Reduction of isoprenaline-induced myocardial TGF-β1 expression and fibrosis in osthole-treated mice

Peroxisome proliferator-activated receptor (PPAR) alpha and PPAR gamma ligands can attenuate myocardial fibrosis. Osthole, an active constituent isolated from the fruit of Cnidium monnieri (L.) Cusson, may be a dual PPAR alpha/gamma agonist, but there has been no report on its effect on myocardial fibrosis. In the present study, we investigated the inhibitory effect of osthole on myocardial fibrotic formation in mice and its possible mechanisms. A mouse model with myocardial fibrosis was induced by hypodermic injection of isoprenaline while the mice were simultaneously treated with 40 and 80 mg/kg osthole for 40 days. After the addition of osthole, the cardiac weight index and hydroxyproline content in the myocardial tissues were decreased, the degree of collagen accumulation in the heart was improved, and the downregulation of myocardial PPAR alpha/gamma mRNA expression induced by isoprenaline was reversed. Moreover, the mRNA expression of transforming growth factor (TGF)-beta 1 and the protein levels of nuclear factor (NF)-kappa B and TGF-beta 1 in the myocardial tissues were decreased. These findings suggest that osthole can prevent isoprenaline-induced myocardial fibrosis in mice, and its mechanisms may be related to the reduction of TGF-beta 1 expression via the activation of PPAR alpha/gamma and subsequent inhibition of NF-kappa B in myocardial tissues. (C) 2011 Elsevier Inc. All rights reserved.