Pulmonary arterial hypertension (PAH) is a progressive and life-threatening disease characterized by pulmonary vascular remodeling. This remodeling is primarily caused by abnormal proliferation of pulmonary arterial smooth muscle cells (PASMCs), facilitated by perivascular inflammatory macrophages. Fingolimod, an immunosuppressive drug approved for multiple sclerosis, modulates sphingosine-1-phosphate (S1P) signaling. In the present study, the effects of fingolimod on the excessive proliferation of PASMCs from patients with idiopathic PAH (IPAH), the viability of human monocyte-derived macrophages, and pulmonary vascular remodeling and survival in monocrotaline (MCT)-induced PAH rats were examined. Fingolimod inhibited the abnormal proliferation of IPAH-PASMCs (IC 50 = 3.8 μM) and reduced the viability of CD163-positive macrophages. S1P receptor 3, predominantly expressed in PASMCs, was upregulated in IPAH-PASMCs and in pulmonary arterial smooth muscle tissues from MCT-PAH rats. Administration of fingolimod (1 mg/kg/day) decreased perivascular accumulation of CD163-positive macrophages, lowered right ventricular systolic pressure, and attenuated pulmonary vascular remodeling in MCT-PAH rats. Kaplan-Meier survival analysis demonstrated that fingolimod prolonged survival. Collectively, these findings indicate that fingolimod ameliorates pulmonary vascular remodeling by inhibiting abnormal PASMC proliferation and CD163-positive macrophage viability, thereby improving survival in experimental PAH rats. Targeting the S1P signaling pathway with fingolimod may represent a promising repositioning strategy for PAH therapy.
Fujiwara et al. (Tue,) studied this question.