Vagus stimulation protects against cardiac diastolic dysfunction in aging mice

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.

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.