Multitarget Strategy for Treatment of Pulmonary Arterial Hypertension: Combination of Mesenchymal Cells with Novel PDE-4 Inhibitor

Background/Objectives. Pulmonary arterial hypertension (PAH) is a rare but severe disease which leads to right ventricular (RV) maladaptation, failure and death. Currently approved drugs have limited impact on disease progression. A multitarget strategy consisting of adenosine A2B receptor activation and phosphodiesterase-4 (PDE4) inhibition, combined with human mesenchymal stromal cells (hMSCs) therapy, was tested in experimental PAH. The main objective was to determine whether the combination improved pulmonary hemodynamics, vascular remodeling, and RV function, given the limited disease-modifying effects of currently approved vasodilators. Methods. Vascular reactivity was assessed in isolated rat pulmonary artery rings exposed to the dual-target compound (LASSBio-1860) alone or in the presence of either ZM-241385 or MRS-1706. PAH was induced in male Wistar rats with monocrotaline (MCT, 60 mg·kg−1) and confirmed by a decrease in pulmonary artery acceleration time to ejection time ratio (PAAT/TET). Animals were randomized to receive vehicle, hMSC (single i.v. dose, 1 × 105 cells), LASSBio-1860 (62 mg·kg−1·day−1, p.o., 14 days), or their combination. Outcomes included PAAT/TET and RV cardiac output (RV-CO) by echocardiography, RV systolic pressure (RVSP) by direct puncture, Fulton index and RV wall thickness, lung histology (perivascular cell counts and wall thickness), and RV protein expression (TGF-β, CaMKII) by Western blot. Results. LASSBio-1860 produced endothelium-independent vasorelaxation of rat pulmonary arteries, consistent with A2B agonism and PDE4 inhibition. In MCT-induced PAH, combination of LASSBio-1860 and hMSCs resulted in recovery of PAAT/TET and RV-CO, decrease in RVSP, RV hypertrophy, vascular inflammation and remodeling by downregulation of ventricular TGF-β and CaMKII. Conclusions. Combination of LASSBio-1860 with hMSC improved RV function, attenuated pulmonary hypertension, RV and vascular remodeling, and reduced inflammatory/proliferative signaling in MCT induced-PAH, supporting a promising multitarget therapeutic strategy for PAH.