Apoptosis

, Volume 17, Issue 9, pp 1009–1018 | Cite as

Electronegative low-density lipoprotein induces cardiomyocyte apoptosis indirectly through endothelial cell-released chemokines

  • An-Sheng Lee
  • Guei-Jane Wang
  • Hua-Chen Chan
  • Fang-Yu Chen
  • Chia-Ming Chang
  • Chao-Yuh Yang
  • Yuan-Teh Lee
  • Kuan-Cheng Chang
  • Chu-Huang Chen
Original Paper

Abstract

Cardiomyocyte apoptosis has a critical role in the pathogenesis of heart failure. L5, the most negatively charged subfraction of human plasma low-density lipoprotein (LDL), induces several atherogenic responses in endothelial cells (ECs), including apoptosis. We hypothesized that L5 also contributes to cardiomyocyte apoptosis and studied whether it does so indirectly by inducing the secretion of factors from ECs. We examined apoptosis of rat cardiomyocytes treated with culture-conditioned medium (CCM) of rat ECs that were exposed to L5 or L1 (the least negatively charged LDL subfraction). Apoptosis at early and late time points was twofold greater in cardiomyocytes treated with L5 CCM than in those treated with L1 CCM. The indirect effect of L5 on cardiomyocyte apoptosis was significantly reduced by pretreating ECs with inhibitors of phosphatidylinositol 3-kinase (PI3K) or CXC receptor 2 (CXCR2). Studies with cytokine protein arrays revealed that L5 CCM, but not L1 CCM, contained high levels of ELR+ CXC chemokines, including lipopolysaccharide-induced chemokine (LIX) and interleukin (IL)-8. The L5-induced release of these chemokines from ECs was abolished by inhibiting the lectin-like oxidized LDL receptor-1 (LOX-1). Addition of recombinant LIX or IL-8 to CCM-free cardiomyocyte cultures increased apoptosis and enhanced production of tumor necrosis factor (TNF)-α and IL-1β by increasing the translocation of NF-κB into the nucleus; these effects were attenuated by inhibiting PI3K and CXCR2. In conclusion, L5 may indirectly induce cardiomyocyte apoptosis by enhancing secretion of ELR+ CXC chemokines from ECs, which in turn activate CXCR2/PI3K/NF-κB signaling to increase the release of TNF-α and IL-1β.

Keywords

Electronegative LDL Chemokine Apoptosis Cardiomyocyte 

Notes

Acknowledgments

This work was supported in part by Research Grant 1-04-RA-13 from the American Diabetes Association, Grant HL-63364 from the National Institutes of Health, a research grant from Merck/Schering-Plough Pharmaceuticals, grant NSC 100-2314-B-039-040-MY3 from the National Science Council of Taiwan, and grant DOH101-TD-B-111-004 from the Taiwan Department of Health Clinical Trial and Research Center of Excellence. The authors thank Nicole Stancel, Ph.D., and Elizabeth M. Gendel, Ph.D., of the Texas Heart Institute at St. Luke’s Episcopal Hospital in Houston, Texas, for editorial assistance.

Conflict of interest

The authors declare that they have no conflicts of interest.

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Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • An-Sheng Lee
    • 1
    • 2
    • 3
  • Guei-Jane Wang
    • 1
    • 3
  • Hua-Chen Chan
    • 1
  • Fang-Yu Chen
    • 1
    • 4
  • Chia-Ming Chang
    • 1
  • Chao-Yuh Yang
    • 1
    • 3
    • 5
    • 6
  • Yuan-Teh Lee
    • 2
    • 3
    • 7
  • Kuan-Cheng Chang
    • 2
    • 3
  • Chu-Huang Chen
    • 1
    • 3
    • 5
    • 6
  1. 1.L5 Research CenterChina Medical University HospitalTaichungTaiwan
  2. 2.Division of CardiologyChina Medical University HospitalTaichungTaiwan
  3. 3.Graduate Institute of Clinical Medical ScienceChina Medical UniversityTaichungTaiwan
  4. 4.Institute of PhysiologyNational Yang-Ming UniversityTaipeiTaiwan
  5. 5.Vascular and Medicinal Research, Wafic Said Molecular Cardiology Research LaboratoriesTexas Heart InstituteHoustonUSA
  6. 6.Department of MedicineBaylor College of MedicineHoustonUSA
  7. 7.Department of Internal MedicineNational Taiwan University HospitalTaipeiTaiwan

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