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

Makhosazane Zungu-Edmondson,Nataliia V Shults,Yuichiro J Suzuki,Oleksiy Melnyk,You-Yang Zhao

doi:10.1371/journal.pone.0182551

Makhosazane Zungu-Edmondson, Nataliia V Shults + Show 3 more

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https://doi.org/10.1371/journal.pone.0182551

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Abstract

AimsPulmonary 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 & resultsAt 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.ConclusionsThese 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.

Highlights

Pulmonary arterial hypertension (PAH) remains a fatal disease without a cure [1,2]
The level of myofibroblasts was elevated at 17-weeks and normalized at 35-weeks. These results suggest that biological systems possess natural ways to resolve pulmonary and right ventricle (RV) remodeling
The resolution of RV fibrosis appears to involve the reduction of myofibroblast-dependent collagen synthesis

Summary

Introduction

Pulmonary arterial hypertension (PAH) remains a fatal disease without a cure [1,2]. In PAH, pulmonary vascular resistance is increased, exerting strain on the right ventricle (RV), which leads to right heart failure and death [3,4,5]. The median survival of PAH patients has been reported to be 2.8 years from the time of diagnosis (3-year survival: 48%) [1,6]. Even with currently available drugs, the 3-year survival of PAH has been reported to be only 58– 75% [7,8,9]. The initial response to chronic pressure overload is to thicken the RV wall to increase the force of cardiac muscle contraction. This compensatory RV hypertrophic event transitions to RV failure, which is the major cause of death among PAH patients [10]. By the time patients are diagnosed with PAH, their RVs are usually already affected.

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