A chronic increase in reactive oxygen species (ROS) plays a critical role in the development and progression of cardiac remodeling associated with heart failure. Oxidative stress is indeed increased in heart failure, hypertension, cardiac fibrosis and hypertrophy. In vitro exposure of cardiac fibroblasts to superoxide anion stimulates their proliferation by increasing the production of transforming growth factor-β1 (TGF-β1), a potent fibrogenic cytokine. TGF-β1 plays an important role in cardiac development, cardiac hypertrophy, ventricular remodeling and the early response to myocardial infarction. In this review the role of TGF-β1 and ROS in the production and deposition of collagens by cardiac fibroblasts and in the induction of gene expression in relation to the development of myocardial fibrosis and to myocardial tissue repair will be discussed.

Our data indicate that ANG II-stimulated mitochondrial reactive oxygen species production in rat cardiac fibroblasts is accompanied by a reduction in the expression of the mitochondrial antioxidant Prx-3, and thereby potentially contributing to oxidative stress in the myocard.

The aim of the present study was to determine whether transforming growth factor-β1 (TGF-β1)induced collagen production in cardiac fibroblasts is affected by reactive oxygen species (ROS). Cardiac fibroblasts (passage 2) from normal male adult rats were cultured to confluency and incubated in serum-free Dulbecco's modified Eagle's medium for 24 h. The cells were then preincubated with(out) the tested inhibitors for 1 h and further incubated with(out) TGF-β1 at various concentrations and for 1, 2, 4, 24 or 48 h. TGF-β1 induced a dose-dependent increase in the soluble collagen production in cardiac fibroblasts after 48 h of incubation. No significant effect of TGF-β1 (600 pmol/l) on collagen production and on α-smooth muscle actin (α-SMA) protein expression was found after 1, 2 and 4 h of incubation. After 24 and 48 h, TGF-β1 stimulated collagen production and α-SMA protein expression in cardiac fibroblasts. Intracellular ROS were not affected by TGF-β1 after 0.5 and 1 h of incubation, began to rise after 2 h, and reached a maximal increase after 4 h. The TGF-β1-stimulated ROS and collagen production is reduced by the ROS inhibitor diphenyleneiodonium chloride (DPI). DPI also decreased the TGF-β1-stimulated α-SMA protein expression in rat cardiac fibroblasts. Our data indicate that the TGF-β1-induced increase in ROS preceded the rise in collagen production and α-SMA protein expression and that ROS inhibition diminished the conversion of fibroblasts into myofibroblasts.

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