Cholesterol esterification in human monocyte-derived macrophages is inhibited by protein kinase C with dual roles for mitogen activated protein kinases.
The possible role of protein kinase C (PKC) and mitogen activated protein (MAP) kinases in the stimulation of cholesterol esterification by acetylated low density lipoprotein (acLDL) in human monocyte-derived macrophages (HMDM) was studied. Cholesterol esterification, as assessed by the rate of incorporation of [3H]-oleate into cholesteryl ester, was markedly higher in HMDM incubated with acLDL as compared to native LDL (nLDL). In the presence of the phorbol ester, phorbol 12-myristate 13-acetate (PMA, 100 nM), however, the rate of incorporation was reduced by about 50% and 85% in incubations with nLDL and acLDL, respectively. Thus, the difference in the rate of cholesteryl esterification induced by the two types of lipoprotein was abolished by PMA, indicating that PKC activation inhibits the process, and this was confirmed by the finding that the PKC inhibitor calphostin C reversed the PMA-induced inhibition of cholesterol esterification. Incubation of HMDM with PMA was found to cause a considerable increase in the activation of p42/44 extracellular signal-regulated MAP kinases (ERK) and p38 MAP kinases, reaching a maximum at 30 min. In the presence of acLDL, the ERK inhibitor PD98059 decreased cholesterol esterification in HMDM by about 35%. In contrast, the p38 inhibitor SB203580 had no effect. However, when PMA was present in addition to SB203580, esterification was reduced to a level lower than that observed with PMA alone. These findings suggest that activation of ERK, but not p38, MAP kinases is involved in the induction of cholesterol esterification by acLDL in HMDM, while p38 MAP kinases may modulate the inhibitory effect of PKC, and thus provide evidence that MAP kinases play a role in the regulation of foam cell formation in human macrophages.
Napolitano
Mariarosaria
M
Istituto Superiore di Sanita, Department of Hematology, Oncology and Molecular Medicine, Viale Regina Elena, 00161 Rome, Italy.
Avella
Michael
M
Goode
Nigel T
NT
Botham
Kathleen M
KM
Bravo
Elena
E
D002788:Cholesterol Esters / Q000378:metabolism; D008078:Cholesterol, LDL / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004951:Esterification / Q000187:drug effects; D006801:Humans; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009000:Monocytes / Q000187:drug effects / Q000201:enzymology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*
D002788:Cholesterol Esters; D008078:Cholesterol, LDL; D004791:Enzyme Inhibitors; D011493:Protein Kinase C; D020928:Mitogen-Activated Protein Kinases