Vagus stimulation protects against cardiac diastolic dysfunction in aging mice

迷走神经刺激可预防衰老小鼠的心脏舒张功能障碍

• 批准号: 7571536
• 负责人: Yifan Li
• 金额: $ 5.88万
• 依托单位: UNIVERSITY OF SOUTH DAKOTA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7571536
• 关键词: Address; Age; Aging; Attenuated; Biological Assay; Cardiac; Catheters; Chronic; Collagen; Computer software; Data; Diastolic heart failure; Elderly; Extracellular Matrix; Fibrillar Collagen; Fibroblasts; Fibrosis; Functional disorder; Future; Goals; Grant; Hand; Heart; Heart Diseases; Heart failure; Homeostasis; Hydroxyproline; Incidence; Left; Left Ventricular Function; Link; Matrix Metalloproteinases; Methods; Modeling; Mus; Nerve; Output; Parasympathetic Nervous System; Population; Prevalence; Prevention; Production; Pump; Regulation; Relaxation; Research; Reverse Transcriptase Polymerase Chain Reaction; Signal Pathway; Signal Transduction; Solid; System; Testing; Therapeutic; Ventricular; Ventricular Remodeling; Western Blotting; age group; age related; aged; cholinergic; improved; insight; novel; pressure; prevent; protective effect; public health relevance; response; restoration; vagus nerve stimulation

DESCRIPTION (provided by applicant): Incidences of heart diseases are increased with age. Particularly, cardiac diastolic dysfunction and diastolic heart failure are more often found in the elderly. Cardiac extracellular matrix (ECM) remodeling and fibrosis are increased with age, resulting in a reduction of diastolic distensibility and relaxation capacity of the heart. On the other hand, the activity of parasympathetic nerve system (PSNS) is declined with age. The attenuated PSNS function commonly coexists with cardiac dysfunction in a variety of pathophysiological states, including aging. A long-term goal of my research is to test whether enhancement of PSNS function elicits a cardiac protective effect in aging. We have developed a model of chronic left vagus nerve stimulation (CLVNS) to increase PSNS output to the heart. Preliminary data suggest that CLVNS improved cardiac function and reduced collagen content in the heart. This project is to further test whether CLVNS can improve ventricular diastolic dysfunction and reduce cardiac ECM remodeling in aged mice. Young (2-month), middle (10-month), and old (20-month) mice will be treated with CLVNS or sham stimulation for 4 weeks. Left ventricular function will be assessed using Millar Pressure-Volume catheter. The expression and accumulation of collagens, and the expression and activity of matrix metalloproteinase (MMPs) will be determined using hydroxyproline assay, RT-PCR, Western blot, and zymography. It is expected that treatment with CLVNS will improve ventricular diastolic dysfunction that is associated with reduced collagen content and increased MMP activity in the heart in aged mice. In addition, fibroblasts will be isolated from the mice of different age groups after CLVNS treatments and collagen production and MMP activity will be assessed. The expected results will suggest that CLVNS reduces collagen accumulation and increase MMP activity in the fibroblasts from the aged hearts. This project will provide solid preliminary data and methods for us to develop an extensive project to further elucidate the mechanism by which CLVNS protects against cardiac remodeling and dysfunction in aging. The overall study will provide novel insight into the PSNS cardiac protective function and suggest a new avenue to prevent and trea cardiac dysfunction in the elderly. PUBLIC HEALTH RELEVANCE: Incidences of heart diseases are increased with age and cardiac diastolic dysfunction and diastolic heart failure are more often found in the elderly. This study is to investigate whether chronic left vagus nerve stimulation (CLVNS) can improve ventricular diastolic dysfunction and reduce cardiac remodeling in aged mice. The expected results of this and the future studies will provide novel insight into the PSNS cardiac protective function and suggest a new avenue to prevent and treat cardiac dysfunction in the elderly.

描述（由申请人提供）：心脏病的发病率随着年龄的增长而增加。特别是，心脏舒张功能障碍和舒张性心力衰竭在老年人中更为常见。心脏细胞外基质（ECM）重塑和纤维化随着年龄的增长而增加，导致心脏舒张扩张和舒张能力降低。另一方面，副交感神经系统（PSNS）的活性随着年龄的增长而下降。 PSNS 功能减弱通常与各种病理生理状态（包括衰老）中的心脏功能障碍共存。我研究的一个长期目标是测试 PSNS 功能的增强是否会在衰老过程中产生心脏保护作用。我们开发了一种慢性左迷走神经刺激 (CLVNS) 模型，以增加 PSNS 向心脏的输出。初步数据表明，CLVNS 可以改善心脏功能并减少心脏中的胶原蛋白含量。本项目旨在进一步测试CLVNS是否可以改善老年小鼠的心室舒张功能障碍并减少心脏ECM重塑。年轻（2个月）、中型（10个月）和老年（20个月）小鼠将接受CLVNS或假刺激治疗4周。将使用 Millar 压力-容量导管评估左心室功能。胶原蛋白的表达和积累，以及基质金属蛋白酶（MMP）的表达和活性将使用羟脯氨酸测定、RT-PCR、蛋白质印迹和酶谱法测定。预计 CLVNS 治疗将改善老年小鼠心室舒张功能障碍，该功能障碍与心脏胶原蛋白含量减少和 MMP 活性增加有关。此外，在CLVNS治疗后，将从不同年龄组的小鼠中分离成纤维细胞，并评估胶原蛋白的产生和MMP活性。预期结果表明，CLVNS 会减少衰老心脏成纤维细胞中胶原蛋白的积累并增加 MMP 活性。该项目将为我们开发一个广泛的项目提供可靠的初步数据和方法，以进一步阐明 CLVNS 预防心脏重塑和衰老功能障碍的机制。总体研究将为 PSNS 心脏保护功能提供新的见解，并提出预防和治疗老年人心功能障碍的新途径。公共卫生相关性：心脏病的发病率随着年龄的增长而增加，心脏舒张功能障碍和舒张性心力衰竭更常见于老年人。本研究旨在探讨慢性左迷走神经刺激（CLVNS）是否可以改善老年小鼠的心室舒张功能障碍并减少心脏重塑。本研究和未来研究的预期结果将为 PSNS 心脏保护功能提供新的见解，并提出预防和治疗老年人心功能障碍的新途径。