Top

Published in:

01-01-2015 | Original Article

Impact of lysophosphatidylcholine on survival and function of UEA-1⁺acLDL⁺ endothelial progenitor cells in patients with coronary artery disease

Authors: Seong Hun Hong, Hyun Hee Jang, So Ra Lee, Kyung Hye Lee, Jong Shin Woo, Jin Bae Kim, Woo-Shik Kim, Byung Il Min, Ki Ho Cho, Kwon Sam Kim, Xianwu Cheng, Weon Kim

Published in: Heart and Vessels | Issue 1/2015

Abstract

Lysophosphatidylcholine (LPC) generated from oxidized low-density lipoprotein by lipoprotein-associated phospholipase A2 plays a key role in plaque inflammation and vulnerability. Endothelial progenitor cells (EPCs) can repair injured endothelium and exert anti-inflammatory effects of vulnerable plaque. We study the impact and mechanisms of LPC on UEA-1 and acLDL binding EPCs (UEA-1⁺acLDL⁺ EPCs). UEA-1⁺acLDL⁺ EPCs from coronary artery disease (CAD) patients were cultured and exposed to LPC at different concentrations and different timepoints. We determined the significant concentration (40 μM). UEA-1⁺acLDL⁺ EPCs were preincubated for 30 min with pravastatin (20 μM) with LY249002, a specific inhibitor of the Akt signaling pathway, and exposed for 24 h to LPC 40 μM. The survival, migration, adhesion, and proliferation of UEA-1⁺acLDL⁺ EPCs were assessed. To examine the mechanisms of LPC toxicity and pravastatin effects, phosphorylated Akt and endothelial nitric oxide synthase (eNOS) levels and the ratio of Bcl-2/Bax protein expression were assessed. LPC induced apoptosis and impaired migration and adhesion of UEA-1⁺acLDL⁺ EPCs significantly. The detrimental effects of LPC were attenuated by pravastatin. However, when UEA-1⁺acLDL⁺ EPCs were pretreated with pravastatin and LY249002, a specific inhibitor of the Akt signaling pathway, simultaneously, the beneficial effects of pravastatin were abolished. Furthermore, LPC suppressed Akt and eNOS phosphorylation and increased Bcl-2/Bax expression. The effects of LPC on Akt/eNOS and Bcl-2/Bax activity were reversed by pravastatin. In conclusion, LPC inhibited UEA-1⁺acLDL⁺ EPCs survival and impaired its functions, and these were attributable to inhibition of the Akt/eNOS and Bcl-2/Bax pathway. Pravastatin reversed the detrimental action of LPC. These findings suggest that LPC inhibition can be a possible strategy for CAD through EPC revitalization.

Rabbani R, Topol EJ (1999) Strategies to achieve coronary arterial plaque stabilization. Cardiovasc Res 41:402–417PubMedCrossRef

Finn AV, Nakano M, Narula J, Kolodgie FD, Virmani R (2010) Concept of vulnerable/unstable plaque. Arterioscler Thromb Vasc Biol 30:1282–1292PubMedCrossRef

Gokce N, Keaney JF Jr, Hunter LM, Watkins MT, Menzoian JO, Vita JA (2002) Risk stratification for postoperative cardiovascular events via noninvasive assessment of endothelial function: a prospective study. Circulation 105:1567–1572PubMedCrossRef

Kugiyama K, Kerns SA, Morrisett JD, Roberts R, Henry PD (1990) Impairment of endothelium-dependent arterial relaxation by lysolecithin in modified low-density lipoproteins. Nature 344:160–162PubMedCrossRef

Hsieh CC, Yen MH, Liu HW, Lau YT (2000) Lysophosphatidylcholine induces apoptotic and non-apoptotic death in vascular smooth muscle cells: in comparison with oxidized LDL. Atherosclerosis 151:481–491PubMedCrossRef

Gonçalves I, Edsfeldt A, Ko NY, Grufman H, Berg K, Björkbacka H, Nitulescu M, Persson A, Nilsson M, Prehn C, Adamski J, Nilsson J (2012) Evidence supporting a key role of Lp-PLA2-generated lysophosphatidylcholine in human atherosclerotic plaque inflammation. Arterioscler Thromb Vasc Biol 32:1505–1512PubMedCrossRef

Asahara T, Murohara T, Sullivan A, Silver M, van der Zee R, Li T, Witzenbichler B, Schatteman G, Isner JM (1997) Isolation of putative progenitor endothelial cells for angiogenesis. Science 275:964–967PubMedCrossRef

