Nucleic acids potentiate Factor VII-activating protease (FSAP)-mediated cleavage of platelet-derived growth factor-BB and inhibition of vascular smooth muscle cell proliferation.
FSAP (Factor VII-activating protease) can cleave and inactivate PDGF-BB (platelet-derived growth factor-BB) and thereby inhibits VSMC (vascular smooth-muscle cell) proliferation. The auto-activation of FSAP is facilitated by negatively charged polyanions such as heparin, dextransulfate or extracellular ribonucleic acids. Since auto-activation is essential for the anti-proliferative function of FSAP, the influence of nucleic acids as cofactors for the FSAP-mediated inhibition of PDGF-BB was investigated. Natural or artificial RNA was an effective cofactor for FSAP mediated PDGF-BB degradation, whereas the effect of DNA was weak. RNA-induced cleavage of PDGF-BB was inhibited by serine protease inhibitors. The pattern of PDGF-BB cleavage was identical with either heparin or RNA as a cofactor. One of the cleavage sites in PDGF-BB was at the positions 160-162 (R160KK162), which is an important region for receptor binding and activation. In VSMCs, PDGF-BB-stimulated DNA synthesis was inhibited by FSAP in the presence of RNA. RNA was more effective than DNA and the cofactor activity of RNA was neutralized after pretreatment with RNase. FSAP binding to RNA protected the nucleic acid from degradation by RNase. These data are relevant to situations where extracellular nucleic acids released from necrotic or apoptotic cells could activate local FSAP, leading to inhibition of PDGF-BB.
Shibamiya
Aya
A
Institute for Biochemistry, Medical Faculty, Justus-Liebig-University, 35392 Giessen, Germany.
Muhl
Lars
L
Tannert-Otto
Susanne
S
Preissner
Klaus T
KT
Kanse
Sandip M
SM
D000818:Animals; D000077214:Becaplermin; D001973:Bromodeoxyuridine / Q000493:pharmacokinetics; D016466:CHO Cells; D002455:Cell Division; D006224:Cricetinae; D003412:Cricetulus; D004247:DNA / Q000235:genetics / Q000302:isolation & purification; D006487:Hemostasis; D006801:Humans; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000502:physiology*; D010982:Platelet-Derived Growth Factor / Q000378:metabolism*; D020574:Proto-Oncogene Proteins c-sis; D012313:RNA / Q000138:chemical synthesis / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D012697:Serine Endopeptidases / Q000378:metabolism*
D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D011994:Recombinant Proteins; D000077214:Becaplermin; D012313:RNA; D004247:DNA; D020929:Mitogen-Activated Protein Kinase Kinases; C433550:HABP2 protein, human; D012697:Serine Endopeptidases; D001973:Bromodeoxyuridine