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

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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.

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References

  1. Olivetti G, Abbi R, Quaini F et al (1997) Apoptosis in the failing human heart. N Engl J Med 336:1131–1141

    Article  PubMed  CAS  Google Scholar 

  2. Sarkar S, Leaman DW, Gupta S et al (2004) Cardiac overexpression of myotrophin triggers myocardial hypertrophy and heart failure in transgenic mice. J Biol Chem 279:20422–20434

    Article  PubMed  CAS  Google Scholar 

  3. Beltrami AP, Urbanek K, Kajstura J et al (2001) Evidence that human cardiac myocytes divide after myocardial infarction. N Engl J Med 344:1750–1757

    Article  PubMed  CAS  Google Scholar 

  4. Kang BY, Wang W, Palade P, Sharma SG, Mehta JL (2009) Cardiac hypertrophy during hypercholesterolemia and its amelioration with rosuvastatin and amlodipine. J Cardiovasc Pharmacol 54:327–334

    Article  PubMed  CAS  Google Scholar 

  5. Lipinski MJ, Cauthen CA, Biondi-Zoccai GG et al (2009) Meta-analysis of randomized controlled trials of statins versus placebo in patients with heart failure. Am J Cardiol 104:1708–1716

    Article  PubMed  CAS  Google Scholar 

  6. Iwai-Kanai E, Hasegawa K, Sawamura T et al (2001) Activation of lectin-like oxidized low-density lipoprotein receptor-1 induces apoptosis in cultured neonatal rat cardiac myocytes. Circulation 104:2948–2954

    Article  PubMed  CAS  Google Scholar 

  7. Chen CH, Jiang T, Yang JH et al (2003) Low-density lipoprotein in hypercholesterolemic human plasma induces vascular endothelial cell apoptosis by inhibiting fibroblast growth factor 2 transcription. Circulation 107:2102–2108

    Article  PubMed  Google Scholar 

  8. Chen HH, Hosken BD, Huang M et al (2007) Electronegative LDLs from familial hypercholesterolemic patients are physicochemically heterogeneous but uniformly proapoptotic. J Lipid Res 48:177–184

    Article  PubMed  CAS  Google Scholar 

  9. Yang CY, Raya JL, Chen HH et al (2003) Isolation, characterization, and functional assessment of oxidatively modified subfractions of circulating low-density lipoproteins. Arterioscler Thromb Vasc Biol 23:1083–1090

    Article  PubMed  CAS  Google Scholar 

  10. Lu J, Jiang W, Yang JH et al (2008) Electronegative LDL impairs vascular endothelial cell integrity in diabetes by disrupting fibroblast growth factor 2 (FGF2) autoregulation. Diabetes 57:158–166

    Article  PubMed  CAS  Google Scholar 

  11. Tang D, Lu J, Walterscheid JP et al (2008) Electronegative LDL circulating in smokers impairs endothelial progenitor cell differentiation by inhibiting Akt phosphorylation via LOX-1. J Lipid Res 49:33–47

    Article  PubMed  CAS  Google Scholar 

  12. Lu J, Yang JH, Burns AR et al (2009) Mediation of electronegative low-density lipoprotein signaling by LOX-1: a possible mechanism of endothelial apoptosis. Circ Res 104:619–627

    Article  PubMed  CAS  Google Scholar 

  13. Tai MH, Kuo SM, Liang HT et al (2006) Modulation of angiogenic processes in cultured endothelial cells by low density lipoproteins subfractions from patients with familial hypercholesterolemia. Atherosclerosis 186:448–457

    Article  PubMed  CAS  Google Scholar 

  14. Kelly RA, Smith TW (1997) Cytokines and cardiac contractile function. Circulation 95:778–781

    Article  PubMed  CAS  Google Scholar 

  15. Opie LH (1998) The heart: physiology, from cell to circulation. Lippincott-Raven, Philadelphia

  16. Chen CH, Lu J, Chen SH et al (2012) Effects of electronegative VLDL on endothelium damage in metabolic syndrome. Diabetes Care 35:648–653

    Article  PubMed  CAS  Google Scholar 

  17. Chen CH, Cartwright J Jr, Li Z et al (1997) Inhibitory effects of hypercholesterolemia and ox-LDL on angiogenesis-like endothelial growth in rabbit aortic explants. Essential role of basic fibroblast growth factor. Arterioscler Thromb Vasc Biol 17:1303–1312

    Article  PubMed  CAS  Google Scholar 

  18. Institute of Laboratory Animal Research CoLS, National Research Council (1996) Guide for the use and care of laboratory animals. National Academy Press, Washington, DC

  19. Wang GJ, Shan J, Pang PK, Yang MC, Chou CJ, Chen CF (1996) The vasorelaxing action of rutaecarpine: direct paradoxical effects on intracellular calcium concentration of vascular smooth muscle and endothelial cells. J Pharmacol Exp Ther 276:1016–1021

    PubMed  CAS  Google Scholar 

  20. Vanhecke TE, Kim R, Raheem SZ, McCullough PA (2010) Myocardial ischemia in patients with diastolic dysfunction and heart failure. Curr Cardiol Rep 12:216–222

