PPAR-gamma agonists induce the expression of VEGF and its receptors in cultured cardiac myofibroblasts.
OBJECTIVE
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.


CONCLUSIONS
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.
Chintalgattu
Vishnu
V
Department of Physiology, The Brody School of Medicine, East Carolina University Greenville, NC 27834, USA.
Harris
Gregory S
GS
Akula
Shaw M
SM
Katwa
Laxmansa C
LC
D000818:Animals; D002478:Cells, Cultured; D002839:Chromans / Q000494:pharmacology*; D003094:Collagen; D004338:Drug Combinations; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005786:Gene Expression Regulation; D007797:Laminin; D008297:Male; D008856:Microscopy, Fluorescence; D018485:Muscle Fibers, Skeletal / Q000502:physiology; D009203:Myocardial Infarction / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism*; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology; D011509:Proteoglycans; D051381:Rats; D017207:Rats, Sprague-Dawley; D040262:Receptors, Vascular Endothelial Growth Factor / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D045162:Thiazolidinediones / Q000494:pharmacology*; D000077288:Troglitazone; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
C477819:15-deoxyprostaglandin J2; D002839:Chromans; D004338:Drug Combinations; D007797:Laminin; D016328:NF-kappa B; D047495:PPAR gamma; D011509:Proteoglycans; D045162:Thiazolidinediones; D042461:Vascular Endothelial Growth Factor A; C059485:matrigel; D003094:Collagen; D040262:Receptors, Vascular Endothelial Growth Factor; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2; D000077288:Troglitazone; D015230:Prostaglandin D2