Effects of atorvastatin on TGF-β1 expression and p44/42 MAPK signal transduction passway in cardiac fibroblasts

Objective: Statins have been shown to reduce the cardiac remodeling independent of their well-known lipid lowering effect. Considering the importance of transforming growth factor-beta1 (TGF-β1) overproduction in heart failure, the effect of atorvastatin on TGF-β1 expression and p44/42 mitogen-activated protein kinases (p44/42 MAPK) signal transduction passway in cardiac fibroblasts was examined. Design andmethods: The cardiac fibroblasts of neonatal rat were culturedby trypsinogen anddifferent speed adherence. The level of TGFβ1 in conditioned medium was measured by EIA. Intracellular TGF-β1, p44/42 MAPK and phospho-p44/42 MAPK levels were evaluated by Western blot, and the expression of TGF-β1 mRNA was detected using RT-PCR. Results: The cardiac fibroblasts, treated with aldosterone at 1×10−7mol/L, significantly up-regulated TGF-β1 mRNA expression (P<0.01), as well as TGF-β1 synthesis (P<0.01) and release (P<0.01). Atorvastatin (1×10−6, 10−5, 10−4mol/L) dose-dependently blocked TGF-β1 mRNA expression (P<0.01, respectively), as well as TGF-β1 synthesis (P<0.01, respectively) and release (P=0.113, P<0.01, P<0.01, respectively). In contrast, atorvastatin-induced inhibitory effects were reversed in the presence of mevalonate. Similarly, phospho-p44/42 MAPK was significantly up-regulated by aldosterone (P<0.01). The increased level of phospho-p44/42 MAPK was reduced when the cells were pretreated with atorvastatin (P<0.01). Our data also showed the recovery of phospho-p44/42 MAPK expression in the presence of mevalonate (P<0.01). Pre-incubation with PD 98059, an antagonist for p44/42 MAPK, abolished aldosterone-induced TGF-β1 secretion (P<0.01). Conclusion: Atorvastatin down-regulated TGF-β1 expression inducedbyaldosterone in aprocess specifically related tomevalonate and p44/42 MAPK pathway in cultured neonatal rat cardiac fibroblasts. Thus, itwas indicated that atorvastatinmight exert therapeutic effects bya new possible mechanism in patients with heart failure.