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EXPERIMENTAL STUDIES

Vascular smooth muscle proliferation

Synergistic interaction between serotonin and low density lipoproteins

^a Department of Internal Medicine, Division of Cardiology, University of Texas Health Science Center at Houston, Houston, Texas, USA
^* Showa University School of Medicine, Tokyo, Japan

Manuscript received September 21, 1998; revised manuscript received May 18, 1999, accepted June 28, 1999.

Reprint requests and correspondence: Dr. Claude R. Benedict, Department of Internal Medicine, Division of Cardiology, The University of Texas Health Science Center, 6431 Fannin, MSB 6.039, Houston, Texas 77030

OBJECTIVES

The purpose of this study was to examine whether low density lipoproteins (LDLs) or mildly oxidized LDL (mox-LDL) are mitogens for vascular smooth muscle cells (VSMCs) and whether they can act synergistically with serotonin (5HT), a known mitogen for VSMC, in potentiating the proliferative effect of 5HT on VSMC.

BACKGROUND

Whether LDL or mox-LDL has a mitogenic effect on VSMC has been controversial. It is possible that LDL may not be mitogenic to VSMC but modification of LDL may confer mitogenic properties on LDL. A known mitogen for VSMC is 5HT that is released by aggregating platelets at sites of atherosclerotic changes or endothelial dysfunction. It is possible that LDL may interact with 5HT to enhance VSMC proliferation induced by 5HT.

METHODS

Growth arrested primary VSMCs were incubated with different concentrations of LDL or mox-LDL for 24 h followed by incubation with 5HT for another 24 h (mild oxidation of LDL was achieved by incubating LDL with Cu⁺⁺ which increased the thiobarbituric acid product formation without a change in electrophoretic mobility). The increase in cell number or the amount of ³H-thymidine incorporated into the DNA was then measured.

RESULTS

Low density lipoprotein and mox-LDL induced significant VSMC proliferation by themselves and this effect was potentiated by 5HT. The 5HT₂ receptor antagonist (LY281067) and pertussis toxin reversed only the proliferative effect of 5HT. Polyinosinic acid (poly-I), an inhibitor of scavenger receptors, did not inhibit the proliferative effect of LDL or mox-LDL or their synergistic interaction with 5HT.

CONCLUSIONS

These results suggest that LDL and mox-LDL act synergistically with 5HT in inducing VSMC proliferation. The synergistic interaction could be blocked by LY281067 and pertussis toxin but not by poly-I acid.

Abbreviations and Acronyms   BSA = bovine serum albumin   DMEM = Dulbecco’s modified Eagle’s medium   EDTA = ethylenediamine tetraacetic acid   FBS = fetal bovine serum   HBSS = Hank’s balanced salt solution   JNK/SAPK = c-Jun N-terminal kinases/stress activated kinase   LDL = low density lipoprotein   Lyso-PC = lysophosphatydilcholine   MAP-kinase = mitogen activated protein kinase   mox-LDL = mildly oxidized low density lipoprotein   PBS = phosphate buffered saline   poly-I = polyinosinic acid   PTX = pertussis toxin   SMC = smooth muscle cell   TBARS = thiobarbituric acid reactive products   VSMC = vascular smooth muscle cell   5HT = serotonin

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