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 consisted of activation of adenosine A2B receptor and inhibition of phosphodiesterase-4 (PDE4) in combination with human mesenchymal stromal cells (hMSCs) was tested in PAH animal model. The main objective was to determine whether the combination improves pulmonary hemodynamics, vascular remodeling, and RV function, given the limited disease-modifying effects of approved vasodilators. Methods. Vascular reactivity was assessed in isolated rat pulmonary artery rings exposed to the dual target compound named LASSBio-1860 alone or in the presence of either A2A (ZM-241385) or A2B (MRS-1706) antagonist. PAH was induced in male Wistar rats through the administration of monocrothaline (MCT, 60 mg·kg−1). After confirmation of PAH, by the decrease of the ratio of pulmonary artery acceleration time and ejection time ratio (PAAT/TET), animals were randomized divided to receive vehicle, hMSC (single i.v. dose, 1×105 cells), LASSBio-1860 (62 mg·kg−1·day−1, p.o., 14 days), or the combination. Outcomes included PAAT/TET and RV cardiac output (RV-CO) using 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 responses. In MCT-induced PAH, the combination of LASSBio-1860 with hMSCs promoted: 1. Recovery of PAAT/TET and RV-CO; 2. Decrease of RVSP; 3. Reduction of RV hypertrophy, vascular inflammation and remodeling; 4. Downregulation of ventricular TGF-β and CaMKII. Conclusions. Combination of LASSBio-1860 with hMSC improved RV function, attenuated pulmonary hypertension, RV and vascular remodeling; reduced inflammatory/proliferative signaling in MCT induced-PAH, supporting a promising multitarget therapeutic strategy for PAH.