Central-acting therapeutics alleviate respiratory weakness caused by heart failure–induced ventilatory overdrive
| Autor: | Ashley L. Eadie, Jason S. Huber, Jeremy A. Simpson, Coral L. Murrant, Andrew J. Foster, Keith R. Brunt, Alicia M. Arkell, Mathew J. Platt, David C. Wright, Nadya Romanova, Todd E. Gillis |
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| Rok vydání: | 2017 |
| Předmět: |
Pressure overload
business.industry Diaphragmatic breathing Muscle weakness General Medicine 030204 cardiovascular system & hematology medicine.disease Pulmonary edema Angiotensin II 3. Good health Diaphragm (structural system) 03 medical and health sciences 0302 clinical medicine Heart failure Anesthesia medicine Diaphragmatic weakness medicine.symptom business 030217 neurology & neurosurgery |
| Zdroj: | Science Translational Medicine. 9 |
| ISSN: | 1946-6242 1946-6234 |
| DOI: | 10.1126/scitranslmed.aag1303 |
| Popis: | Diaphragmatic weakness is a feature of heart failure (HF) associated with dyspnea and exertional fatigue. Most studies have focused on advanced stages of HF, leaving the cause unresolved. The long-standing theory is that pulmonary edema imposes a mechanical stress, resulting in diaphragmatic remodeling, but stable HF patients rarely exhibit pulmonary edema. We investigated how diaphragmatic weakness develops in two mouse models of pressure overload-induced HF. As in HF patients, both models had increased eupneic respiratory pressures and ventilatory drive. Despite the absence of pulmonary edema, diaphragmatic strength progressively declined during pressure overload; this decline correlated with a reduction in diaphragm cross-sectional area and preceded evidence of muscle weakness. We uncovered a functional codependence between angiotensin II and β-adrenergic (β-ADR) signaling, which increased ventilatory drive. Chronic overdrive was associated with increased PERK (double-stranded RNA-activated protein kinase R-like ER kinase) expression and phosphorylation of EIF2α (eukaryotic translation initiation factor 2α), which inhibits protein synthesis. Inhibition of β-ADR signaling after application of pressure overload normalized diaphragm strength, Perk expression, EIF2α phosphorylation, and diaphragmatic cross-sectional area. Only drugs that were able to penetrate the blood-brain barrier were effective in treating ventilatory overdrive and preventing diaphragmatic atrophy. These data provide insight into why similar drugs have different benefits on mortality and symptomatology, despite comparable cardiovascular effects. |
| Databáze: | OpenAIRE |
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