Smooth muscle cell-specific genetic ablation or pharmacological inhibition of p110α prevented the onset and progression of pulmonary hypertension and reversed established vascular remodeling in rodent models.
Does genetic ablation or pharmacological inhibition of p110α prevent or reverse pulmonary hypertension and vascular remodeling in rodent models?
Inhibition of the PI3K catalytic subunit p110α prevents and reverses pulmonary vascular remodeling and right ventricular hypertrophy in rodent models of pulmonary hypertension, identifying it as a potential therapeutic target.
Enhanced signaling via RTKs in pulmonary hypertension (PH) impedes current treatment options because it perpetuates proliferation and apoptosis resistance of pulmonary arterial smooth muscle cells (PASMCs). Here, we demonstrated hyperphosphorylation of multiple RTKs in diseased human vessels and increased activation of their common downstream effector phosphatidylinositol 3'-kinase (PI3K), which thus emerged as an attractive therapeutic target. Systematic characterization of class IA catalytic PI3K isoforms identified p110α as the key regulator of pathogenic signaling pathways and PASMC responses (proliferation, migration, survival) downstream of multiple RTKs. Smooth muscle cell-specific genetic ablation or pharmacological inhibition of p110α prevented onset and progression of pulmonary hypertension (PH) as well as right heart hypertrophy in vivo and even reversed established vascular remodeling and PH in various animal models. These effects were attributable to both inhibition of vascular proliferation and induction of apoptosis. Since this pathway is abundantly activated in human disease, p110α represents a central target in PH.
Berghausen et al. (Thu,) conducted a other in Pulmonary hypertension. p110α inhibition (genetic ablation or pharmacological inhibitors PIK75 and BYL719) vs. Vehicle or wild-type controls was evaluated on Pulmonary vascular remodeling, right ventricular systolic pressure (RVSP), and right ventricular hypertrophy. Smooth muscle cell-specific genetic ablation or pharmacological inhibition of p110α prevented the onset and progression of pulmonary hypertension and reversed established vascular remodeling in rodent models.