PT  - JOURNAL ARTICLE
AU  - Agapios Sachinidis
AU  - Stefan Seewald
AU  - Petra Epping
AU  - Claudia Seul
AU  - Yon Ko
AU  - Hans Vetter
TI  - The Growth-Promoting Effect of Low-Density Lipoprotein May Be Mediated by a Pertussis Toxin-Sensitive Mitogen-Activated Protein Kinase Pathway
AID  - 10.1124/mol.52.3.389
DP  - 1997 Sep 01
TA  - Molecular Pharmacology
PG  - 389--397
VI  - 52
IP  - 3
4099  - http://molpharm.aspetjournals.org/content/52/3/389.short
4100  - http://molpharm.aspetjournals.org/content/52/3/389.full
SO  - Mol Pharmacol1997 Sep 01; 52
AB  - Low-density lipoprotein (LDL) is known to be a mitogenic factor for vascular smooth muscle cells (VSMCs), fibroblasts, and endothelial cells. In the current study, we describe possible intracellular mechanisms by which LDL elicits its mitogenic effects. Stimulation of VSMCs with LDL resulted in a pertussis-toxin (PTX)-sensitive stimulation of the 44-kDa mitogen-activated protein (MAP) kinase (p44mapk) and 42-kDa MAP kinase (p42mapk) isoforms as well as in a PTX-sensitive increase in intracellular free Ca2+ concentration ([Ca2+]i). Binding of the LDL-induced increase in [Ca2+]i to the intracellular Ca2+ chelator bis(2-amino-5-methylphenoxy)ethane-N,N,N′,N′-tetraacetic acid tetraacetoxymethyl ester resulted in a 2-fold increase in the phosphorylated p44mapk and p42mapk isoforms but did not influence the LDL effect of VSMC DNA synthesis. PD 98059, a MAP kinase kinase inhibitor, remarkably attenuated the LDL-induced activation of MAP kinases and DNA synthesis. Treatment of normal human skin fibroblasts and human fibroblasts isolated from patients with familial hypercholesterolemia homozygote class 1 mutations, which are not able to produce the classic LDL receptor, resulted also in a PTX-sensitive increase in cell DNA synthesis and stimulation of the p44mapk and p42mapk isoforms in both cell types. These results demonstrate that the mitogenic effect of LDL is mediated by a PTX-sensitive Gi-coupled receptor that is independent of its classic receptor and involves activation of MAP kinase isoforms. Furthermore, the mitogenic effect of LDL may be mediated by the activation of the MAP kinase pathway. In contrast, the LDL-induced increase in [Ca2+]i may be implicated in this process only in conjugation with other signaling components.