[R01] Role of Hydrogen Sulfide in Exercise Intolerance in HFpEF

Ente: National Heart Lung and Blood Institute

Scadenza: 2031-03-31

Importo max: 736.602 EUR

Paese: US

Descrizione

PROJECT ABSTRACT Heart failure with preserved ejection fraction (HFpEF) will soon become the predominant form of heart failure. Patients with cardiometabolic HFpEF have multiple co-morbidities including obesity, hypertension, and diabetes. The cardinal symptom and strongest predictor of mortality in HFpEF is exercise intolerance. Dysfunctional skeletal muscle metabolism and perfusion are primary, cardiac-independent, drivers of exercise intolerance in HFpEF. Hydrogen sulfide (H2S) is an essential endogenous gaseous signaling molecule important for metabolic and cardiovascular health. Our preliminary studies demonstrate in patients and animals with HFpEF severe H2S dysregulation. We show that in human patients with HFpEF, circulating plasma H2S bioavailability is reduced by 80%. Animal models demonstrate a similar reduction in circulating H2S but also show a significant reduction in skeletal muscle H2S bioavailability. The loss of H2S induces skeletal muscle metabolic dysfunction that reduces the full oxidation of fatty acids and branched-chain amino acids (BCAA). Reduced H2S also causes vascular dysfunction that reduces tissue perfusion. H2S donor therapy increases H2S bioavailability and restores skeletal muscle metabolic function and exercise capacity in animal models of HFpEF. These preliminary studies demonstrate that H2S is involved in the physiological response to exercise in HFpEF. Our Central Hypothesis is that reductions in H2S synthesis and bioavailability drive skeletal muscle metabolic and perfusion dysfunction in cardiometabolic HFpEF. We will investigate the impact of endogenous H2S-producing enzymes cystathionine-γ-lyase (CSE) and 3-mercaptopyrutvate sulfurtransferase (3-MST) in the endothelium (EC) and skeletal muscle (SKM) during the progression of HFpEF. In Aim 1 we will determine the role of EC-CSE and SKM-3-MST on whole-body exercise capacity and peak oxygen consumption, skeletal muscle contractile performance, and perfusion. Aim 2 will determine the specific role of mitochondrial H2S in skeletal muscle mitochondrial function, fatty acid, and BCAA metabolism. Finally, in Aim 3 we will investigate a novel mitochondrial-targeted H2S therapy to improve exercise capacity in rodent models of cardiometabolic HFpEF. The long-term objective of our proposed studies is to understand how H2S contributes to exercise intolerance in HFpEF. Istituzione: LSU PENNINGTON BIOMEDICAL RESEARCH CTR PI: Timothy Allerton Progetto: 1R01HL183876-01

Settori: National Heart Lung and Blood Institute

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