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Protective effect of HDL on endothelial NO production: the role of DDAH/ADMA pathway

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Abstract

Accumulating studies have demonstrated that the dimethylarginine dimethylaminohydrolase/asymmetric dimethylarginine (DDAH/ADMA) system is a novel pathway for modulating nitric oxide (NO) production. The aim of this study was to investigate whether the protective effect of high density lipoprotein (HDL) on endothelial NO production was related to its effect on DDAH/ADMA pathway. Human umbilical vein endothelial cells (HUVECs) were prior exposed to HDL (10, 50, or 100 μg/ml) for 1 h, and then incubated with oxidized low density lipoprotein (ox-LDL) (100 μg/ml) for 24 h. The cultured medium was collected for measuring the concentration of NO and ADMA. The cells were collected for measuring the mRNA and protein expression of DDAH-II as well as DDAH activity. HUVECs treated with ox-LDL (100 μg/ml) for 24 h significantly decreased the concentration of NO, the mRNA and protein expression of DDAH-II as well as DDAH activity and increased the level of ADMA. Pretreatment with HDL (10, 50, or 100 μg/ml) could counteract these changes induced by ox-LDL (100 μg/ml). HDL significantly increased the attenuated endothelial cell NO production induced by ox-LDL, which was attributed to its effect on DDAH/ADMA pathway.

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Abbreviations

DDAH:

Dimethylarginine dimethylaminohydrolase

ADMA:

Asymmetric dimethylarginine

NO:

Nitric oxide

NOS:

NO synthases

HDL:

High density lipoprotein

ox-LDL:

Oxidized low density lipoprotein

HUVECs:

Human umbilical vein endothelial cells

RT-PCR:

Reverse transcription polymerase chain reaction

BSA:

Bovine serum albumin

MDA:

Malondialdehyde

FBS:

Fetal bovine serum

HPLC:

High performance liquid chromatography

References

  1. Deanfield JE, Halcox JP, Rabelink TJ (2007) Endothelial function and dysfunction: testing and clinical relevance. Circulation 115:1285–1295

    PubMed  Google Scholar 

  2. Sessa WC (2004) eNOS at a glance. J Cell Sci 117:2427–2429

    Article  PubMed  CAS  Google Scholar 

  3. Böger RH (2003) Association of asymmetric dimethylarginine and endothelial dysfunction. Clin Chem Lab Med 41:1467–1472

    Article  PubMed  Google Scholar 

  4. Cable DG, Celotto AC, Evora PR, Schaff HV (2009) Asymmetric dimethylarginine endogenous inhibition of nitric oxide synthase causes differential vasculature effects. Med Sci Monit 15:BR248–BR253

    PubMed  CAS  Google Scholar 

  5. Palm F, Onozato ML, Luo Z, Wilcox CS (2007) Dimethylarginine dimethylaminohydrolase (DDAH): expression, regulation, and function in the cardiovascular and renal systems. Am J Physiol Heart Circ Physiol 293:H3227–H3245

    Article  PubMed  CAS  Google Scholar 

  6. Lin KY, Ito A, Asagami T, Tsao PS, Adimoolam S, Kimoto M, Tsuji H, Reaven GM, Cooke JP (2002) Impaired nitric oxide synthase pathway in diabetes mellitus: role of asymmetric dimethylarginine and dimethylarginine dimethylaminohydrolase. Circulation 106:987–992

    Article  PubMed  CAS  Google Scholar 

  7. Fiedler L (2008) The DDAH/ADMA pathway is a critical regulator of NO signalling in vascular homeostasis. Cell Adhes Migr 2:149–150

    Article  Google Scholar 

  8. Singh IM, Shishehbor MH, Ansell BJ (2007) High-density lipoprotein as a therapeutic target: a systematic review. JAMA 298:786–798

    Article  PubMed  CAS  Google Scholar 

  9. Florentin M, Liberopoulos EN, Wierzbicki AS, Mikhailidis DP (2008) Multiple actions of high-density lipoprotein. Curr Opin Cardiol 23:370–378

    Article  PubMed  Google Scholar 

  10. Lupattelli G, Marchesi S, Roscini AR, Siepi D, Gemelli F, Pirro M, Sinzinger H, Schillaci G, Mannarino E (2002) Direct association between high density lipoprotein cholesterol and endothelial function in hyperlipemia. Am J Cardiol 90:648–650

    Article  PubMed  CAS  Google Scholar 

  11. Zeiher AM, Schächlinger V, Hohnloser SH, Saurbier B, Just H (1994) Coronary atherosclerotic wall thickening and vascular reactivity in humans: elevated high-density lipoprotein levels ameliorate abnormal vasoconstriction in early atherosclerosis. Circulation 89:2525–2532