Vasa M, Fichtlscherer S, Aicher A, Urbich C, Martin H, Zeiher AM, Dimmeler S (2001) Number and migratory activity of circulating endothelial progenitor cells inversely correlate with risk factors for coronary artery disease. Circ Res 89(1):E1–E7PubMedCrossRef

Briguori C, Testa U, Riccioni R, Colombo A, Petrucci E, Condorelli G, Mariani G, D’Andrea D, De Micco F, Rivera NV, Puca AA, Peschle C, Condorelli G (2010) Correlations between progression of coronary artery disease and circulating endothelial progenitor cells. FASEB J 24(6):1981–1988PubMedCrossRef

10.

Chen MC, Chen CJ, Yang CH, Liu WH, Fang CY, Hsieh YK, Chang HW (2008) Relationship of the percentage of circulating endothelial progenitor cell to the severity of coronary artery disease. Heart Vessels 23(1):47–52PubMedCrossRef

11.

Ma ZL, Mai XL, Sun JH, Ju SH, Yang X, Ni Y, Teng GJ (2009) Inhibited atherosclerotic plaque formation by local administration of magnetically labeled endothelial progenitor cells (EPCs) in a rabbit model. Atherosclerosis 205(1):80–86PubMedCrossRef

12.

Fadini GP, Agostini C, Sartore S, Avogaro A (2007) Endothelial progenitor cells in the natural history of atherosclerosis. Atherosclerosis 194(1):46–54PubMedCrossRef

13.

Wang X, Chen J, Tao Q, Zhu J, Shang Y (2004) Effects of ox-LDL on number and activity of circulating endothelial progenitor cells. Drug Chem Toxicol 27(3):243–255PubMedCrossRef

14.

Tie G, Yan J, Yang Y, Park BD, Messina JA, Raffai RL, Nowicki PT, Messina LM (2010) Oxidized low-density lipoprotein induces apoptosis in endothelial progenitor cells by inactivating the phosphoinositide 3-kinase/Akt pathway. J Vasc Res 47(6):519–530PubMedCentralPubMedCrossRef

15.

Ma FX, Zhou B, Chen Z, Ren Q, Lu SH, Sawamura T, Han ZC (2006) Oxidized low density lipoprotein impairs endothelial progenitor cells by regulation of endothelial nitric oxide synthase. J Lipid Res 47(6):1227–1237PubMedCrossRef

16.

Sugiura T, Kondo T, Kureishi-Bando Y, Numaguchi Y, Yoshida O, Dohi Y, Kimura G, Ueda R, Rabelink TJ, Murohara T (2008) Nifedipine improves endothelial function: role of endothelial progenitor cells. Hypertension 52:491–498PubMedCrossRef

17.

Richardson MR, Yoder MC (2011) Endothelial progenitor cells: quo vadis? J Mol Cell Cardiol 50(2):266–272PubMedCentralPubMedCrossRef

18.

Hill JM, Zalos G, Halcox JP, Schenke WH, Waclawiw MA, Quyyumi AA, Finkel T (2003) Circulating endothelial progenitor cells, vascular function, and cardiovascular risk. N Engl J Med 348(7):593–600PubMedCrossRef

19.

Schmidt-Lucke C, Rössig L, Fichtlscherer S, Vasa M, Britten M, Kämper U, Dimmeler S, Zeiher AM (2005) Reduced number of circulating endothelial progenitor cells predicts future cardiovascular events: proof of concept for the clinical importance of endogenous vascular repair. Circulation 111:2981–2987PubMedCrossRef

20.

Werner N, Kosiol S, Schiegl T, Ahlers P, Walenta K, Link A, Böhm M, Nickenig G (2005) Circulating endothelial progenitor cells and cardiovascular outcomes. N Engl J Med 353:999–1007PubMedCrossRef

21.

Bozdag-Turan I, Turan RG, Paranskaya L, Arsoy NS, Turan CH, Akin I, Kische S, Ortak J, Schneider H, Ludovicy S, Hermann T, D’Ancona G, Durdu S, Akar AR, Ince H, Nienaber CA (2012) Correlation between the functional impairment of bone marrow-derived circulating progenitor cells and the extend of coronary artery disease. J Transl Med 10:143PubMedCentralPubMedCrossRef

22.

