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Articles by E. Ikonen
Total Records ( 3 ) for E. Ikonen
  M. D Linder , M. I Mayranpaa , J Peranen , T. E Pietila , V. M Pietiainen , R. L Uronen , V. M Olkkonen , P. T Kovanen and E. Ikonen
 

Objective— ATP-binding cassette transporter A1 (ABCA1) is thought to lipidate apolipoprotein A-I (apoA-I) at the plasma membrane, with endosomal cholesterol contributing as substrate. The mechanisms of ABCA1 surface delivery are not well understood. We have shown that Rab8 regulates endosomal cholesterol removal to apoA-I in human fibroblasts. Here, we investigated whether Rab8 plays a role in ABCA1 plasma membrane expression and cholesterol removal in primary human macrophages.

Methods and Results— We found that Rab8 was abundantly expressed in human atherosclerotic lesional macrophages and upregulated on lipid loading of macrophages in vitro. Adenoviral overexpression of Rab8 increased ABCA1 protein levels and reduced cholesterol deposition in macrophage foam cells incubated with apoA-I. Depletion of Rab8 decreased the fraction of ABCA1 at the plasma membrane and inhibited the efflux of lipoprotein-derived endosomal cholesterol to apoA-I. In Rab8-depleted cells, ABCA1-GFP localized in β1 integrin and transferrin receptor containing recycling organelles.

Conclusion— Rab8 reduces foam cell formation by facilitating ABCA1 surface expression and stimulating endosomal cholesterol efflux to apoA-I in primary human macrophages.

  T Blom , N Back , A. L Mutka , R Bittman , Z Li , A de Lera , P. T Kovanen , U Diczfalusy and E. Ikonen
 

Rationale: The synthetic sphingosine analog FTY720 is undergoing clinical trials as an immunomodulatory compound, acting primarily via sphingosine 1-phosphate receptor activation. Sphingolipid and cholesterol homeostasis are closely connected but whether FTY720 affects atherogenesis in humans is not known.

Objective: We examined the effects of FTY720 on the processing of scavenged lipoprotein cholesterol in human primary monocyte-derived macrophages.

Methods and Results: FTY720 did not affect cholesterol uptake but inhibited its delivery to the endoplasmic reticulum, reducing cellular free cholesterol cytotoxicity. This was accompanied by increased levels of Niemann–Pick C1 protein (NPC1) and ATP-binding cassette transporter (ABC)A1 proteins and increased efflux of endosomal cholesterol to apolipoprotein A-I. These effects were not dependent on sphingosine 1-phosphate receptor activation. Instead, FTY720 stimulated the production of 27-hydroxycholesterol, an endogenous ligand of the liver X receptor, leading to liver X receptor–induced upregulation of ABCA1. Fluorescently labeled FTY720 was targeted to late endosomes, and the FTY720-induced upregulation of ABCA1 was NPC1-dependent, but the endosomal exit of FTY720 itself was not.

Conclusions: We conclude that FTY720 decreases cholesterol toxicity in primary human macrophages by reducing the delivery of scavenged lipoprotein cholesterol to the endoplasmic reticulum and facilitating its release to physiological extracellular acceptors. Furthermore, FTY720 stimulates 27-hydroxycholesterol production, providing an explanation for the atheroprotective effects and identifying a novel mechanism by which FTY720 modulates signaling.

  T. Hieta , M. Vainio , C. Moser and E. Ikonen
  We present two external-cavity diode lasers that utilize a volume holographic grating as the frequency selective feedback element. By using the grating at normal incidence, it is possible to design simple and compact external-cavity diode lasers that have sufficient tunability for molecular spectroscopy. The first design utilizes a long-cavity designed for narrow linewidth and good long-term stability. The laser operates near 635 nm and it has a PZT-controlled tuning range of 28 GHz and a 1-s linewidth of 900 kHz. The second design utilizes a grating attached very close to the laser diode, making the laser compact, robust and easy to operate. The short external-cavity laser operates near 658 nm and it has a linewidth of 30 MHz. Continuous and mode-hop free tuning range of 145 GHz can be obtained by using a simple temperature tuning method.
 
 
 
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