    PubMed  CAS  Google Scholar 

  12. Mineo C, Yuhanna IS, Quon MJ, Shaul PW (2003) High density lipoprotein-induced endothelial nitric-oxide synthase activation is mediated by Akt and MAP kinases. J Biol Chem 278:9142–9149

    Article  PubMed  CAS  Google Scholar 

  13. Nofer JR, van der Giet M, Tölle M, Wolinska I, von Wnuck Lipinski K, Baba HA, Tietge UJ, Gödecke A, Ishii I, Kleuser B, Schäfers M, Fobker M, Zidek W, Assmann G, Chun J, Levkau B (2004) HDL induces NO-dependent vasorelaxation via the lysophospholipid receptor S1P3. J Clin Invest 113:569–581

    PubMed  CAS  Google Scholar 

  14. Ayer JG, Harmer JA, Nakhla S, Xuan W, Ng MK, Raitakari OT, Marks GB, Celermajer DS (2009) HDL-cholesterol, blood pressure, and asymmetric dimethylarginine are significantly associated with arterial wall thickness in children. Arterioscler Thromb Vasc Biol 29:943–949

    Article  PubMed  CAS  Google Scholar 

  15. Yang TL, Chen MF, Xia X, Luo BL, Li YJ (2006) Effect of fenofibrate on the level of asymmetric dimethylarginine in individuals with hypertriglyceridemia. Eur J Clin Pharmacol 62:179–184

    Article  PubMed  CAS  Google Scholar 

  16. Matsumura T, Sakai M, Kobori S, Biwa T, Takemura T, Matsuda H, Hakamata H, Horiuchi S, Shichiri M (1997) Two intracellular signaling pathways for activation of protein kinase C are involved in oxidized low-density lipoprotein-induced macrophage growth. Arterioscler Thromb Vasc Biol 17:3013–3020

    PubMed  CAS  Google Scholar 

  17. Zhao SP, Yu BL, Xie XZ, Dong SZ, Dong J (2008) Dual effects of oxidized low-density lipoprotein on LXR-ABCA1-apoA-I pathway in 3T3–L1 cells. Int J Cardiol 128:42–47

    Article  PubMed  Google Scholar 

  18. Feng Q, Lu X, Jones DL, Shen J, Arnold JM (2001) Increased inducible nitric oxide synthase expression contributes to myocardial dysfunction and higher mortality after myocardial infarction in mice. Circulation 104:700–704

    Article  PubMed  CAS  Google Scholar 

  19. Chen BM, Xia LW, Zhao RQ (1997) Determination of N(G), N(G)-dimethylarginine in human plasma by high-performance liquid chromatography. J Chromatogr B 692:467–471

    Article  CAS  Google Scholar 

  20. Scalera F, Borlak J, Beckmann B, Martens-Lobenhoffer J, Thum T, Täger M, Bode-Böger SM (2004) Endogenous nitric oxide synthesis inhibitor asymmetric dimethyl l-arginine accelerates endothelial cell senescence. Arterioscler Thromb Vasc Biol 24:1816–1822

    Article  PubMed  CAS  Google Scholar 

  21. Davignon J, Ganz P (2004) Role of endothelial dysfunction in atherosclerosis. Circulation 109:III27–III32

    PubMed  Google Scholar 

  22. Böger RH, Sullivan LM, Schwedhelm E, Wang TJ, Maas R, Benjamin EJ, Schulze F, Xanthakis V, Benndorf RA, Vasan RS (2009) Plasma asymmetric dimethylarginine and incidence of cardiovascular disease and death in the community. Circulation 119:1592–1600

    Article  PubMed  Google Scholar 

  23. Böger RH, Bode-Böger SM, Szuba A, Tsao PS, Chan JR, Tangphao O, Blaschke TF, Cooke JP (1998) Asymmetric dimethylarginine (ADMA): a novel risk factor for endothelial dysfunction: its role in hypercholesterolemia. Circulation 98:1842–1847

    PubMed  Google Scholar 

  24. Tasci I, Erdem G, Tapan S (2009) The relation of ADMA and apelin to endothelial dysfunction and angiogenesis in patients with type 2 diabetes mellitus. Diabetes Res Clin Pract 86:e37–e38

    Article  PubMed  CAS  Google Scholar 

  25. Jiang DJ, Jia SJ, Yan J, Zhou Z, Yuan Q, Li YJ (2006) Involvement of DDAH/ADMA/NOS pathway in nicotine-induced endothelial dysfunction. Biochem Biophys Res Commun 349:683–693

    Article  PubMed  CAS  Google Scholar 

  26. Young JM, Terrin N, Wang X, Greene T, Beck GJ, Kusek JW, Collins AJ, Sarnak MJ, Menon V (2009) Asymmetric dimethylarginine and mortality in stages 3 to 4 chronic kidney disease. Clin J Am Soc Nephrol 4:1115–1120

