PKCδ signalling regulates SR-A and CD36 expression and foam cell formation.
OBJECTIVE
The formation of foam cells is crucial in the initiation and progression of atherosclerosis. One of the critical steps in foam cell formation is the uptake of low-density lipoprotein (LDL) by macrophages via scavenger receptors (SRs). This study examined the role of protein kinase C (PKC) isoforms on foam cell formation.


RESULTS
The effects of short-hairpin RNA (shRNA) and small interfering RNA (siRNA) against classical PKC and novel PKC isoforms were investigated in THP-1-derived macrophages and primary macrophages. The knockdown of PKCδ inhibited oxidized LDL (OxLDL) uptake and intracellular cholesterol accumulation in both cell models. The reduction of PKCδ resulted in decreased expression of SR-A and CD36. Similar conclusions were obtained in examining the effects of a PKCδ inhibitor, rottlerin. Molecular investigation revealed that a decrease in PKCδ inhibited protein kinase B (PKB/Akt) expression and extracellular-signal-regulated kinase (ERK) phosphorylation. Surprisingly, PKCδ-knockdown selectively decreased protein but not the mRNA level of PKCβI and PKCβII. We showed that the inhibition of phosphatidylinositol 3-kinase (PI3K)/Akt upstream of ERK decreased SR-A and CD36 expression; however, the inhibition of ERK or PKCβ downstream of ERK attenuated SR-A but not CD36 expression. We further demonstrated that PKCδ could be induced by pro-atherogenic mediators, OxLDL and interferon-γ. Notably, PKCδ, phosphorylated ERK, Akt, and SR-A were highly expressed in human atherosclerotic arteries and CD68-positive macrophages as visualized by immunohistochemical staining.


CONCLUSIONS
Through regulating PI3K/Akt and ERK activity, PKCδ affects SR-A and CD36 expression and foam cell formation. The results suggest PKCδ as a potential target for atherosclerosis therapeutics.
Graduate Institute of Medical Science, National Defense Medical Center, No. 161 Sec. 6 Minquan E. Rd., Neihu, Taipei, Taiwan, ROC.
Chin-Sheng
CS
Lin
Feng-Yen
FY
Lin
Ling-Jun
LJ
Ho
Chien-Sung
CS
Tsai
Shu-Mung
SM
Cheng
Wan-Lin
WL
Wu
Chuan-Yueh
CY
Huang
Chen-Hao
CH
Lian
Shih-Ping
SP
Yang
Jenn-Haung
JH
Lai
D050197:Atherosclerosis / Q000201:enzymology* / Q000235:genetics / Q000276:immunology; D018955:CD36 Antigens / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005487:Foam Cells / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism; D064546:Protein Kinase C beta; D051745:Protein Kinase C-delta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D051117:Scavenger Receptors, Class A / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection
D018955:CD36 Antigens; D008077:Lipoproteins, LDL; C495139:MSR1 protein, human; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D051117:Scavenger Receptors, Class A; C099252:oxidized low density lipoprotein; D007371:Interferon-gamma; D002784:Cholesterol; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; C497258:PRKCD protein, human; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D051745:Protein Kinase C-delta; D048049:Extracellular Signal-Regulated MAP Kinases