Angiotensin II (Ang II), a product of renin-angiotensin-system activation, enhances collagen synthesis which is a key event in cardiac remodeling following myocardial infarction. Inhibition of cardiac remodeling is now a target of multiple therapies, including HMG Coenzyme A reductase inhibitors, commonly known as statins, and peroxisome proliferator-activated receptor-(PPAR-) ligands. We examined the potential anti-fibrotic effect of the combination of a statin (pravastatin) and a PPAR- ligand (pioglitazone) in Ang II-treated mouse cardiac fibroblasts. Ang II treatment induced pro-collagen-1 expression, which was inhibited by pravastatin and pioglitazone in a dose-dependent fashion. Pre-treatment of fibroblasts with low therapeutic concentrations of either pravastatin (0.1µM) or pioglitazone (5µM) only slightly decreased Ang II-induced NADPH oxidase expression, superoxide anion production and pro-collagen-1 expression; but the combination of pravastatin and pioglitazone markedly modulated these effects of Ang II. The combination also blocked Ang II-mediated p38MAPK and p44/42 MAPK activation. Electrophoretic mobility shift assay showed that Ang II activated transcription factors NF-|B and AP-1. While pravastatin and pioglitazone alone had a variable effect on NF-B and AP-1 activation, their combination exerted a potent inhibitory effect on the activation of both NF-B and AP-1. The effects of pravastatin and pioglitazone combination on superoxide generation and pro-collagen-1 expression mimicked those of -tocopherol and -tocopherol, two potent antioxidants. Thus it appears that there is a positive interaction between pravastatin and pioglitazone in modulating Ang II-mediated oxidative stress, inhibiting MAPK activation and pro-collagen-1 expression.