Mitochondrial transplantation, particularly when combined with sildenafil, significantly reduced right ventricular systolic pressure and limited pulmonary vascular remodeling in experimental PAH.
Does mitochondrial transplantation combined with sildenafil improve right ventricular dysfunction and vascular remodeling in experimental pulmonary arterial hypertension?
Mitochondrial transplantation combined with sildenafil shows promise in attenuating cardiopulmonary remodeling and improving right ventricular function in a preclinical model of pulmonary arterial hypertension.
Pulmonary arterial hypertension (PAH) is characterized by progressive vascular remodeling and right ventricular (RV) dysfunction, processes that are increasingly associated with disturbances in cellular metabolism. We investigated whether transplantation of exogenous mitochondria derived from bone marrow mesenchymal stromal cells, alone or combined with sildenafil, could improve mitochondrial homeostasis and attenuate cardiopulmonary remodeling in monocrotaline-induced PAH. Male Wistar rats were assigned to control (CTRL, n = 8) or PAH (n = 32) groups. Fourteen days after induction of PAH, animals were randomized to receive saline, sildenafil (20 mg/kg/day for 14 days), intravenous mitochondrial transplantation (100 μg, days 14 and 21), or combined therapy. On day 28, echocardiography, invasive measurement of RV systolic pressure (RVSP), pulmonary vascular histology, gene expression analyses (vimentin, VE-cadherin, and mitochondrial metabolism–related genes), and high-resolution respirometry were performed. All treatments significantly reduced RVSP compared with untreated PAH. Mitochondrial therapy, alone or combined with sildenafil, decreased arteriolar α-smooth muscle actin content, whereas endothelial–mesenchymal transition was attenuated only with combined treatment. Mitochondrial transplantation and sildenafil increased Complex I–dependent respiration, whereas Complex IV activity improved exclusively with mitochondrial therapy. Combined treatment reduced plasma IL-6 and IL-1β levels compared with PAH. Thus, mitochondrial transplantation, particularly when combined with sildenafil, improved RV function, limited pulmonary vascular remodeling, reduced plasma inflammatory markers, and changed key mitochondrial pathways in experimental PAH.
Onofre et al. (Thu,) conducted a other in Pulmonary arterial hypertension (n=40). Mitochondrial transplantation alone or combined with sildenafil vs. Saline (untreated PAH) and healthy control was evaluated on Right ventricular systolic pressure (RVSP), pulmonary vascular histology, gene expression, and high-resolution respirometry. Mitochondrial transplantation, particularly when combined with sildenafil, significantly reduced right ventricular systolic pressure and limited pulmonary vascular remodeling in experimental PAH.