Osthole Regulates TGF-β1 and MMP-2/9 Expressions via Activation of PPARα/γ in Cultured Mouse Cardiac Fibroblasts Stimulated with Angiotensin II

PURPOSE. Our previous studies have demonstrated that osthole, an active constituent isolated from the fruit of Cnidium monnieri (L.) Cusson, can prevent isoprenaline-induced myocardial fibrosis in mice, but the underlying mechanism is still unclear. METHODS. The mouse cardiac fibroblasts (CFs) stimulated with angiotensin II (Ang II) were cultured and treated with different concentrations of osthole. The mRNA expressions of peroxisome proliferator-activated receptor (PPAR) alpha/gamma, transforming growth factor beta 1 (TGF-beta 1), and matrix metalloproteinase (MMP)-2/9 were detected by reverse transcription polymerase chain reaction method, and the protein expressions of nuclear factor-kappa B (NF-kappa B) and TGF-beta 1 were detected by Western blot method, respectively. RESULTS. Following treatment of cells with osthole at 2.5, 5, 10 and 20 mu g/mL, the NF-kappa B and TGF-beta 1 expressions were dose-dependently decreased, while the expressions of PPAR alpha/gamma and MMP-2/9 were dose-dependently increased. After the cells were preincubated with PPAR alpha antagonist (MK886) or/and PPAR gamma antagonist (GW9662), the inhibitions of osthole on the NF-kappa B and TGF-beta 1 expressions were decreased or completely halted and the increment of osthole on the MMP-2/9 expressions were also decreased or completely cancelled. CONCLUSION. Osthole could inhibit the NF-kappa B and TGF-beta 1 expressions by activation of PPAR alpha/gamma, and subsequently enhance the MMP-2/9 expressions in cultured CFs, and these effects of osthole may play the beneficial roles in the prevention and treatment of myocardial fibrosis.