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Natural reversal of pulmonary vascular remodeling and right ventricular remodeling in SU5416/hypoxia-treated Sprague-Dawley rats.

Natural reversal of pulmonary vascular remodeling and right ventricular remodeling in SU5416/hypoxia-treated Sprague-Dawley rats.
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Zungu-Edmondson M, Shults NV, Melnyk O, Suzuki YJ,


Zungu-Edmondson M, Shults NV, Melnyk O, Suzuki YJ, (click to view)

Zungu-Edmondson M, Shults NV, Melnyk O, Suzuki YJ,

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PloS one 2017 08 1512(8) e0182551 doi 10.1371/journal.pone.0182551
Abstract
AIMS
Pulmonary arterial hypertension (PAH) is a lethal disease and improved therapeutic strategies are needed. Increased pulmonary arterial pressure, due to vasoconstriction and vascular remodeling, causes right ventricle (RV) failure and death in patients. The treatment of Sprague-Dawley rats with SU5416 injection and exposure to chronic hypoxia for three weeks followed by maintenance in normoxia promote progressive and severe PAH with pathologic features that resemble human PAH. At 5-17 weeks after the SU5416 injection, PAH is developed with pulmonary vascular remodeling as well as RV hypertrophy and fibrosis. The present study investigated subsequent events that occur in these PAH animals.

METHODS & RESULTS
At 35 weeks after the SU5416 injection, rats still maintained high RV pressure, but pulmonary vascular remodeling was significantly reduced. Metabolomics analysis revealed that lungs of normal rats and rats from the 35-week time point had different metabolomics profiles. Despite the maintenance of high RV pressure, fibrosis was resolved at 35-weeks. Masson’s trichrome stain and Western blotting monitoring collagen 1 determined 12% fibrosis in the RV at 17-weeks, and this was decreased to 5% at 35-weeks. The level of myofibroblasts was elevated at 17-weeks and normalized at 35-weeks.

CONCLUSIONS
These results suggest that biological systems possess natural ways to resolve pulmonary and RV remodeling. The resolution of RV fibrosis appears to involve the reduction of myofibroblast-dependent collagen synthesis. Understanding these endogenous mechanisms should help improve therapeutic strategies to treat PAH and RV failure.

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