The basic helix-loop-helix transcription factor scleraxis regulates fibroblast collagen synthesis.
The transcription factor scleraxis has been implicated in regulating the development of collagen-rich tissues such as tendons and cardiac valves, but its role in general collagen synthesis in the heart is unknown. Scleraxis expression in cardiac fibroblasts was examined, and its ability to regulate gene expression of collagen I alpha 2, the predominant cardiac collagen isoform, was assayed. Using real-time PCR, we demonstrate here that scleraxis mRNA is up-regulated by the profibrotic agonist TGF-beta(1) in rat cardiac myofibroblasts, and that phenoconversion of fibroblasts to myofibroblasts similarly increases scleraxis expression. Over-expression of scleraxis in NIH-3T3 or primary rat cardiac fibroblasts by adenoviral gene delivery is sufficient to significantly increase collagen I alpha 2 gene expression. Using luciferase reporter assays, we demonstrate that scleraxis transactivates the human collagen I alpha 2 promoter in a DNA- and protein-binding dependent manner. Intriguingly, examination of infarcted rat hearts reveals a nearly four-fold increase in scleraxis expression in the infarct scar, but not in non-infarcted tissue. These data support a novel and previously unknown role for scleraxis in the regulation of collagen gene expression in the heart, including in post-infarct scar formation.
Espira
Leon
L
Institute of Cardiovascular Sciences, St. Boniface General Hospital Research Centre, University of Manitoba, 351 Tache Avenue, Winnipeg, Manitoba, Canada.
Lamoureux
Lise
L
Jones
Stephen C
SC
Gerard
Robert D
RD
Dixon
Ian M C
IM
Czubryt
Michael P
MP
D000818:Animals; D001483:Base Sequence; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D003094:Collagen / Q000096:biosynthesis* / Q000235:genetics; D024042:Collagen Type I; D005347:Fibroblasts / Q000378:metabolism*; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009203:Myocardial Infarction / Q000235:genetics / Q000378:metabolism; D041681:NIH 3T3 Cells; D011401:Promoter Regions, Genetic / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D015533:Transcriptional Activation / Q000235:genetics
D051792:Basic Helix-Loop-Helix Proteins; D003094:Collagen; D024042:Collagen Type I; C503819:Scx protein, rat