Objectives: Myofibroblasts (myoFb) are the major cell types that appear at the site of myocardial infarction (MI) in response to injury and play a vital role in tissue repair/remodeling. Since vascular endothelial growth factor (VEGF) plays a crucial role in the infarcted/ischemic heart, we hypothesized that activation of the peroxisome proliferator-activated receptor (PPAR)-gamma by its agonists induces VEGF expression while simultaneously decreasing inflammation (NF-kappaB). Such an increase in myoFb VEGF expression by PPAR-gamma agonists may play a role in angiogenesis.
Methods: Rat myoFb were treated with PPAR-gamma agonists and VEGF expression was measured by ELISA. The effect of these agonists on VEGF receptors was determined by qRT-PCR and flow-cytometric analysis. VEGF produced by these cells was also used for analysis of in vitro tubule formation (Matrigel assay).
Results: The PPAR-gamma activators troglitazone (TZ) and 15-deoxy-prostaglandin J2 (15J2) induced the expression of VEGF and its receptors (Flt-1 and KDR) in myoFb. TZ and 15J2 elicited a significant increase in the expression of KDR (14.7+/-1.0% and 9.6+/-2.1% respectively) and Flt-1 (24.5+/-2.0%, and 14.0+/-2.2% respectively) when compared to untreated myoFb. MyoFb treated with PPAR-gamma agonists increased extracellular VEGF, augmenting tubule formation on a Matrigel. The PPAR-gamma activator 15J2 significantly decreased the NF-kappaB activity in myoFb.
Conclusion: This study demonstrates the induction of the VEGF accompanied by a reduction of NF-kappaB activity (inflammatory signaling) by PPAR-gamma agonists in cardiac myoFb. These results may further the understanding of the beneficial effects of PPAR-gamma agonists on infarcted tissue repair and angiogenesis.