George J, Afek A, Abashidze A, Shmilovich H, Deutsch V, Kopolovich J, Miller H, Keren G (2005) Transfer of endothelial progenitor and bone marrow cells influences atherosclerotic plaque size and composition in apolipoprotein E knockout mice. Arterioscler Thromb Vasc Biol 25(12):2636–2641PubMedCrossRef

23.

Sata M, Saiura A, Kunisato A, Tojo A, Okada S, Tokuhisa T, Hirai H, Makuuchi M, Hirata Y, Nagai R (2002) Hematopoietic stem cells differentiate into vascular cells that participate in the pathogenesis of atherosclerosis. Nat Med 8(4):403–409PubMedCrossRef

24.

Min TQ, Zhu CJ, Xiang WX, Hui ZJ, Peng SY (2004) Improvement in endothelial progenitor cells from peripheral blood by ramipril therapy in patients with stable coronary artery disease. Cardiovasc Drugs Ther 18:203–209PubMedCrossRef

25.

Imanishi T, Moriwaki C, Hano T, Nishio I (2005) Endothelial progenitor cell senescence is accelerated in both experimental hypertensive rats and patients with essential hypertension. J Hypertens 23:1831–1837PubMedCrossRef

26.

Wang CH, Ciliberti N, Li SH, Szmitko PE, Weisel RD, Fedak PW, Al-Omran M, Cherng WJ, Li RK, Stanford WL, Verma S (2004) Rosiglitazone facilitates angiogenic progenitor cell differentiation toward endothelial lineage: a new paradigm in glitazone pleiotropy. Circulation 109:1392–1400PubMedCrossRef

27.

Pistrosch F, Herbrig K, Oelschlaegel U, Richter S, Passauer J, Fischer S, Gross P (2005) PPARgamma-agonist rosiglitazone increases number and migratory activity of cultured endothelial progenitor cells. Atherosclerosis 183:163–167PubMedCrossRef

28.

Fadini GP, de Kreutzenberg S, Albiero M, Coracina A, Pagnin E, Baesso I, Cignarella A, Bolego C, Plebani M, Nardelli GB, Sartore S, Agostini C, Avogaro A (2008) Gender differences in endothelial progenitor cells and cardiovascular risk profile: the role of female estrogens. Arterioscler Thromb Vasc Biol 28:997–1004PubMedCrossRef

29.

Toutain CE, Filipe C, Billon A, Fontaine C, Brouchet L, Guéry JC, Gourdy P, Arnal JF, Lenfant F (2009) Estrogen receptor alpha expression in both endothelium and hematopoietic cells is required for the accelerative effect of estradiol on reendothelialization. Arterioscler Thromb Vasc Biol 29(10):1543–1550PubMedCrossRef

30.

Chen TG, Chen JZ, Xie XD (2006) Effects of aspirin on number, activity and inducible nitric oxide synthase of endothelial progenitor cells from peripheral blood. Acta Pharmacol Sin 27(4):430–436PubMedCrossRef

31.

Hu Z, Zhang F, Yang Z, Zhang J, Zhang D, Yang N, Zhang Y, Cao K (2008) Low-dose aspirin promotes endothelial progenitor cell migration and adhesion and prevents senescence. Cell Biol Int 32(7):761–768PubMedCrossRef

32.

Ramirez R, Carracedo J, Nogueras S, Buendia P, Merino A, Cañadillas S, Rodríguez M, Tetta C, Martin-Malo A, Aljama P (2009) Carbamylated darbepoetin derivative prevents endothelial progenitor cell damage with no effect on angiogenesis. J Mol Cell Cardiol 47(6):781–788PubMedCrossRef

33.

Kawachi K, Iso Y, Sato T, Wakabayashi K, Kobayashi Y, Takeyama Y, Suzuki H (2012) Effects of erythropoietin on angiogenesis after myocardial infarction in porcine. Heart Vessels 27(1):79–88PubMedCrossRef

34.

Rabini RA, Galassi R, Fumelli P, Dousset N, Solera ML, Valdiguie P, Curatola G, Ferretti G, Taus M, Mazzanti L (1994) Reduced Na(+)-K(+)-ATPase activity and plasma lysophosphatidylcholine concentrations in diabetic patients. Diabetes 43:915–919PubMedCrossRef

35.

Chen L, Liang B, Froese DE, Liu S, Wong JT, Tran K, Hatch GM, Mymin D, Kroeger EA, Man RY, Choy PC (1997) Oxidative modification of low density lipoprotein in normal and hyperlipidemic patients: effect of lysophosphatidylcholine composition on vascular relaxation. J Lipid Res 38(3):546–553PubMed

36.

