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）：随着年龄的增长，心脏病的发生率会增加。特别是，在老年人中经常发现心脏舒张功能障碍和舒张期心力衰竭。心脏外基质（ECM）重塑和纤维化随着年龄的增长而增加，导致心脏舒张性舒张性和松弛能力的降低。另一方面，副交感神经系统（PSN）的活性随着年龄的增长而降低。衰减的PSN功能通常在包括衰老在内的多种病理生理状态下与心脏功能障碍共存。我的研究的长期目标是测试PSN功能的增强是否在衰老中产生心脏保护作用。我们已经开发了一种慢性左迷走神经刺激（CLVN）的模型，以增加对心脏的PSN输出。初步数据表明，CLVNS改善了心脏功能并减少心脏的胶原蛋白含量。该项目是为了进一步测试CLVN是否可以改善心室舒张功能障碍并减少老年小鼠的心脏ECM重塑。年轻（2个月），中（10个月）和旧（20个月）小鼠将用CLVN或假刺激治疗4周。左心室功能将使用Millar压力卷导管进行评估。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基磷酸化测定，RT-PCR，Western blot和Zymography确定。预计用CLVN的治疗将改善与胶原蛋白含量降低和老年小鼠心脏中MMP活性增加有关的心室舒张功能障碍。此外，将评估CLVN治疗和胶原蛋白产生和MMP活性后，将从不同年龄组的小鼠中分离成纤维细胞。预期的结果将表明，CLVN会减少胶原蛋白的积累并增加来自老年心脏的成纤维细胞中的MMP活性。该项目将为我们开发一个广泛的项目提供坚实的初步数据和方法，以进一步阐明CLVNS保护衰老中心脏重塑和功能障碍的机制。整个研究将提供对PSNS心脏保护功能的新见解，并提出一种新的途径，以预防和trea心脏功能障碍。公共卫生相关性：随着年龄的增长和心脏舒张功能障碍和舒张期心力衰竭，心脏病的发病率更高。这项研究是为了研究慢性左迷走神经刺激（CLVN）是否可以改善心室舒张功能障碍并减少老年小鼠的心脏重塑。该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，并提出了一种新的途径，以预防和治疗老年人的心脏功能障碍。