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Published on: January 16, 2015
Sildenafil Prevents Marfan-Associated Emphysema and Early Pulmonary Artery Dilation in Mice
Zoe White1, Nadia Milad2, Arash Y Tehrani1
1Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, British Columbia, Canada; Centre for Heart Lung Innovation, St. Paul's Hospital, Vancouver, British Columbia, Canada.
Abstract:
Marfan syndrome (MFS) is a connective tissue disorder caused by mutations in fibrillin-1 (Fbn1). Although aortic rupture is the major cause of mortality in MFS, patients also experience pulmonary complications, which are poorly understood. Loss of basal nitric oxide (NO) production and vascular integrity has been implicated in MFS aortic root disease, yet their contribution to lung complications remains unknown. Because of its capacity to potentiate the vasodilatory NO/cyclic guanylate monophosphate signaling pathway, we assessed whether the phosphodiesterase-5 inhibitor, sildenafil (SIL), could attenuate aortic root remodeling and emphysema in a mouse model of MFS. Despite increasing NO-dependent vasodilation, SIL unexpectedly elevated mean arterial blood pressure, failed to inhibit MFS aortic root dilation, and exacerbated elastic fiber fragmentation. In the lung, early pulmonary artery dilation observed in untreated MFS mice was delayed by SIL treatment, and the severe emphysema-like alveolar destruction was prevented. In addition, improvements in select parameters of lung function were documented. Subsequent microarray analyses showed changes to gene signatures involved in the inflammatory response in the MFS lung treated with SIL, without significant down-regulation of connective tissue or transforming growth factor-β signaling genes. Because phosphodiesterase-5 inhibition leads to improved lung histopathology and function, the effects of SIL against emphysema warrant further investigation in the settings of MFS despite limited efficacy on aortic root remodeling.
Insights
Sildenafil (SIL) did not improve Marfan syndrome (MFS) aortic root issues but unexpectedly protected against lung emphysema in a mouse model. Further research into SIL for MFS-related lung complications is warranted.
Area of Science:
- Cardiovascular Research
- Pulmonary Medicine
- Genetics
Background:
- Marfan syndrome (MFS) is a genetic connective tissue disorder caused by fibrillin-1 (Fbn1) mutations.
- Aortic rupture is the primary cause of mortality, but pulmonary complications in MFS are poorly understood.
- Nitric oxide (NO) pathway dysfunction is implicated in MFS aortic disease, but its role in lung complications is unclear.
Purpose of the Study:
- To investigate the efficacy of sildenafil (SIL), a phosphodiesterase-5 inhibitor, in a mouse model of Marfan syndrome.
- To assess SIL's impact on aortic root remodeling and pulmonary emphysema.
- To explore the potential of NO-potentiating therapies for MFS complications.
Main Methods:
- Utilized a mouse model of Marfan syndrome (MFS).
- Administered sildenafil (SIL) to assess its effects on aortic root and lung pathology.
- Conducted microarray analysis to examine gene expression changes in lung tissue.
Main Results:
- Sildenafil increased NO-dependent vasodilation but elevated blood pressure and worsened aortic root dilation and elastic fiber fragmentation.
- SIL treatment delayed pulmonary artery dilation and prevented severe emphysema-like alveolar destruction in MFS mice.
- Improvements in lung function parameters and alterations in inflammatory gene signatures were observed in the MFS lung treated with SIL.
Conclusions:
- Sildenafil shows promise in mitigating pulmonary emphysema in Marfan syndrome, despite limited efficacy on aortic root issues.
- The phosphodiesterase-5 inhibitor warrants further investigation for treating lung complications associated with MFS.
- SIL's effects on lung inflammation and function suggest potential therapeutic benefits beyond its cardiovascular actions in MFS.
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