Lead-dependent effects on arachidonic acid accumulation and the proliferation of vascular smooth muscle.
Lead (Pb(2+)) has been implicated in the development of hypertension and atherosclerosis. The proliferation of vascular smooth muscle cells (VSMC) is a central feature of both conditions and there is evidence that Pb(2+) potentiates serum-dependent cell growth. The aim of this work was to examine the role of phospholipase A(2) in mitogen-dependent VSMC proliferation and determine if Pb(2+) interacts with this system in order to potentiate mitotic events. It was observed that cell proliferation induced by angiotensin II, or fetal bovine serum, required the activation of a Ca(2+)-dependent cytosolic phospholipase A(2) and the subsequent release of unesterified arachidonic acid. This path was affected by Pb(2+) as the metal increased the amount of arachidonic acid accumulation induced by either mitogen. In addition, Pb(2+) potentiated mitogen-induced DNA synthesis when present at lower doses (0.02 or 0.2 mg%), but had no effect on DNA synthesis, or cell numbers, in unstimulated cells. However, a high dose (2 mg%) of Pb(2+) attenuated the DNA synthesis stimulated by angiotensin II, or serum, but induced the accumulation of unesterified arachidonic acid in unstimulated cells. A biphasic effect of Pb(2+) on cell numbers and viability was also observed as 0.02 or 0.2 mg% Pb(2+) did not affect cell numbers or trypan blue exclusion in unstimulated cells, while 2 mg% Pb(2+) reduced cell numbers and viability. It appeared, therefore, that the lower concentrations of Pb(2+) increased arachidonic acid release and DNA synthesis only in stimulated VSMC, perhaps due to further activation of a Ca(2+)-dependent processes. In contrast, the high dose of Pb(2+) reduced DNA synthesis in stimulated cells and reduced cell numbers and viability in unstimulated cells, which may relate to the noted increase in unesterified arachidonic acid.
Dorman
Robert V
RV
Department of Biological Sciences, Kent State University, Kent, OH 44242, USA.
Freeman
Ernest J
EJ
D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic; D016718:Arachidonic Acid / Q000378:metabolism*; D002452:Cell Count; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D007854:Lead / Q000633:toxicity*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010741:Phospholipases A / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D051381:Rats; D012710:Serum Albumin, Bovine / Q000494:pharmacology
D011506:Proteins; D000804:Angiotensin II; D012710:Serum Albumin, Bovine; D016718:Arachidonic Acid; D007854:Lead; D004247:DNA; D010741:Phospholipases A