Resveratrol inhibits monocrotaline-induced pulmonary arterial remodeling by suppression of SphK1-mediated NF-κB activation

Aims: This study aims to explore the molecular mechanisms underlying sphingosine kinase 1 (SphK1) inducing pulmonary vascular remodeling and resveratrol suppressing pulmonary arterial hypertension (PAH). Material and methods: monocrotaline (MCT) was used to induce PAH in rats. The right ventricular systolic pressure (RVSP), right ventricle hypertrophy index (RVHI) and histological analyses including hematoxylin and eosin staining, the percentage of medial wall thickness (%MT), α-SMA staining and Ki67 staining were performed to evaluate the development of PAH. Protein levels of SphK1, nuclear factor-kappaB (NF-κB)-p65 and cyclin D1 were determined using immunoblotting. Sphingosine-1-phosphate (S1P) concentration was measured using enzyme-linked immunosorbent assay. Key findings: SphK1 protein level, S1P production, NF-κB activation and cyclin D1 expression were significantly increased in MCT-induced PAH rats. Inhibition of SphK1 by PF543 suppressed S1P synthesis and NF-κB activation and down-regulated cyclin D1 expression in PAH rats. Suppression of NF-κB by pyrrolidine dithiocarbamate (PDTC) also reduced cyclin D1 expression in PAH model. Treatment of PAH rats with either PF543 or PDTC dramatically decreased RVSP, RVHI and %MT and reduced pulmonary arterial smooth muscle cells proliferation and pulmonary vessel muscularization. In addition, resveratrol effectively inhibited the development of PAH by suppression of SphK1/S1P-mediated NF-κB activation and subsequent cyclin D1 expression. Significance: SphK1/S1P signaling induces the development of PAH by activation of NF-κB and subsequent up-regulation of cyclin D1 expression. Resveratrol inhibits the MCT-induced PAH by targeting on SphK1 and reverses the downstream changes of SphK1, indicating that resveratrol might be a therapeutic agent for the prevention of PAH.