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Abstract 14297: Potential Role of the Tumor Suppressor WWOX in Mediating Skeletal Muscle-Lung Vasculature Crosstalk in PH-HFpEF
Ist Teil von
Circulation (New York, N.Y.), 2020-11, Vol.142 (Suppl_3 Suppl 3), p.A14297-A14297
Ort / Verlag
by the American College of Cardiology Foundation and the American Heart Association, Inc
Erscheinungsjahr
2020
Link zum Volltext
Quelle
The Electronic Journals Library
Beschreibungen/Notizen
IntroductionPulmonary hypertension due to left heart disease (PH-LHD; Group 2), particularly in the context of heart failure with preserved ejection fraction (HFpEF), is the most common cause of PH worldwide. At present, no specific effective therapy has been identified mainly due to the fact that major pathways involved in the regulation of PH-HFpEF are still not well understood.ResultsWe have recently reported on a role of skeletal muscle sirtuin-3 (SIRT3) in modulating PH-HFpEF. Using skeletal muscle-specific SIRT3 knockout mice (Sirt3), we showed that absence of SIRT3 in skeletal muscle drastically reduced the pulmonary vascular tree accompanied by vascular proliferative remodeling. Interestingly, we found that expression levels of the tumor suppressor WW domain-containing oxidoreductase (WWOX) were decreased in pulmonary arterial smooth muscle cells (PASMCs) obtained from Sirt3 mice, while no changes in SIRT3 activation levels were detected. Reduced WWOX expression levels were also found in PASMCs isolated from SU5416/Obese ZSF1 (Ob-Su) rat model of PH-HFpEF, in which the levels of SIRT3 activation were found to be decreased in skeletal muscle, but not in the lungs and PASMCs. No changes of WWOX levels were observed in skeletal muscle of Ob-Su rats or in pulmonary artery endothelial cells (PAECs) treated with plasma obtained from Ob-Su rats.ConclusionsSince reduction of WWOX in PASMCs has been shown to promote cell proliferation, HIF1α stabilization and pulmonary arterial hypertension (PAH; Group 1), our data suggest a potential role of WWOX in mediating skeletal muscle SIRT3 deficiency-associated remote pulmonary vascular remodeling in PH-HFpEF.