过臂袖测量血压、体重、直肠温度和形态测量，包括腰围和臀围以及血压。在收集基线数据后，16只猴子被分配给致动脉粥样硬化饮食，7只猴子被分配给对照饮食。 我们已经获得了血管硬度的测量：多普勒脉搏波速度和压平张力测量;动脉粥样硬化的形态学表征：CE-MRI;和血液化学测量：葡萄糖、胆固醇、甘油三酯、HDL、LDL、ox-LDL、CRP、MMPs、TIMPs、MTMMPs、MCP-1、TGF-β 1。 处死后，我们采集动脉组织，包括主动脉：胸升动脉和胸降动脉、主动脉弓;颈动脉：右侧和左侧;冠状动脉：左冠状动脉降支、右冠状动脉。这些组织将在转录、翻译、分布水平上分析先前提到的生物分子。 此外，我们已经从这些猴子中分离出动脉内皮细胞和平滑肌细胞用于体外研究。 结果表明，脉搏波速度（PWV）确定的超声检查，和内膜和中膜厚度（IMT）确定的MRI，动态增加的猴子随着年龄的增长和高胆固醇饮食。 组织化学观察和形态学分析表明，年龄增加内膜厚度和中膜厚度沿着与动脉粥样硬化病变在这些家庭饲养正常饮食的猴子。有趣的是，年龄影响这些高胆固醇饮食的家猴动脉壁内的脂肪沉积。我们将通过对上述分子的血液生化、回声、MRI、组织病理学以及基因和蛋白表达等参数的综合分析，进一步确定衰老过程中动脉粥样硬化形成的分子和细胞机制。