Inhibition of astroglia-induced endothelial differentiation by inorganic lead: a role for protein kinase C.

Abstract

Microvascular endothelial function in developing brain is particularly sensitive to lead toxicity, and it has been hypothesized that this results from the modulation of protein kinase C (PKC) by lead. We examined the effects of

Immediate Early Gene Expression in PC12 Cells Exposed to Lead: Requirement for Protein Kinase C

“…Moreover, we had found previously that activation of the transcription factor AP-1 in PC12 cells after exposure to lead required PKC (Chakraborti et al, 1999). In our studies on PC12 cells, the concentrations of lead acetate were greater than the concentrations used by us to activate PKC in neural endothelial cells and glioma cells (Laterra et al, 1992). The concentration is also severalfold higher than the blood level in affected children.…”

“…We were surprised that activation of the cPKC did not occur, as activation of cPKC has been shown repeatedly in cultured cells (Laterra et al, 1992;Belloni-Olivi et al, 1996), and lead partially satisfies the requirement for calcium in PKC assays (Markovac and Goldstein, 1988;Long et al, 1994). The differences in responsiveness of the cPKC and nPKC to lead are most likely related to the differences in the intracellular cofactors required by these different families of PKC.…”

“…In contrast, higher concentrations of lead in the presence of calcium inhibited PKC activity (Tomsig and Suszkiw, 1995). Nonetheless, lead has been shown to activate PKC in erythrocytes (Belloni-Olivi et al, 1996), glioma cells, and bovine endothelial cells (Laterra et al, 1992).…”

Induction of Vascular Endothelial Growth Factor in Human Astrocytes by Lead

“…The PKC family comprises more than ten isoforms categorized into three structurally related groups: conventional PKCs (cPKCs: α,β and γ) are regulated by calcium and diacylglycerol or phorbol ester; novel PKCs (nPKCs: δ,θ,η and ε) are sensitive to diacylglycerol and phorbol ester but are calcium-independent; and atypical PKCs (aPKCs: ζ, µ and ι) are insensitive to calcium, diacylglycerol and phorbol ester (45). Activation of both calciumdependent and calcium-independent PKC isoforms by lead has been described in rodent and bovine cells such as glial, endothelial and PC12 pheochromocytoma cell lines (12,46,47). It has been proposed that lead alters PKC function by interacting with a high affinity site within the Nterminal regulatory domain either at the calcium activation site or cysteine-rich zinc-finger-like binding site (11,15,48).…”

“…Lead is reported to alter a number of calciummediated cellular processes including calcium channels and second messenger systems. Lead is a potent blocker of calcium channels, activates calmodulin with higher affinity than calcium (Ca 2+ ), and most importantly picomolar concentrations can substitute for Ca 2+ in activating protein kinase C (PKC) (11)(12)(13). PKC is a phospholipid-dependent diacylglycerol-activated serine/threonine protein kinase consisting of a multigene family of closely related, but distinct, isoenzymes (14,15).…”