Increased expression of disintegrin-metalloproteinases ADAM-15 and ADAM-9 following upregulation of integrins alpha5beta1 and alphavbeta3 in atherosclerosis.
Regulation of alphavbeta3 and alpha5beta1 integrin function plays a crucial role in atherosclerosis. Possible regulators of integrin-matrix interactions are integrin-binding ADAMs (proteins with a disintegrin- and metalloproteinase-domain), like ADAM-15 and ADAM-9. Molecular interactions between ADAM-15, alpha5beta1, and alphavbeta3 have been demonstrated. ADAM-9 and ADAM-15 were found to be interdependently regulated. This study, therefore, investigated whether the upregulation of integrins alpha5beta1 and alphavbeta3 was correlated with the expression of integrin-binding ADAMs in atherosclerotic processes. Human arterial and venous vascular smooth muscle cells (VSMCs) were incubated with PDGF over different time intervals up to a 3-day culture period. mRNA concentrations, quantified by real-time RT-PCR and normalized to PBGD, of integrins alphavbeta3 and alpha5beta1 were strongly increased after a 12-h PDGF-incubation in arterial and venous VSMC. ADAM-15 and ADAM-9 mRNA production showed a corresponding increase following integrin upregulation after a 24-h incubation period. Western blot anaylsis revealed an increased protein expression of integrins and ADAMs in PDGF-stimulated VSMC. Additionally, mRNA concentrations of atherosclerotic and normal human specimens were quantified by real-time RT-PCR. mRNA of ADAMs and integrins was significantly increased in atherosclerotic arteries compared to normal arteries. Immunohistochemistry of these specimens showed an increased expression and codistribution of both ADAMs and integrins in atherosclerosis. In conclusion, upregulation of ADAM-15 and ADAM-9 in atherosclerosis appears to follow an increase in alpha5beta1 and alphavbeta3 integrins. Since alpha5beta1 and alphavbeta3 are known to promote smooth muscle cell migration and proliferation, upregulation of ADAM-15 and ADAM-9 could balance integrin-matrix interactions and cell migration, thus modulating neointima progression.
Al-Fakhri
Nadia
N
Institute of Clinical Chemistry and Pathobiochemistry, Justus Liebig University, Giessen, Germany. nadia.al-fakhri@klinchemie.med.uni-giessen.de
Wilhelm
Jochen
J
Hahn
Meinhard
M
Heidt
Martin
M
Hehrlein
Friedrich W
FW
Endisch
Andrea M
AM
Hupp
Thomas
T
Cherian
Sanjay M
SM
Bobryshev
Yuri V
YV
Lord
Reginald S A
RS
Katz
Norbert
N
D051722:ADAM Proteins; D000368:Aged; D001158:Arteries / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D001161:Arteriosclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D017931:DNA Primers / Q000235:genetics; D019483:Disintegrins / Q000096:biosynthesis* / Q000378:metabolism*; D005260:Female; D006801:Humans; D039081:Integrin alpha5beta1 / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D039302:Integrin alphaVbeta3 / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000378:metabolism; D008666:Metalloendopeptidases / Q000096:biosynthesis* / Q000378:metabolism; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000473:pathology; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D015854:Up-Regulation; D014680:Veins / Q000166:cytology / Q000378:metabolism / Q000473:pathology
D017931:DNA Primers; D019483:Disintegrins; D039081:Integrin alpha5beta1; D039302:Integrin alphaVbeta3; D008565:Membrane Proteins; D010982:Platelet-Derived Growth Factor; D012333:RNA, Messenger; D051722:ADAM Proteins; C098660:ADAM15 protein, human; C098339:ADAM9 protein, human; D008666:Metalloendopeptidases