Friday, July 26, 2024
7/26/2024
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.
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