Induction of the matrix metalloproteinase-2 activation system in arteries by tensile stress. Involvement of the p38 MAP-kinase pathway.
Matrix metalloproteinases (MMPs) play an important role in vascular remodeling and cardiovascular diseases by degrading extracellular matrix. Regulation of MMPs can be mediated by mitogen-activated protein kinases (MAPKs). Effects of pressure application on the proteolytic activity of MMP-2 and MAPK pathways were investigated in an organ culture of porcine muscular arteries. Inhibition of MAPKs (ERK1/2 and p38 MAPK) was carried out to prove their effects on MMP-2 activation. After tensile stress, activity and gene expression of MMP-2 were increased (p<0.05) as shown by gelatinase assays and real-time PCR. Whereas protein expression of MMP-2 and TIMP-2 showed no changes, its regulator MT1-MMP decreased in Western blot (p<0.001) and immunohistochemistry. In addition, p38 and ERK1/2 were activated (p38, p<0.05; ERK1/2, p<0.001) by pressure. After inhibition of p38 and ERK1/2 with SB203580 or PD98059, only the inhibition of the p38 pathway had an inhibitory effect on MMP-2 gelatinolytic activity. Tensile stress activates the MMP-2 system in muscular arterial walls. This mechanical signal is mediated by p38 MAPK and can be attenuated by blocking the p38 signal pathway. The regulation of the vascular gelatinolytic system by MAP kinases suggests a therapeutic option against cardiovascular diseases at the level of MAPK signal transduction.
Grabellus
Florian
F
Institute of Pathology and Neuropathology, University Hospital of Essen, Essen, Germany. florian.grabellus@uk-essen.de
Worm
Karl
K
Schmid
Kurt W
KW
D000818:Animals; D001158:Arteries / Q000201:enzymology; D015153:Blotting, Western; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology; D015870:Gene Expression; D007093:Imidazoles / Q000494:pharmacology; D007150:Immunohistochemistry; D020935:MAP Kinase Signaling System / Q000187:drug effects; D053511:Matrix Metalloproteinase 14 / Q000235:genetics / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism*; D040542:Mechanotransduction, Cellular / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology*; D009924:Organ Culture Techniques; D011312:Pressure; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013314:Stress, Mechanical; D013552:Swine; D013718:Tensile Strength; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
D005419:Flavonoids; D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D012333:RNA, Messenger; D019716:Tissue Inhibitor of Metalloproteinase-2; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020778:Matrix Metalloproteinase 2; D053511:Matrix Metalloproteinase 14; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one