    Article  PubMed  CAS  Google Scholar 

  27. Kurose I, Wolf R, Grisham MB, Granger DN (1995) Effects of an endogenous inhibitor of nitric oxide synthesis on postcapillary venules. Am J Physiol Heart Circ Physiol 268:H2224–H2231

    CAS  Google Scholar 

  28. Chapman MJ, Assmann G, Fruchart JC, Shepherd J, Sirtori C, European Consensus Panel on HDL-C (2004) Raising high-density lipoprotein cholesterol with reduction of cardiovascular risk: the role of nicotinic acid—a position paper developed by the European Consensus Panel on HDL-C. Curr Med Res Opin 20:1253–1268

    Article  PubMed  CAS  Google Scholar 

  29. Leiper JM, Santa Maria J, Chubb A, MacAllister RJ, Charles IG, Whitley GS, Vallance P (1999) Identification of two human diemthylarginine dimethylaminohydrolases with distinct tissue distributions and homology with microbial arginine deiminases. Biochem J 343:209–214

    Article  PubMed  CAS  Google Scholar 

  30. Lu CW, Guo Z, Feng M, Wu ZZ, He ZM, Xiong Y (2010) Ex vivo gene transferring of human dimethylarginine dimethylaminohydrolase-2 improved endothelial dysfunction in diabetic rat aortas and high glucose-treated endothelial cells. Atherosclerosis 209:66–73

    Article  PubMed  CAS  Google Scholar 

  31. Hasegawa K, Wakino S, Tatematsu S, Yoshioka K, Homma K, Sugano N, Kimoto M, Hayashi K, Itoh H (2007) Role of asymmetric dimethylarginine in vascular injury in transgenic mice overexpressing dimethylarginie dimethylaminohydrolase 2. Circ Res 101:e2–e10

    Article  PubMed  CAS  Google Scholar 

  32. Wang D, Gill PS, Chabrashvili T, Onozato ML, Raggio J, Mendonca M, Dennehy K, Li M, Modlinger P, Leiper J, Vallance P, Adler O, Leone A, Tojo A, Welch WJ, Wilcox CS (2007) Isoform-specific regulation by N(G), N(G)-dimethylarginine dimethylaminohydrolase of rat serum asymmetric dimethylarginine and vascular endothelium-derived relaxing factor/NO. Circ Res 101:627–635

    Article  PubMed  CAS  Google Scholar 

  33. Scalera F, Martens-Lobenhoffer J, Bukowska A, Lendeckel U, Täger M, Bode-Böger SM (2008) Effect of telmisartan on nitric oxide–asymmetrical dimethylarginine system: role of angiotensin II type 1 receptor gamma and peroxisome proliferator activated receptor gamma signaling during endothelial aging. Hypertension 51:696–703

    Article  PubMed  CAS  Google Scholar 

  34. Garbin U, Pasini AF, Stranieri C, Manfro S, Boccioletti V, Cominacini L (2007) Nebivolol reduces asymmetric dimethylarginine in endothelial cells by increasing dimethylarginine dimethylaminohydrolase 2 (DDAH2) expression and activity. Pharmacol Res 56:515–521

    Article  PubMed  CAS  Google Scholar 

  35. Xiao J, Xiao ZJ, Liu ZG, Gong HY, Yuan Q, Wang S, Li YJ, Jiang DJ (2009) Involvement of dimethylarginine dimethylaminohydrolase-2 in visfatin-enhanced angiogenic function of endothelial cells. Diabetes Metab Res Rev 25:242–249

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This manuscript has been supported by the National Nature Science Foundation of China (Project 30770857).

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Authors and Affiliations

  1. Department of Cardiology, Second Xiangya Hospital, Central South University, Middle Ren-Min Road 139, Changsha, 410011, China

    Zhen-yu Peng, Shui-ping Zhao & Dao-quan Peng

  2. Department of Emergency, Second Xiangya Hospital, Central South University, Middle Ren-Min Road 139, Changsha, 410011, China

    Zhen-yu Peng

  3. Department of Respiratory Medicine, Xiangya Hospital, Central South University, Xiangya Road 88, Changsha, 410078, China

    Bai-mei He

  4. Department of Clinical Laboratories, Second Xiangya Hospital, Central South University, Middle Ren-Min Road 139, Changsha, 410011, China

    Min Hu

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  1. Zhen-yu Peng
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Correspondence to Shui-ping Zhao.

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Peng, Zy., Zhao, Sp., He, Bm. et al. Protective effect of HDL on endothelial NO production: the role of DDAH/ADMA pathway. Mol Cell Biochem 351, 243–249 (2011). https://doi.org/10.1007/s11010-011-0731-7

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  • DOI: https://doi.org/10.1007/s11010-011-0731-7

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