Background:

Cardiac remodeling after ischemic injury is a major cause of heart failure. In this process, fibroblast growth and collagen synthesis and degradation play a critical role. Recent studies indicate that ligands of the peroxisome proliferator-activated receptors-γ (PPAR-γ) alter cardiac remodeling during chronic ischemia. This study was designed to investigate if the PPAR-γ ligand pioglitazone would modulate fibroblast growth and collagen type-I synthesis (and expression) in cardiac fibroblasts exposed to anoxia-reoxygenation (AR).

Methods and Results:

Cardiac fibroblasts were exposed to anoxia (95% N 2/5% CO 2) and then reoxygenation (95% air/5% CO 2). AR increased fibroblast growth (MTT assay) as well as collagen type-I synthesis (3 H-proline incorporation) and protein expression (Western analysis). Concurrently, there was a parallel increase in the expression of matrix metalloproteinase-1 (MMP-1) in fibroblasts. Pretreatment of cardiac fibroblasts with pioglitazone (10− 5 M) reduced all these effects of AR. Further, AR stimulated intracellular reactive oxygen species (ROS) generation and activated the redox-sensitive transcription factor NF-κB (both P< 0.05). Both these phenomena were inhibited by pretreatment of cells with pioglitazone.

Conclusion:

Thus, it appears that AR stimulates fibroblast cell growth, collagen type-I synthesis, and MMP-1 expression in cardiac fibroblasts, most likely a result of ROS generation. Inhibition of ROS generation and induction of NF-κB in cardiac fibroblasts during AR may be a mechanism of action of pioglitazone.