Mannheim D, Herrmann J, Versari D (2008) Enhanced expression of Lp-PLA2 and lysophosphatidylcholine in symptomatic carotid atherosclerotic plaques. Stroke 39(5):1448–1455PubMedCrossRef

37.

Dohi T, Miyauchi K, Ohkawa R, Nakamura K, Kishimoto T, Miyazaki T, Nishino A, Nakajima N, Yaginuma K, Tamura H, Kojima T, Yokoyama K, Kurata T, Shimada K, Yatomi Y, Daida H (2012) Increased circulating plasma lysophosphatidic acid in patients with acute coronary syndrome. Clin Chim Acta 413(1–2):207–212PubMedCrossRef

38.

Dohi T, Miyauchi K, Ohkawa R, Nakamura K, Kurano M, Kishimoto T, Yanagisawa N, Ogita M, Miyazaki T, Nishino A, Yaginuma K, Tamura H, Kojima T, Yokoyama K, Kurata T, Shimada K, Daida H, Yatomi Y (2013) Increased lysophosphatidic acid levels in culprit coronary arteries of patients with acute coronary syndrome. Atherosclerosis 229(1):192–197PubMedCrossRef

39.

Oka H, Kugiyama K, Doi H, Matsumura T, Shibata H, Miles LA, Sugiyama S, Yasue H (2000) Lysophosphatidylcholine induces urokinase-type plasminogen activator and its receptor in human macrophages partly through redox-sensitive pathway. Arteriosclero Thromb Vasc Biol 20(1):244–250CrossRef

40.

Oestvang J, Johansen B (2006) PhospholipaseA2: a key regulator of inflammatory signalling and a connector to fibrosis development in atherosclerosis. Biochim Biophys Acta 1761(11):1309–1316PubMedCrossRef

41.

Massa M, Rosti V, Ferrario M, Campanelli R, Ramajoli I, Rosso R, De Ferrari GM, Ferlini M, Goffredo L, Bertoletti A, Klersy C, Pecci A, Moratti R, Tavazzi L (2005) Increased circulating hematopoietic and endothelial progenitor cells in the early phase of acute myocardial infarction. Blood 105(1):199–206PubMedCrossRef

42.

Shintani S, Murohara T, Ikeda H, Ueno T, Honma T, Katoh A, Sasaki K, Shimada T, Oike Y, Imaizumi T (2001) Mobilization of endothelial progenitor cells in patients with acute myocardial infarction. Circulation 103(23):2776–2779PubMedCrossRef

43.

Kakizaki M, Nobori K, Watanabe H, Iino K, Ishida M, Ito H (2013) Increased circulating CD3(+)/CD31 (+) T cells in patients with acute coronary syndrome. Heart Vessels 28(5):566–569PubMedCrossRef

44.

Takahashi M, Okazaki H, Ogata Y, Takeuchi K, Ikeda U, Shimada K (2002) Lysophosphatidylcholine induces apoptosis in human endothelial cells through a p38-mitogen activated protein kinase-dependent mechanism. Atherosclerosis 161:387–394PubMedCrossRef

45.

Ozaki H, Ishii K, Arai H, Kume N, Kita T (1999) Lysophosphatidylcholine activates mitogen-activated protein kinases by a tyrosine kinase-dependent pathway in bovine aortic endothelial cells. Atherosclerosis 143:261–266PubMedCrossRef

46.

Fernández-Hernando C, Ackah E, Yu J, Suárez Y, Murata T, Iwakiri Y, Prendergast J, Miao RQ, Birnbaum MJ, Sessa WC (2007) Loss of Akt1 leads to severe atherosclerosis and occlusive coronary artery disease. Cell Metab 6(6):446–457PubMedCentralPubMedCrossRef

47.

Lyon CA, Johnson JL, Williams H, Sala-Newby GB, George SJ (2009) Soluble N-cadherin overexpression reduces features of atherosclerotic plaque instability. Arterioscler Thromb Vasc Biol 29(2):195–201PubMedCentralPubMedCrossRef

48.

Nakagawa K, Shibata A, Saito T, Sookwong P, Kato S, Tsuduki T, Matsubara K, Miyazawa T (2011) Phosphatidylcholine hydroperoxide promotes VEGF-induced angiogenesis in endothelial cells and rat aorta ring cultures. Biochim Biophys Acta 1810(12):1205–1211PubMedCrossRef

49.

