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Delineating the molecular and histological events that govern right ventricular recovery using a novel mouse model of pulmonary artery de-banding.

Cardiovascular research (2019-11-19)
Mario Boehm, Xuefei Tian, Yuqiang Mao, Kenzo Ichimura, Melanie J Dufva, Khadem Ali, Svenja Dannewitz Prosseda, Yiwei Shi, Kazuya Kuramoto, Sushma Reddy, Vitaly O Kheyfets, Ross J Metzger, Edda Spiekerkoetter
ABSTRACT

The temporal sequence of events underlying functional right ventricular (RV) recovery after improvement of pulmonary hypertension-associated pressure overload is unknown. We sought to establish a novel mouse model of gradual RV recovery from pressure overload and use it to delineate RV reverse-remodelling events. Surgical pulmonary artery banding (PAB) around a 26-G needle induced RV dysfunction with increased RV pressures, reduced exercise capacity and caused liver congestion, hypertrophic, fibrotic, and vascular myocardial remodelling within 5 weeks of chronic RV pressure overload in mice. Gradual reduction of the afterload burden through PA band absorption (de-PAB)-after RV dysfunction and structural remodelling were established-initiated recovery of RV function (cardiac output and exercise capacity) along with rapid normalization in RV hypertrophy (RV/left ventricular + S and cardiomyocyte area) and RV pressures (right ventricular systolic pressure). RV fibrotic (collagen, elastic fibres, and vimentin+ fibroblasts) and vascular (capillary density) remodelling were equally reversible; however, reversal occurred at a later timepoint after de-PAB, when RV function was already completely restored. Microarray gene expression (ClariomS, Thermo Fisher Scientific, Waltham, MA, USA) along with gene ontology analyses in RV tissues revealed growth factors, immune modulators, and apoptosis mediators as major cellular components underlying functional RV recovery. We established a novel gradual de-PAB mouse model and used it to demonstrate that established pulmonary hypertension-associated RV dysfunction is fully reversible. Mechanistically, we link functional RV improvement to hypertrophic normalization that precedes fibrotic and vascular reverse-remodelling events.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Anti-Actin, α-Smooth Muscle - Cy3 antibody, Mouse monoclonal, clone 1A4, purified from hybridoma cell culture
Sigma-Aldrich
Anti-POSTN antibody produced in rabbit, Prestige Antibodies® Powered by Atlas Antibodies, affinity isolated antibody, buffered aqueous glycerol solution

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