HEART FAILURE & AGING: MECHANISTIC BASES OF MUSCLE VASCULAR DYSFUNCTION

 描述（由申请人提供）：慢性心力衰竭（CHF）会损害老年人，损害O2运输系统，特别是肌肉O2输送，从而削弱运动耐量。尽管如此，CHF研究绝大多数使用年轻而不是老年动物，其中CHF（CHF+老年）是一种完全不同的疾病。因此，功能障碍的机制基础和治疗对策必须在这一人群中得到具体解决。CHF损害多个系统（特别是交感神经（SNS）、免疫、心血管、肌肉），这些效应相互作用，降低骨骼肌微循环血-肌细胞O2通量。我们的第一轮R15提供的证据表明，CHF诱导的SNS和肌肉O2输送失调可以通过增加一氧化氮（NO）生物利用度的策略来改善，即，靶向全身炎症介质（即，TNF α）与喷替福林治疗和直接用甜菜根汁增加NO。该提案从一个新的垂直整合的角度阐述了CHF+衰老诱导的功能障碍的机制基础：交感神经系统-心血管-微循环-血管蛋白控制。我们建议解决的全球假说，在CHF+老年大鼠，SNS和心功能不全凝聚在骨骼肌微循环损害肌肉O2运输和运动耐量。因此，多靶向治疗干预（PTX、<$SNS激活、<$心脏功能;西地那非或硝酸盐补充、<$NO生物利用度+<$O2需求）将恢复肌肉毛细血管功能， O2输送/利用平衡和运动耐量。我们方法的优势包括：1）解决了高度相关的CHF模型（即，CHF+老年人）; 2）我们独特的活体显微镜模型（大鼠脊髓）有利于利用收缩期间的磷光猝灭直接和快速地观察肌肉微循环和血-肌细胞O2通量。3)使用NO合酶阻断定量NO生物利用度如何促进毛细血管血流动力学。4)提供新的经验证据支持CHF患者的最佳治疗策略;和5）询问毛细血管功能的最新原理和血-肌细胞O2通量，以构建收缩肌肉毛细血管血流动力学的新模型。拟议的研究将提供解决CHF+衰老中肌肉和运动功能障碍的原始数据，定义其机制基础并评估CHF患者治疗策略的有效性，同时履行AREA奖的授权，将真实的科学与学生的研究经验相结合。

 DESCRIPTION (provided by applicant): Chronic heart failure (CHF) disproportionally afflicts the aged, impairing the O2 transport system, specifically muscle O2 delivery, thereby crippling exercise tolerance. Despite this fact, CHF research has overwhelmingly utilized young rather than old animals, where CHF (CHF+Aged) is a profoundly different disease. Therefore, the mechanistic bases for dysfunction and therapeutic countermeasures must be addressed specifically in this population. CHF compromises multiple systems (especially sympathetic nervous (SNS), immune, cardiovascular, muscular) with these effects interacting to decrease skeletal muscle micro- circulatory blood-myocyte O2 flux. Our first round of this R15 provided evidence that that both CHF-induced SNS and muscle O2 delivery dysregulation may be ameliorated by strategies that increase nitric oxide (NO) bioavailability i.e., targeting systemic inflammatory mediators (i.e., TNFa) with pentoxifylline therapy and increasing NO directly with beetroot juice. This proposal addresses the mechanistic bases for CHF+Aging- induced dysfunction from a novel vertically-integrated perspective: sympathetic nervous system - cardiovascular - microcirculation - vascular protein control. We propose to address the global hypothesis that, in CHF+Aged rats, SNS and cardiac dysfunction coalesce within the skeletal muscle microcirculation to impair muscle O2 transport and exercise tolerance. Thus, multi-targeted therapeutic interventions (PTX, ¿SNS activation, ¿cardiac function; sildenafil or nitrat supplementation, ¿ NO bioavailability + ¿O2 requirements) will restore muscle capillary function, O2 delivery/utilization balance and exercise tolerance. Strengths of our approach include: 1) Resolving the mechanisms responsible for impaired muscle O2 delivery and exercise intolerance among systems in a highly relevant CHF model (i.e., CHF+Aged); 2) our unique intravital micro- scopy model (rat spinotrapezius) facilitates direct and rapid observation of muscle microcirculation and blood- myocyte O2 flux using phosphorescence quenching during contractions. 3) Quantitating how NO bioavailability facilitates capillary hemodynamics using NO synthase blockade. 4) Provision of novel empirical evidence supporting optimal treatment strategies for CHF patients; and 5) interrogation of the latest principles of capillary function an blood-myocyte O2 flux to construct a novel model of contracting muscle capillary hemodynamics. The proposed studies will provide original data addressing muscle and exercise dysfunction in CHF+Aging, defining their mechanistic bases and assessing the efficacy of treatment strategies for CHF patients whilst fulfilling the AREA award mandate to integrate authentic science with student research experience.