Recovery from Cachexia in Heart and Skeletal Muscle

简介(申请人提供)：背景。充血性心力衰竭是一种全身性疾病。根植于神经激素的激活，它的特点是氧化应激和软组织的损耗，最终导致恶病质，通常被认为是不可逆转的。然而，长时间卧床可使心力衰竭持续恢复，心脏大小正常化；左心室辅助装置也是如此。从恶病质中恢复的机制令人感兴趣。神经激素撤退的作用是可以推断的，但还没有确定。在接受4周醛固酮/盐治疗(ALDOST)的恶病质大鼠中的初步研究发现，心脏和骨骼肌的转录组发生了变化，包括上调的泛素特定蛋白2和下调的胰岛素生长因子(IGF)-1。随着ALDOST的停止，体重和萎缩的肌肉在4周后自然恢复，当ALDOST继续并辅以Aldo受体拮抗剂螺内酯(螺内酯)4周时，ALDOST得到辅助恢复。假设。慢性ALDOST在第4周的消退可通过停药、与干扰醛固酮受体结合、钙超载或氧化应激的药物联合治疗，或单独使用合成代谢药物或与选择性的Aldo受体拮抗剂依普利酮(Epler)联合治疗而逆转。从基因表达异常中恢复应该让我们深入了解每种药物的有效性和缺点。计划一下。我们将使用ALDOST模型(在该模型中，甲状旁腺激素介导的细胞内钙超载与氧化应激诱导在临床前阶段(Wk 1)随后是恶病质(Wk 4))被证明是导致恶病质的分子事件的进展。由ALDOST引起的神经激素异常很容易被停用。基因表达阵列使我们能够揭示导致恶病质的途径，以及每种治疗方法在多大程度上逆转心脏和骨骼肌基因组、生化和结构的异常。目的1：研究慢性ALDOST临床前(Wk 1)和病理(Wk 4)时心肌和骨骼肌的生化和基因表达异常，以及4周后停用ALDOST后自然恢复的可能性；并将这种逆转与当ALDOST包括在第4周开始的2或4周的Spiro或Epler联合治疗时的辅助恢复进行比较。目的#2：表征在第6周和第8周ALDOST时病变心脏和骨骼肌中的恢复和分子事件，以响应a)Cinacalcet，一种重置甲状旁腺的钙感受器以抑制继发性甲状旁腺功能亢进(SHPT)的拟钙剂，a)Cinacalcet，一种重置甲状旁腺的钙感受器以抑制继发性甲状旁腺功能亢进(SHPT)的仿钙剂，b)氨氯地平，一种L型钙通道阻滞剂，在SHPT的环境中阻止氧化应激，以及c)通过用抗氧化剂N-乙酰半胱氨酸阻断氧化应激而提供的辅助恢复目标3：确定当在第4周开始用合成代谢药物治疗4周时，是否会在病变的心肌和骨骼肌的转录组和结构中出现恢复的分子证据，使用单独给药或Epler给药。充血性心力衰竭(CHF)是一个主要的健康问题。晚期充血性心力衰竭伴有神经激素激活和组织萎缩，或恶病质，具有不祥的预后，被认为是不可逆转的。这项研究将阐述在使用醛固酮/盐治疗的大鼠中出现恶病质恢复的分子机制，以及通过停药或药物干预可以从这种方案中恢复。公共卫生相关性：充血性心力衰竭(CHF)是一个主要的健康问题。晚期充血性心力衰竭伴 神经激素的激活和组织的损耗，或恶病质，带来不祥的预后，被认为是不可逆转的。这项研究将阐述在使用醛固酮/盐治疗的大鼠中出现恶病质恢复的分子机制，以及通过停药或药物干预可以从这种方案中恢复。

DESCRIPTION (provided by applicant): Background. Congestive heart failure (CHF) is a systemic illness. Rooted in neurohormonal activation, it features oxidative stress and a wasting of soft tissues eventuating in cachexia, generally considered irreversible. However, prolonged bed rest leads to a sustained recovery from CHF and normalization in heart size; so too does a left ventricular assist device. Mechanisms involved in the recovery from cachexia are of interest. The role of neurohormonal withdrawal could be inferred but is not defined. Preliminary studies in cachectic rats receiving 4 wks aldosterone/salt treatment (ALDOST) identified altered transcriptome of heart and skeletal muscle that included upregulated ubiquitin-specific protease2 and downregulated insulin growth factor (IGF)-1. A natural recovery in body weight and atrophic muscle occurred over 4 wks with the discontinuation of ALDOST, and an assisted recovery when ALDOST was continued and supplemented with an ALDO receptor antagonist, spironolactone (Spiro), for 4 wks. Hypothesis. The wasting seen at wk 4 of chronic ALDOST can be reversed by its discontinuation, by cotreatment with agents interfering with either aldosterone receptor binding, Ca2+ overloading, or oxidative stress, or by an anabolic agent alone or in combination with eplerenone (Epler), a selective ALDO receptor antagonist. Recovery from gene expression abnormalities should give us insights into the effectiveness and shortcomings of each agent. Plan. We will use the ALDOST model (in which parathyroid hormone-mediated intracellular Ca2+ overloading with induction of oxidative stress has been demonstrated during a preclinical stage (wk 1) followed by cachexia (wk 4)) to address the progression of molecular events leading to cachexia. Neurohormonal abnormality, caused by ALDOST, can be readily discontinued. Gene expression arrays allow us to reveal pathways leading to cachexia and to what extent abnormalities in heart and skeletal muscle genome, biochemistry and structure are reversed by each treatment. Aim #1: to characterize biochemical and gene expression abnormalities at preclinical (wk 1) and pathologic (wk 4) stages of chronic ALDOST in cardiac and skeletal muscle, together with their potential for natural recovery by discontinuing ALDOST after 4 wks; and to compare this reversal to assisted recovery when 6 and 8 wks ALDOST includes 2 or 4 wks of Spiro or Epler cotreatment begun at wk 4. Aim#2: to characterize recovery and molecular events in diseased heart and skeletal muscle at wks 6 and 8 ALDOST in response to assisted recovery provided by attenuated intracellular Ca2+ overloading using a) cinacalcet, a calcimimetic that resets the parathyroid glands' Ca2+- sensing receptor to suppress secondary hyperparathyroidism (SHPT), b) amlodipine, an L-type Ca2+ channel blocker that prevents Ca2+ entry in the setting of SHPT, and c) by negating oxidative stress with N-acetylcysteine, an antioxidant, each begun at wk 4. Aim #3: to determine whether molecular evidence of recovery would appear in the transcriptome and structure of diseased cardiac and skeletal muscle, when 4 wks treatment with an anabolic agent is introduced at wk 4 ALDOST, using an infusion of IGF-1, given alone or with Epler. Congestive heart failure (CHF) is a major health problem. Advanced CHF accompanied by neurohormonal activation and a wasting of tissues, or cachexia, carries an ominous prognosis and is thought to be irreversible. This study will address molecular mechanisms involved in the recovery from cachexia that appears in rats treated with aldosterone/salt and where recovery from this regimen can be achieved by its withdrawal or pharmacologic intervention. PUBLIC HEALTH RELEVANCE: Congestive heart failure (CHF) is a major health problem. Advanced CHF accompanied by neurohormonal activation and a wasting of tissues, or cachexia, carries an ominous prognosis and is thought to be irreversible. This study will address molecular mechanisms involved in the recovery from cachexia that appears in rats treated with aldosterone/salt and where recovery from this regimen can be achieved by its withdrawal or pharmacologic intervention.