Vagus stimulation protects against cardiac diastolic dysfunction in aging mice

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更常见于老年人。心脏细胞外基质（ECM）重塑和纤维化随着年龄的增长而增加，导致心脏舒张性和舒张能力的降低。另一方面，副交感神经系统（PSNS）的活动随着年龄的增长而下降。在包括衰老在内的多种病理生理状态下，PSNS功能减弱通常与心功能障碍共存。我研究的一个长期目标是测试PSNS功能的增强是否在衰老过程中引起心脏保护作用。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可改善心脏功能，降低心脏胶原蛋白含量。本项目旨在进一步检验CLVNS是否能改善老年小鼠心室舒张功能障碍，减少心脏ECM重构。幼龄（2个月）、中期（10个月）和老年（20个月）小鼠分别接受CLVNS或假刺激治疗4周。左心室功能评估采用米勒压-容积导管。胶原蛋白的表达和积累以及基质金属蛋白酶（MMPs）的表达和活性将通过羟脯氨酸测定、RT-PCR、Western blot和酶谱分析来确定。预计CLVNS治疗将改善与老年小鼠心脏胶原含量降低和MMP活性增加相关的心室舒张功能障碍。此外，CLVNS治疗后，将从不同年龄组的小鼠中分离成纤维细胞，并评估胶原生成和MMP活性。预期结果将提示CLVNS减少老化心脏成纤维细胞的胶原积累并增加MMP活性。该项目将为我们进一步研究CLVNS在衰老过程中对心脏重构和功能障碍的保护机制提供坚实的初步数据和方法。本研究将对PSNS的心脏保护功能提供新的认识，为预防和治疗老年人心功能障碍提供新的途径。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）是否能改善老年小鼠心室舒张功能障碍，减少心脏重构。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，并为预防和治疗老年人心功能障碍提供新的途径。

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.