Mechanisms contributing to increased synthesis of plasminogen activator inhibitor type 1 in endothelial cells by constituents of platelets and their implications for thrombolysis

• Published in: Circulation (New York, N.Y.) Vol. 83; no. 2; pp. 645 - 651
• Main Authors: FUJII, S, HOPKINS, W. E, SOBEL, B. E
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 01.02.1991
• Subjects: Biological and medical sciences; Blood Platelets - metabolism; Blood vessels and receptors; Endothelium, Vascular - metabolism; Enzyme-Linked Immunosorbent Assay; Fundamental and applied biological sciences. Psychology; Humans; In Vitro Techniques; Plasminogen Inactivators - metabolism; Platelet Activation - physiology; Precipitin Tests; Thrombolytic Therapy; Transforming Growth Factor alpha - metabolism; Transforming Growth Factor beta - metabolism; Vertebrates: cardiovascular system; Human; Cell culture; Platelet; Exploration; Plasminogen activator; Inhibitor; Circulatory system; Fibrinolysis; Umbilical vein; Endothelium
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/01.CIR.83.2.645

We recently hypothesized that after pharmacologically induced coronary thrombolysis, increased activity of plasminogen activator inhibitor type 1 (PAI-1) retards recanalization, contributes to early reocclusion, or both. This hypothesis was based on the increased elaboration of PAI-1 that we observed in cultured liver cells exposed to growth factors releasable from platelets activated at sites of thrombosis in vivo. PAI-1 released locally is particularly likely to attenuate lysis of thrombi that are targets of thrombolytic drugs. Accordingly, the present study was performed to determine whether synthesis of PAI-1 by endothelial cells is augmented by products of platelets. Lysates from platelets (0.5-8.0 x 10(4)/mm3 media, i.e. less than 10% of the concentration of platelets in blood) increased synthesis and release of PAI-1 into both the extracellular matrix and conditioned media (by 2.8-fold and 3.3-fold within 6 and 24 hours, respectively). Synthesis of neither tissue-type plasminogen activator nor overall protein increased. Increased synthesis of PAI-1 was confirmed by immunoprecipitation of [35S]PAI-1 after metabolic labeling of cells. The increased elaboration of PAI-1 was consistent with increased transcription as reflected by the observed increase in PAI-1 mRNA of 2.2-fold in 4 hours. Effects of platelet lysates were simulated by transforming growth factor beta (TGF-beta), known to be present in platelet alpha-granules and released with platelet activation. Antibody to TGF-beta reduced the stimulation of PAI-1 synthesis by TGF-beta, as expected, by 82%.