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Cardiovascular Research 1997 36(1):92-100; doi:10.1016/S0008-6363(97)00139-9
© 1997 by European Society of Cardiology
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Copyright © 1997, European Society of Cardiology

Low density lipoprotein enhances the thrombin-induced growth of vascular smooth muscle cells

Stefan Seewald1, Georg Nickenig1, Yon Ko, Hans Vetter and Agapios Sachinidis*

Medizinische Universitäts-Poliklinik, Wilhelmstr. 35–37, 53111 Bonn, Germany

* Corresponding author. Tel.: (+49 228) 2872589 or 2580; fax: (+49 228) 2872674 or 2266.

Objective: In the present study we investigated whether low density lipoprotein is able to enhance the growth promoting effects of thrombin in vascular smooth muscle cells. Methods: DNA synthesis was examined by measurement of the [3H]thymidine incorporation into the cell DNA. Cell count was measured with a Neubauer cell box. Thrombin receptor mRNA was determined by Northern blotting. Ca2+ was measured by the fura 2-method. Results: Thrombin (5 nmol/l), thrombin receptor activating protein (3 µmol/l) and low density lipoprotein (33 nmol/l) induce a 652±80%, 593±80% and a 316±60% increase in [3H]thymidine incorporation into DNA (mean±SD, n = 3), respectively. A coincubation of thrombin or thrombin receptor activating protein with low density lipoprotein led to a 1245±160% or 1200±40% increase of DNA synthesis (mean±SD, n = 3). Thus, coincubation of low density lipoprotein and thrombin causes a synergistic rather than an additive mitogenic effect on smooth muscle cells. Thrombin and low density lipoprotein induced a 22±8,4% and a 29%±6% increase in cell number, respectively. Simultaneous treatment of vascular smooth muscle cells with thrombin and low density lipoprotein caused a 63±14% increase in cell number (mean±SD, n = 3). To further elucidate the underlying mechanism, we studied the effect of low density lipoprotein on the expression of thrombin receptor mRNA. Low density lipoprotein caused a 2.5-fold increase of thrombin receptor mRNA within 24 h, as assessed by Northern analysis. Preincubation of cells for 24 h with 33 nmol/l low density lipoprotein resulted in an elevation of the thrombin-induced increase in cytosolic free Ca2+ concentration from 538±54 to 923±75 nmol/l (mean±SD, n = 4). Conclusion: In summary, low density lipoprotein may enhance the mitogenic effect of thrombin probably by an up-regulation of thrombin receptor gene expression in vascular smooth muscle cells or by an elevation of the thrombin-induced increase in cytosolic free Ca2+ concentration.

KEYWORDS Low density lipoprotein; Smooth muscle cell; Thrombin

1 Equal contributor to this work.


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