Inhibitory mechanisms of activated matrix metalloproteinase-9 on platelet activation.
The intracellular mechanisms underlying the signaling pathways of activated matrix metalloproteinase-9 (MMP-9) in platelets are not yet completely understood. Therefore, the aim of this study was to further examine the effects of activated MMP-9 in preventing platelet aggregation. In this study, activated MMP-9 time-dependently (3-60 min) inhibited platelet aggregation in washed human platelet suspensions stimulated by agonists. However, activated MMP-9 had no significant effect on the binding of FITC-triflavin to the platelet glycoprotein IIb/IIIa complex. Triflavin is a specific antagonist of the glycoprotein IIb/IIIa complex purified from snake venom. Moreover, activated MMP-9 (21 and 90 ng/ml) markedly decreased the fluorescence intensity of platelet membranes tagged with diphenylhexatriene. The thrombin-evoked increase in pHi was inhibited in the presence of activated MMP-9 (21 and 90 ng/ml). In addition, activated MMP-9 (21 and 90 ng/ml) markedly reduced the electron spin resonance (ESR) signal intensity of hydroxyl radicals in collagen (1 mug/ml)-activated platelets. These results indicate that the antiplatelet activity of activated MMP-9 may involve the following pathways: (1) activated MMP-9 may initially induce conformational changes in platelet membranes and hydroxyl radical formation, leading to inhibition of platelet aggregation; and (2) activated MMP-9 also inhibits the Na(+)/H(+) exchanger, leading to reduced intracellular Ca(2+) mobilization, and ultimately to inhibition of platelet aggregation. This study further provides new insights concerning the effects of activated MMP-9 on platelet aggregation.
Lee
Ye-Ming
YM
Department of Surgery, Hsinchu Mackay Memorial Hospital, Hsinchu, Taiwan.
Lee
Jie-Jen
JJ
Shen
Ming-Yi
MY
Hsiao
George
G
Sheu
Joen-Rong
JR
D001792:Blood Platelets / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D006801:Humans; D006863:Hydrogen-Ion Concentration; D017665:Hydroxyl Radical / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000032:analysis; D020780:Matrix Metalloproteinase 9 / Q000494:pharmacology*; D008560:Membrane Fluidity / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000378:metabolism
D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D017665:Hydroxyl Radical; D007770:L-Lactate Dehydrogenase; D020780:Matrix Metalloproteinase 9