期刊
CARDIOVASCULAR RESEARCH
卷 95, 期 3, 页码 346-355出版社
OXFORD UNIV PRESS
DOI: 10.1093/cvr/cvs189
关键词
Atherosclerosis; Protein kinase C; Foam cell; Oxidized LDL; Macrophages
资金
- National Science Council, Taiwan, R.O.C. [NSC 100-2314-B-016-014, NSC 98-2314-B-400-002-MY3]
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. 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 PKC inhibited oxidized LDL (OxLDL) uptake and intracellular cholesterol accumulation in both cell models. The reduction of PKC resulted in decreased expression of SR-A and CD36. Similar conclusions were obtained in examining the effects of a PKC inhibitor, rottlerin. Molecular investigation revealed that a decrease in PKC inhibited protein kinase B (PKB/Akt) expression and extracellular-signal-regulated kinase (ERK) phosphorylation. Surprisingly, PKC-knockdown selectively decreased protein but not the mRNA level of PKCI and PKCII. 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 PKC downstream of ERK attenuated SR-A but not CD36 expression. We further demonstrated that PKC could be induced by pro-atherogenic mediators, OxLDL and interferon-. Notably, PKC, phosphorylated ERK, Akt, and SR-A were highly expressed in human atherosclerotic arteries and CD68-positive macrophages as visualized by immunohistochemical staining. Through regulating PI3K/Akt and ERK activity, PKC affects SR-A and CD36 expression and foam cell formation. The results suggest PKC as a potential target for atherosclerosis therapeutics.
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