The regulation of p42/p44 mitogen-activated protein kinases in the injured rat carotid artery.
Arterial smooth muscle cell (SMC) proliferation is an important factor in the development of atherosclerotic plaques and restenotic lesions following arterial reconstruction. Basic fibroblast growth factor (bFGF), platelet-derived growth factor (PDGF), and thrombin are known to induce SMC proliferation and migration in vitro and in vivo. In cultured cells the proliferative responses to these mitogens depend on the activation of the p42/p44 mitogen-activated protein kinases (MAPKs), whereas the role of these kinases in vivo has yet to be established. We tested whether MAPK activity is induced following vessel injury and whether activity is dependent on the release of bFGF, PDGF, and thrombin. Following balloon injury of the left carotid of male Sprague-Dawley rats, arteries were removed and analyzed with respect to MAPK activity, BrdU-labeled nuclei, and/or luminal, medial, and intimal areas. MAPK activity is induced in the rat carotid artery following balloon-catheter injury with a maximum activation at 30 min with a return to just above baseline at 11 hr after injury. Intravenous administration of heparin or neutralizing antibodies to bFGF or PDGF prior to injury reduced SMC proliferation and neointimal lesional formation but did not affect the early induction of MAPK activity. Administration of a tissue factor inhibitor or thrombin inhibitor also did not affect MAPK activity, although it impaired the initiation of the coagulation cascade.


CONCLUSIONS
(1) MAPK is activated in a time-dependent manner in response to injury; (2) the antiproliferative effect of heparin in vivo is not mediated through the inhibition of MAPK activity induced 30 min after injury; (3) the activation of MAPK after 30 min is not dependent on PDGF, bFGF, or thrombin following vessel injury in the rat.
Lille
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S
Department of Surgery, University of Washington, Seattle 98195-6410, USA.
Daum
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Clowes
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Clowes
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AW
D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002339:Carotid Arteries / Q000201:enzymology; D020212:Carotid Artery Injuries; D002404:Catheterization / Q000009:adverse effects*; D004789:Enzyme Activation; D005346:Fibroblast Growth Factors / Q000502:physiology; D006493:Heparin / Q000494:pharmacology; D006629:Hirudins / Q000494:pharmacology; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1; D010982:Platelet-Derived Growth Factor / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
D006629:Hirudins; D010982:Platelet-Derived Growth Factor; D005346:Fibroblast Growth Factors; D006493:Heparin; D011505:Protein-Tyrosine Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1