Brunt KR, Fenrich KK, Kiani G, Tse MY, Pang SC, Ward CA, Melo LG (2006) Protection of human vascular smooth muscle cells from H2O2-induced apoptosis through functional codependence between HO-1 and AKT. Arterioscler Thromb Vasc Biol 26(9):2027–2034PubMedCrossRef

50.

Cheng J, Cui R, Chen CH, Du J (2007) Oxidized low-density lipoprotein stimulates p53-dependent activation of proapoptotic Bax leading to apoptosis of differentiated endothelial progenitor cells. Endocrinology 148(5):2085–2094PubMedCrossRef

51.

Dimmeler S, Aicher A, Vasa M, Mildner-Rihm C, Adler K, Tiemann M, Rütten H, Fichtlscherer S, Martin H, Zeiher AM (2001) HMG-CoA reductase inhibitors (statins) increase endothelial progenitor cells via the PI3-kinase/Akt pathway. J Clin Invest 108(3):391–397PubMedCentralPubMedCrossRef

52.

Yukihito H, Hidehiro M, Hidekazu U, Ryo S, Yuichi F, Junko S, Yasuki K, Kazuaki C, Tsutomu I (2010) Endothelial function in subjects with isolated low HDL cholesterol: role of nitric oxide and circulating progenitor cells. Am J Physiol Endocrinol Metab 298:E202–E209CrossRef

53.

Petra JM, Antonio JL, Pilar C, Priscila RM, Carlos M, Francisco JS, Guillermo M (2008) Pravastatin increases the expression of the tissue inhibitor of matrix metalloproteinase-1 and the oncogene Bax in human aortic abdominal aneurysms. Can J Physiol Pharmacol 86:431–437CrossRef

54.

Takahashi Y, Satoh M, Tabuchi T, Nakamura M (2012) Prospective, randomized, single-blind comparison of effects of 6 months’ treatment with atorvastatin versus pravastatin on leptin and angiogenic factors in patients with coronary artery disease. Heart Vessels 27(4):337–343PubMedCrossRef

55.

Serruys PW, García-García HM, Buszman P, Erne P, Verheye S, Aschermann M, Duckers H, Bleie O, Dudek D, Bøtker HE, von Birgelen C, D’Amico D, Hutchinson T, Zambanini A, Mastik F, van Es GA, van der Steen AF, Vince DG, Ganz P, Hamm CW, Wijns W, Zalewski A, Integrated Biomarker and Imaging Study-2 Investigators (2008) Effects of the direct lipoprotein-associated phospholipase A(2) inhibitor darapladib on human coronary atherosclerotic plaque. Circulation 118(11):1172–1182PubMedCrossRef

Title: Impact of lysophosphatidylcholine on survival and function of UEA-1+acLDL+ endothelial progenitor cells in patients with coronary artery disease
Authors: Seong Hun Hong
Hyun Hee Jang
So Ra Lee
Kyung Hye Lee
Jong Shin Woo
Jin Bae Kim
Woo-Shik Kim
Byung Il Min
Ki Ho Cho
Kwon Sam Kim
Xianwu Cheng
Weon Kim
Publication date: 01-01-2015
Publisher: Springer Japan
Published in: Heart and Vessels / Issue 1/2015
Print ISSN: 0910-8327
Electronic ISSN: 1615-2573
DOI: https://doi.org/10.1007/s00380-014-0473-z

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Impact of lysophosphatidylcholine on survival and function of UEA-1⁺acLDL⁺ endothelial progenitor cells in patients with coronary artery disease

Abstract

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 1/2015

Platelet–larger cell ratio and the risk of periprocedural myocardial infarction after percutaneous coronary revascularization

Natural history of low-intensity neointimal tissue after an everolimus-eluting stent implantation: a serial observation with optical coherence tomography

Association of atherosclerosis-related markers and its relationship to n-3 polyunsaturated fatty acids levels with a prevalence of coronary artery disease in an urban area in Japan

Nucleotide differences of coxsackievirus B3 and chronic myocarditis

Association of intramural fat deposition in the interatrial septum with focal atrial tachyarrhythmias originating near the atrioventricular node

Resting qualitative and quantitative myocardial contrast echocardiography to predict cardiac events in patients with acute myocardial infarction and percutaneous revascularization

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page