Differential effect of wall tension on matrix metalloproteinase promoter activation in the thoracic aorta.
BACKGROUND
Vascular remodeling relies upon extracellular matrix restructuring by the matrix metalloproteinases (MMPs). Induction of MMP-2 and MMP-9 by biological signaling molecules has been defined, but whether a mechanical stimulus such as elevated wall tension may generate MMP promoter activation remains unknown. Accordingly, this study examined whether MMP promoter activation would occur as a function of wall tension.


METHODS
The MMP-2 or MMP-9 promoter sequences were fused to the reporter gene lacZ and inserted into the mouse genome. Thoracic aortic rings were harvested (6 preparations/construct) and maintained under physiological conditions at predetermined tension values corresponding to 0, 70, 85, and 100 mm Hg for 3 h. Relative gene expression of lacZ, directly reflecting MMP promoter activity, was then quantified by QPCR.


RESULTS
MMP-2 promoter activity decreased to 0.42 +/- 0.11 at 0 mm Hg and increased to 1.57 +/- 0.24-fold at 100 mm Hg (P < 0.05), whereas MMP-9 was unaffected.


CONCLUSIONS
Using unique transgenic constructs with homology to human MMP promoters, this study demonstrated that a physiologically relevant mechanical stimulus was sufficient to differentially induce MMP promoter activation.
Division of Cardiothoracic Surgery, Department of Surgery, Medical University of South Carolina, Charleston, South Carolina 29425, USA.
Jean Marie
JM
Ruddy
Jeffrey A
JA
Jones
Robert E
RE
Stroud
Rupak
R
Mukherjee
Francis G
FG
Spinale
John S
JS
Ikonomidis
D000818:Animals; D001013:Aorta, Thoracic / Q000502:physiology*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D017930:Genes, Reporter / Q000502:physiology; D007763:Lac Operon; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics* / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D011817:Rabbits; D051381:Rats; D013314:Stress, Mechanical; D014661:Vasoconstriction / Q000502:physiology*
D012333:RNA, Messenger; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9