HEART FAILURE & AGING: MECHANISTIC BASES OF MUSCLE VASCULAR DYSFUNCTION

 描述(申请人提供)：慢性心力衰竭(CHF)不成比例地困扰着老年人，损害氧气运输系统，特别是肌肉氧气输送，从而削弱运动耐量。尽管如此，CHF研究压倒性地利用了年轻动物而不是老年动物，在这些动物中，CHF(CHF+老年性心衰)是一种截然不同的疾病。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专门的解决。CHF涉及多个系统(特别是交感神经、免疫、心血管、肌肉)，这些影响相互作用，降低骨骼肌微循环血液-心肌细胞氧流量。我们的第一轮R15提供的证据表明，CHF诱导的SNS和肌肉O2传递障碍都可以通过提高一氧化氮(NO)生物利用度的策略得到改善，即用己酮可可碱治疗靶向全身炎症介质(即TNFa)，用甜菜根汁直接增加NO。本研究从交感神经系统-心血管-微循环-血管蛋白控制这一新的垂直整合角度探讨了CHF+衰老所致功能障碍的机制基础。我们建议解决全球假说，在CHF+老年大鼠，SNS和心脏功能障碍合并在骨骼肌微循环中，损害肌肉的氧气运输和运动耐量。因此，多目标治疗干预(PTX、SNS激活、心功能；补充西地那非或硝酸盐，无生物利用度+氧气需求)将恢复肌肉毛细血管功能， 氧输送/利用平衡和运动耐量。我们方法的优势包括：1)在高度相关的CHF模型(即CHF+AGE)中解决导致肌肉氧气输送受损和不同系统之间运动耐量的机制；2)我们独特的活体显微模型(大鼠脊柱斜方肌)便于在收缩期间使用磷光猝灭来直接、快速地观察肌肉微循环和血液-心肌细胞的氧通量。3)量化NO生物利用度如何在不使用合成酶阻断剂的情况下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；5)询问毛细血管功能的最新原理和血液-心肌细胞O2通量，以构建收缩肌肉毛细血管血流动力学的新模型。拟议的研究将提供针对CHF+Aging的肌肉和运动功能障碍的原始数据，确定其机制基础，并评估CHF患者治疗策略的有效性，同时履行AREA奖的授权，将真实科学与学生研究经验相结合。

 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.