Aging, aortic stiffness, and intracellular signaling.

描述（由申请人提供）：心血管疾病是65岁以上人群的头号死因，84%的死亡发生在老年人群中。为什么衰老会增加血管疾病的风险尚不清楚，但与年龄相关的动脉顺应性降低是心血管风险的独立预测因素。我们的长期目标是阐明衰老对血管结构和功能产生负面影响的机制。本研究的目的是1）。确定主动脉形态变化和负荷诱导的主动脉信号传导之间的时间过程和相互关系，以及2.）确定药物干预在预防和/或逆转年龄相关的主动脉结构和功能变化方面的疗效。这些数据将提供关于血管结构和功能的年龄相关变化之间因果关系的重要信息。我们的中心假设是，衰老将与血管僵硬度增加和负荷诱导的丝裂原活化蛋白激酶（MAPK）、Akt和eNOS信号通路活化减少相关，并且这些变化可以通过药物干预减弱和/或逆转。具体目标是：（1）确定衰老如何改变主动脉顺应性、形态学和蛋白质表达，（2）确定衰老如何影响主动脉中机械诱导的信号转导，（3）确定糖基化终产物交联阻断剂治疗如何影响与年龄相关的主动脉顺应性和主动脉中机械诱导的信号转导，以及（4）使有前途的本科生接触生理学研究。这项工作的预期成果将：1。确定老化如何影响血管机械传导，2。确定血管材料性质、蛋白质表达和信号传导的年龄相关变化的时程和相互关系，以及3.）确定药物干预是否能有效预防和/或逆转年龄相关的血管功能障碍。这些结果将是重要的，因为预计有关血管信号与衰老的新信息将为预防和治疗干预提供新的目标，这将直接有助于治疗与年龄相关的心血管疾病。

DESCRIPTION (provided by applicant): Cardiovascular disease is the number one cause of death in people over age 65 and 84% of the deaths caused by this affliction occur in the elderly population. Why aging increases the risk of vascular disease is unknown, however age-related decreases in arterial compliance are an independent predictor of cardiovascular risk. Our long-range goal is to delineate the mechanisms by which aging negatively influences vascular structure and function. The objectives of this study are to 1.) Determine the time course and inter- relatedness between changes in aortic morphology and load-induced aortic signaling and 2.) Determine the efficacy of pharmacological intervention in preventing and / or reversing age-associated changes in aortic structure and function. These data will provide important information regarding the causality between age- related changes in vascular structure and function. Our central hypothesis is that aging will be associated with increases in vascular stiffness and a diminished load-induced activation of the mitogen activated protein kinase (MAPK), Akt, and eNOS signaling pathways and that these changes can be attenuated and /or reversed by pharmacological intervention. The specific aims are: (1) To establish how aging alters aortic compliance, morphology and protein expression, (2) To establish how aging influences mechanically-induced signal transduction in the aorta (3) To establish how glycation end-product cross-link breaker treatment influences age-related aortic compliance and mechanically-induced signal transduction in the aorta, and (4) To expose promising undergraduate students to physiological research. The expected outcomes of this work will: 1.) Determine how aging influences vascular mechanotransduction, 2.) Determine the time course and inter- relatedness of age-associated changes in the vascular material properties, protein expression and signaling, and, 3.) Determine if pharmacological intervention is effective in preventing and/or reversing age-associated vascular dysfunction. Such outcomes will be significant because it is expected to that the new information regarding vascular signaling with aging will provide new targets for preventive and therapeutic interventions that will directly aid in the treatment of age-related cardiovascular disorders.