Vagus stimulation protects against cardiac diastolic dysfunction in aging mice

简介(申请人提供)：心脏病发病率随年龄增长而增加。尤其是心脏舒张期功能障碍和舒张性心力衰竭更多见于老年人。心脏细胞外基质(ECM)的重塑和纤维化随着年龄的增长而增加，导致心脏的舒张性和舒张性降低。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功能减弱通常与心功能不全共存于各种病理生理状态，包括衰老。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侧迷走神经刺激(CLVNS)模型，以增加PSNS对心脏的输出。初步数据表明，CLVNS改善了心脏功能，降低了心脏中的胶原含量。本项目旨在进一步测试CLVNS是否能改善老年小鼠的心脏舒张期功能障碍，减少心脏ECM重构。幼龄(2月龄)、中期(10月龄)和老年(20月龄)小鼠接受CLVNS或假刺激治疗4周。左心功能将使用米勒压力-容量导管进行评估。用羟脯氨酸分析、RT-PCR、Western印迹和酶谱检测胶原的表达和积累，以及基质金属蛋白酶(MMPs)的表达和活性。预计CLVNS治疗将改善老年小鼠心脏中与胶原含量减少和基质金属蛋白酶活性增加相关的左室舒张功能障碍。此外，在CLVNS治疗后，将从不同年龄组的小鼠分离成纤维细胞，并将评估胶原产生和基质金属蛋白酶的活性。预期的结果将表明，CLVNS减少了胶原的积累，并增加了来自老龄心脏的成纤维细胞中的基质金属蛋白酶的活性。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防止心脏重构和衰老功能障碍的机制。整个研究将为PSNS的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一种新的途径。公共卫生相关性：心脏病的发病率随着年龄的增长而增加，心脏舒张期功能障碍和舒张性心力衰竭更多见于老年人。本研究旨在探讨慢性左迷走神经刺激(CLVNS)能否改善老年小鼠左室舒张功能障碍，减少心脏重构。这项研究和未来研究的预期结果将为PSNS的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.