PKCδ signalling regulates SR-A and CD36 expression and foam cell formation

Chin Sheng Lin, Feng Yen Lin, Ling Jun Ho, Chien Sung Tsai, Shu Mung Cheng, Wan Lin Wu, Chuan Yueh Huang, Chen Hao Lian, Shih Ping Yang, Jenn Haung Lai

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

Aims: 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. Methods and 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 PKCd inhibited oxidized LDL (OxLDL) uptake and intracellular cholesterol accumulation in both cell models. The reduction of PKCd resulted in decreased expression of SR-A and CD36. Similar conclusions were obtained in examining the effects of a PKCd 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, PKCd-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, PKCd, phosphorylated ERK, Akt, and SR-A were highly expressed in human atherosclerotic arteries and CD68-positive macrophages as visualized by immunohistochemical staining. Conclusion: Through regulating PI3K/Akt and ERK activity, PKCd affects SR-A and CD36 expression and foam cell formation. The results suggest PKCδ as a potential target for atherosclerosis therapeutics.

Original languageEnglish
Pages (from-to)346-355
Number of pages10
JournalCardiovascular Research
Volume95
Issue number3
DOIs
Publication statusPublished - 2012

Keywords

  • Atherosclerosis
  • Foam cell
  • Macrophages
  • Oxidized LDL
  • Protein kinase Cδ

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)
  • Physiology

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    Lin, C. S., Lin, F. Y., Ho, L. J., Tsai, C. S., Cheng, S. M., Wu, W. L., Huang, C. Y., Lian, C. H., Yang, S. P., & Lai, J. H. (2012). PKCδ signalling regulates SR-A and CD36 expression and foam cell formation. Cardiovascular Research, 95(3), 346-355. https://doi.org/10.1093/cvr/cvs189