Downregulation of vascular matrix metalloproteinase inducer and activator proteins in hypertensive patients.
BACKGROUND
Peripheral vasculature undergoes extensive vascular remodeling in the hypertensive state. Regulation of extracellular matrix turnover by the matrix metalloproteinase (MMP) system is an important step in the vascular remodeling process. However, the expression pattern of the vascular MMP system in human hypertension remained unknown.


RESULTS
Internal mammary artery specimens were obtained from normotensive (n = 13) and hypertensive (n = 19) patients undergoing coronary artery bypass grafting surgery. Zymographic analysis indicated a threefold decrease in total gelatinolytic activity of MMP-2 and MMP-9 in hypertension. MMP-1 activity was also decreased by fourfold without a significant change in protein levels. Tissue levels of extracellular matrix inducer protein (EMMPRIN), MMP activator protein (MT1-MMP), MMP-1, MMP-2, and MMP-9, as well as tissue inhibitors of MMPs (TIMP-1 and TIMP-2) were assessed by immunoblotting and yielded a significant decrease in MMP-9, EMMPRIN, and MT1-MMP levels in hypertension. In addition, measurement of plasma markers of collagen synthesis (procollagen type I amino-terminal propeptide [PINP]) and collagen degradation (carboxy-terminal telopeptide of collagen type I [ICTP]) indicated no difference in PINP levels but suppressed degradation of collagen in hypertension. Evaluation of profibrotic growth factors demonstrated higher levels of fibroblast growth factor (FGF)-2 in tissue preparations from hypertensive patients but no difference in transforming growth factor-beta1 levels.


CONCLUSIONS
These findings demonstrate that not only MMP-1 and MMP-9, but MMP inducer and activator proteins are also downregulated in the hypertensive state. Augmented FGF-2 levels may contribute to parallel decreases in MMP activity and MMP induction system resulting in enhanced collagen deposition in hypertension.
Ergul
Adviye
A
Program in Clinical and Experimental Therapeutics, University of Georgia College of Pharmacy, Medical College of Georgia, Augusta, Georgia 30912, USA. aergul@mail.mcg.edu
Portik-Dobos
Vera
V
Hutchinson
Jimmie
J
Franco
Jennifer
J
Anstadt
Mark P
MP
D015703:Antigens, CD / Q000378:metabolism; D000951:Antigens, Neoplasm / Q000378:metabolism; D051926:Basigin; D001026:Coronary Artery Bypass; D015536:Down-Regulation; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D006801:Humans; D006973:Hypertension / Q000378:metabolism*; D008297:Male; D008323:Mammary Arteries / Q000378:metabolism; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases / Q000378:metabolism; D008875:Middle Aged; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism*; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D053773:Transforming Growth Factor beta1
D015703:Antigens, CD; D000951:Antigens, Neoplasm; C497886:BSG protein, human; C508960:TGFB1 protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D016222:Fibroblast Growth Factor 2; D019716:Tissue Inhibitor of Metalloproteinase-2; D051926:Basigin; D020782:Matrix Metalloproteinases; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D020781:Matrix Metalloproteinase 1