Interleukin-1beta attenuates beta-very low-density lipoprotein uptake and its receptor expression in vascular smooth muscle cells.
The very low-density lipoprotein (VLDL) receptor is a member of the low-density lipoprotein (LDL) receptor gene family with distinct tissue distribution and function. VLDL receptors are also expressed in vascular smooth muscle cells (VSMCs) and have been shown to be upregulated in atherosclerotic lesions. In the present study, we examined the effects of interleukin-1beta (IL-1beta) on the uptake of betaVLDL and its receptor expression in rat VSMCs. IL-1beta downregulated expression of the VLDL receptor in a time and dose-dependent manner as shown by Western blotting, Northern blotting, and reverse transcriptase-polymerase chain reaction (RT-PCR) analysis. Treatment with IL-1beta significantly reduced the uptake of beta-VLDL but not LDL in VSMCs. Use of specific pharmacologic inhibitors indicated that the tyrosine kinase inhibitors, herbimycin A and geldanamycin, completely reversed IL-1beta-induced downregulation of the VLDL receptor expression. Another tyrosine kinase inhibitor, genistein, the protein kinase C inhibitors, GF109203X and H7, the mitogen-activated protein (MAP) kinase inhibitors (MEK inhibitor PD098059 for [MEK] and SB203580 for p38-MAP kinase), and the protein kinase A inhibitor, KT5270 all had no effect on receptor expression. In addition, the c-Src specific inhibitor PP2 or adenoviral-mediated gene transfer of kinase inactive (KI)-c-Src failed to reverse IL-1beta-induced downregulation of VLDL receptor expression. These results indicate that IL-1beta attenuates uptake of VLDL through downregulation of its receptor in VSMCs, and that this downregulation is mediated through a benzoquinone ansamycin-dependent but c-Src-independent pathway.
Takahashi
Masafumi
M
Department of Organ Regeneration, Shinshu University Graduate School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan. masafumi@sch.md.shinshu-u.ac.jp
Takahashi
Sadao
S
Suzuki
Chihiro
C
Jia
Lijing
L
Morimoto
Hajime
H
Ise
Hirohiko
H
Iwasaki
Tadao
T
Hattori
Hiroaki
H
Suzuki
Jinya
J
Miyamori
Isamu
I
Kobayashi
Eiji
E
Ikeda
Uichi
U
D000818:Animals; D016207:Cytokines / Q000494:pharmacology; D015536:Down-Regulation; D004730:Endothelium, Vascular / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D007375:Interleukin-1 / Q000494:pharmacology / Q000502:physiology*; D008079:Lipoproteins, VLDL / Q000378:metabolism*; D008297:Male; D032389:Myocytes, Smooth Muscle / Q000166:cytology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011494:Protein Kinases / Q000187:drug effects; D051381:Rats; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
D016207:Cytokines; D007375:Interleukin-1; D008079:Lipoproteins, VLDL; D047428:Protein Kinase Inhibitors; D011973:Receptors, LDL; C036053:VLDL receptor; D011494:Protein Kinases