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DPP-4 inhibitors repress foam cell formation by inhibiting scavenger receptors through protein kinase C pathway

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Abstract

Studies show that dipeptidyl peptidase-4 (DPP-4) inhibitors may have an anti-atherosclerotic effect. Since foam cells are key components of atherosclerotic plaque, we studied the effect of DPP-4 inhibitors on foam cell formation. Foam cell formation was studied by treatment of THP-1 macrophages with oxidized low-density lipoprotein in the absence or presence of DPP-4 inhibitors (sitagliptin and NVPDPP728). The expression of scavenger receptors SRA, CD36 and LOX-1 was measured, and their role in foam cell formation in the presence of DPP-4 inhibitors was examined. In additional studies, role of protein kinase C and A in the effect of DPP-4 inhibitors was examined. Foam cell formation was markedly reduced by both DPP-4 inhibitors, as was the expression of CD36 and LOX-1 (CD36 ≫ LOX-1), but not SRA. Simultaneously, there was a reduction in phosphorylated PKC, but not PKA, content. Recovery of phosphorylated PKC following treatment of cells negated the effect of DPP-4 inhibitors on foam cell formation. Further, overexpression of CD36 or LOX-1 blocked the effect of DPP-4 inhibitors on foam cell formation. DPP-4 inhibitors repress foam cell formation through the inhibition of SRs CD36 and LOX-1, most likely via the inhibition of PKC activity. This study provides novel insights into the mechanism of inhibition of atherosclerosis by DPP-4 inhibitors.

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Acknowledgments

This study was supported by funds from the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development, Washington, DC. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

Conflict of interest

Yao Dai, Xianwei Wang, Zufeng Ding, Dongsheng Dai, Jawahar L. Mehta declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Endocrinology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, People’s Republic of China

    Yao Dai

  2. Cardiovascular Division, Department of Cardiology, University of Arkansas for Medical Sciences and the Central Arkansas Veterans Healthcare System, Little Rock, AR, 72212, USA

    Yao Dai, Xianwei Wang, Zufeng Ding & Jawahar L. Mehta

  3. Department of Cell Biology, College of Life Science and Technology, Xinxiang Medical University, Xinxiang, Henan, People’s Republic of China

    Xianwei Wang

  4. Department of Cardiology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, People’s Republic of China

    Dongsheng Dai

Authors
  1. Yao Dai
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  2. Xianwei Wang
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  3. Zufeng Ding
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  4. Dongsheng Dai
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  5. Jawahar L. Mehta
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Corresponding author

Correspondence to Jawahar L. Mehta.

Additional information

Communicated by Massimo Federici.

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592_2013_541_MOESM1_ESM.tif

Figure supplement 1 (A) Dose-dependent effect of sitagliptin on foam cell formation. *P < 0.05 vs. 0 μg. (B) DPP-4 inhibitors repress the protein expression of CD36, LOX-1 and CD68 *P < 0.05 vs. control, †P < 0.05 vs. ox-LDL alone treatment group. Abbreviations same as in previous figures. (TIFF 240 kb)

592_2013_541_MOESM2_ESM.tif

Figure supplement 2 DAG reversed the inhibitory effects of DPP-4 inhibitors on CD36 and LOX-1 expression. (representative Western blotting, quantitative data on the right). *P < 0.05 vs. ox-LDL plus sitagliptin treatment, †P < 0.05 vs. ox-LDL plus NVPDPP728 treatment. (B) DPP-4 inhibitors repress the protein expression of IL-6. *P < 0.05 vs. control, †P < 0.05 vs. ox-LDL alone treatment group. (TIFF 84 kb)

592_2013_541_MOESM3_ESM.tif

Figure supplement 3 Confirmation of hCD36 and hLOX-1 cDNAs transfection efficiency. (A) CD36 and LOX-1 expression increased after transfection with hCD36 and hLOX-1 cDNA, respectively. *P < 0.05 vs. ox-LDL plus sitagliptin + empty vector; †P < 0.05 vs. ox-LDL plus NVPDPP728 + empty vector. B. IL-6, interleukin-6 expression increased after ox-LDL treatment and this increase was reversed by DPP-4 inhibitors. Abbreviations same as in previous figures. (TIFF 115 kb)

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Dai, Y., Wang, X., Ding, Z. et al. DPP-4 inhibitors repress foam cell formation by inhibiting scavenger receptors through protein kinase C pathway. Acta Diabetol 51, 471–478 (2014). https://doi.org/10.1007/s00592-013-0541-3

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  • DOI: https://doi.org/10.1007/s00592-013-0541-3

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