Regulation of fibrinolysis by non-esterified fatty acids.
The ability of oleic acid to modulate fibrinolysis was measured by following the urokinase-mediated and plasminogen-dependent cleavage of 125I-labelled fibrin clots. Oleic acid levels within the physiological range exerted a concentration-dependent inhibition of urokinase-mediated fibrinolytic activity. SDS/PAGE revealed that oleic acid enhances urokinase activity but simultaneously increases the autolytic cleavage of the newly formed low-molecular-mass subunit of plasmin. Oleic acid-induced cleavage of this subunit containing the catalytic site of plasmin was suppressed by the plasmin substrate H-D-valyl-L-leucyl-L-lysine-p-nitroanilide (S-2251) and was prevented by alpha 2-antiplasmin. A concentration-dependent inhibition of the activity of purified plasmin on 125I-labelled fibrin clot was also observed; 93% and 50% inhibition was noted with 150 microM and 32 microM oleic acid respectively. Oleic acid at 200 microM also effectively displaced plasmin prebound to a polylysine-Sepharose column. Examination of the fatty acid specificity showed that a minimal chain length of 16 carbon atoms and the presence of at least one double bond, preferably in a cis configuration, were required for inhibition of the fibrinolytic activity of plasmin. Oleic acid at a concentration that produced only a minimal inhibition of plasmin activity induced a marked inhibition by palmitic acid, while palmitic acid alone is ineffective. The findings suggest that oleic acid stimulates plasminogen activation and modulates the fibrinolytic and autolytic activities of plasmin.
Higazi
A A
AA
Department of Clinical Biochemistry, Hadassah Medical Center, Jerusalem, Israel.
Aziza
R
R
Samara
A A
AA
Mayer
M
M
D000595:Amino Acid Sequence; D002384:Catalysis; D005230:Fatty Acids, Nonesterified / Q000494:pharmacology*; D005341:Fibrinolysin / Q000096:biosynthesis / Q000378:metabolism; D005342:Fibrinolysis / Q000187:drug effects*; D006801:Humans; D008969:Molecular Sequence Data; D019301:Oleic Acid; D009829:Oleic Acids / Q000494:pharmacology; D010958:Plasminogen / Q000378:metabolism
D005230:Fatty Acids, Nonesterified; D009829:Oleic Acids; D019301:Oleic Acid; D010958:Plasminogen; D005341:Fibrinolysin