    Article  PubMed  Google Scholar 

  21. Davani EY, Boyd JH, Dorscheid DR et al (2006) Cardiac ICAM-1 mediates leukocyte-dependent decreased ventricular contractility in endotoxemic mice. Cardiovasc Res 72:134–142

    Article  PubMed  CAS  Google Scholar 

  22. Abe Y, Fornage M, Yang CY et al (2007) L5, the most electronegative subfraction of plasma LDL, induces endothelial vascular cell adhesion molecule 1 and CXC chemokines, which mediate mononuclear leukocyte adhesion. Atherosclerosis 192:56–66

    Article  PubMed  CAS  Google Scholar 

  23. Oral H, Dorn GW II, Mann DL (1997) Sphingosine mediates the immediate negative inotropic effects of tumor necrosis factor-alpha in the adult mammalian cardiac myocyte. J Biol Chem 272:4836–4842

    Article  PubMed  CAS  Google Scholar 

  24. Cain BS, Meldrum DR, Dinarello CA et al (1999) Tumor necrosis factor-alpha and interleukin-1beta synergistically depress human myocardial function. Crit Care Med 27:1309–1318

    Article  PubMed  CAS  Google Scholar 

  25. Chandrasekar B, Smith JB, Freeman GL (2001) Ischemia-reperfusion of rat myocardium activates nuclear factor-KappaB and induces neutrophil infiltration via lipopolysaccharide-induced CXC chemokine. Circulation 103:2296–2302

    Article  PubMed  CAS  Google Scholar 

  26. Chandrasekar B, Mitchell DH, Colston JT, Freeman GL (1999) Regulation of CCAAT/Enhancer binding protein, interleukin-6, interleukin-6 receptor, and gp130 expression during myocardial ischemia/reperfusion. Circulation 99:427–433

    Article  PubMed  CAS  Google Scholar 

  27. Chandrasekar B (2002) Chemokine–cytokine cross-talk. The ELR+CXC chemokine LIX (CXCL5) amplifies a proinflammatory cytokine response via a phosphatidylinositol 3-kinase-NF-kappa B pathway. J Biol Chem 278:4675–4686

    Article  PubMed  Google Scholar 

  28. Bowie A, O’Neill LA (2000) Oxidative stress and nuclear factor-kappaB activation: a reassessment of the evidence in the light of recent discoveries. Biochem Pharmacol 59:13–23

    Article  PubMed  CAS  Google Scholar 

  29. Mercurio F, Manning AM (1999) NF-kappaB as a primary regulator of the stress response. Oncogene 18:6163–6171

    Article  PubMed  CAS  Google Scholar 

  30. Yang M, Wu J, Martin CM, Kvietys PR, Rui T (2008) Important role of p38 MAP kinase/NF-kappaB signaling pathway in the sepsis-induced conversion of cardiac myocytes to a proinflammatory phenotype. Am J Physiol Heart Circ Physiol 294:H994–1001

    Article  PubMed  CAS  Google Scholar 

  31. Yokoyama T, Vaca L, Rossen RD, Durante W, Hazarika P, Mann DL (1993) Cellular basis for the negative inotropic effects of tumor necrosis factor-alpha in the adult mammalian heart. J Clin Invest 92:2303–2312

    Article  PubMed  CAS  Google Scholar 

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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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Authors and Affiliations

  1. L5 Research Center, China Medical University Hospital, Taichung, Taiwan

    An-Sheng Lee, Guei-Jane Wang, Hua-Chen Chan, Fang-Yu Chen, Chia-Ming Chang, Chao-Yuh Yang & Chu-Huang Chen

  2. Division of Cardiology, China Medical University Hospital, 2 Yuh-Der Road, Taichung, Taiwan

    An-Sheng Lee, Yuan-Teh Lee & Kuan-Cheng Chang

  3. Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan

    An-Sheng Lee, Guei-Jane Wang, Chao-Yuh Yang, Yuan-Teh Lee, Kuan-Cheng Chang & Chu-Huang Chen

  4. Institute of Physiology, National Yang-Ming University, Taipei, Taiwan

    Fang-Yu Chen

  5. Vascular and Medicinal Research, Wafic Said Molecular Cardiology Research Laboratories, Texas Heart Institute, 6770 Bertner Avenue, MC 2-255, Houston, TX, 77030, USA

    Chao-Yuh Yang & Chu-Huang Chen

  6. Department of Medicine, Baylor College of Medicine, Houston, TX, USA

    Chao-Yuh Yang & Chu-Huang Chen

  7. Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan

    Yuan-Teh Lee

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  1. An-Sheng Lee
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  2. Guei-Jane Wang
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Correspondence to Kuan-Cheng Chang or Chu-Huang Chen.

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Lee, AS., Wang, GJ., Chan, HC. et al. Electronegative low-density lipoprotein induces cardiomyocyte apoptosis indirectly through endothelial cell-released chemokines. Apoptosis 17, 1009–1018 (2012). https://doi.org/10.1007/s10495-012-0726-1

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  • DOI: https://doi.org/10.1007/s10495-012-0726-1

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