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Thromb Haemost 2001; 85(04): 730-735
DOI: 10.1055/s-0037-1615660
Review Articles
Schattauer GmbH

High Density Lipoproteins Induce Cell Cycle Entry in Vascular Smooth Muscle Cells Via Mitogen Activated Protein Kinase-dependent Pathway

Jerzy-Roch Nofer
1   Institut für Klinische Chemie und Laboratoriumsmedizin, Westfälische Wilhelms-Universität, Münster
2   Institut für Arterioskleroseforschung an der Universität Münster, Germany
,
Ralf Junker
1   Institut für Klinische Chemie und Laboratoriumsmedizin, Westfälische Wilhelms-Universität, Münster
2   Institut für Arterioskleroseforschung an der Universität Münster, Germany
,
Ewa Pulawski
2   Institut für Arterioskleroseforschung an der Universität Münster, Germany
,
Manfred Fobker
1   Institut für Klinische Chemie und Laboratoriumsmedizin, Westfälische Wilhelms-Universität, Münster
,
Bodo Levkau
2   Institut für Arterioskleroseforschung an der Universität Münster, Germany
,
Arnold von Eckardstein
1   Institut für Klinische Chemie und Laboratoriumsmedizin, Westfälische Wilhelms-Universität, Münster
2   Institut für Arterioskleroseforschung an der Universität Münster, Germany
,
Udo Seedorf
2   Institut für Arterioskleroseforschung an der Universität Münster, Germany
,
Gerd Assmann
1   Institut für Klinische Chemie und Laboratoriumsmedizin, Westfälische Wilhelms-Universität, Münster
2   Institut für Arterioskleroseforschung an der Universität Münster, Germany
,
Michael Walter
1   Institut für Klinische Chemie und Laboratoriumsmedizin, Westfälische Wilhelms-Universität, Münster
2   Institut für Arterioskleroseforschung an der Universität Münster, Germany
› Author Affiliations
Further Information

Publication History

Received 31 May 2001

Accepted after resubmission 14 November 2000

Publication Date:
08 December 2017 (online)

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Summary

In this study we found that HDL acts as a potent and specific mitogen in vascular smooth muscle cells (VSMC) by stimulating entry into S-phase and DNA synthesis in a time- and concentration-dependent manner, induction of cyclins D1, E, and A, as well as activation of cyclin D-dependent kinases as inferred from phosphorylation of the retinoblastoma protein (pRb). Moreover, HDL induced activation of the mitogen-activated protein kinase pathway including Raf-, MEK-1, and ERK1/2, as well as the expression of proto-oncogen c-fos, which is controlled by ERK1/2. PD98059, an inhibitor of MEK-1 blocked the mitogenic activity of HDL and cyclin D1 expression. HDL-induced VSMC proliferation, cell cycle progression, cyclin D1 expression, and activation of the Raf-1/MEK-1/ERK1/2 cascade were blocked by pre-incubation of cells with pertussis toxin indicating involvement of trimeric G-protein. By contrast, none of these responses was inhibited by the protein kinase C inhibitor, GF109203X. The mitogenic effects of native HDL were not mimicked by apo A-I, reconstituted HDL containing apo A-I, or cholesterol-containing liposomes. In conclusion, HDL possesses an intrinsic property to induce G-protein- and MAP-kinase-dependent proliferation and cell cycle progression in VSMC. The strong and specific mitogenic effect of HDL should be taken into account, when therapeutic strategies to elevate the plasma level of these lipoproteins are developed.

Keywords

High density lipoproteins - smooth muscle cells - signal transduction - arteriosclerosis
 

  • References

  • 1 Gordon T, Rifkind BM. High density lipoproteins – the clinical implication of recent studies. N Engl J Med 1989; 321: 1311-5.
    CrossrefPubMedGoogle Scholar
  • 2 Assmann G, Schulte H. Relation of high-density lipoprotein cholesterol and triglycerides to incidence of atherosclerotic coronary artery disease (the PROCAM experience). Prospective Cardiovascular Munster Study. Am J Cardiol. 1992; 70: 733-72.
    CrossrefPubMedGoogle Scholar
  • 3 Oram JF, Yokoyama S. Apolipoprotein-mediated removal of cellular cholesterol and phospholipids. J Lipid Res 1996; 37: 2473-91.
    PubMedGoogle Scholar
  • 4 von Eckardstein A, Nofer J-R, Assmann G. Acceleration of reverse cholesterol transport. Curr Opin Cardiol 2000; 15: 348-54.
    CrossrefPubMedGoogle Scholar
  • 5 Chen JK, Hoshi H, McClure DB, McKeehan WL. Role of lipoproteins in growth of human adult arterial endothelial and smooth muscle cells in low lipoprotein-deficient serum. J Cell Physiol 1986; 129: 207-14.
    CrossrefPubMedGoogle Scholar
  • 6 Björkerund S, Björkerud B. Lipoproteins are primary mitogens and growth promoters for human arterial smooth muscle cells and lung fibroblasts in vitro. Arterioscler Thromb Vasc Biol 1994; 14: 288-98.
    CrossrefPubMedGoogle Scholar
  • 7 Gospodarowicz D, Hirabayshi K, Giguere L, Tauber JP. Factors controlling the proliferative rate, final cell density, and life span of bovine vascular smooth muscle cells in culture. J Cell Biol 1981; 89: 568-78.
    CrossrefPubMedGoogle Scholar
  • 8 Libby P, Miao P, Ordovas JM, Shaeffer EJ. Lipoprotein increase growth of mitogen-stimulated arterial smooth muscle cells. J Cell Physiol 1985; 124: 1-8.
    CrossrefPubMedGoogle Scholar
  • 9 Cuthbert JA, Lipsky PE. Lipoproteins may provide fatty acids necessary for human lymphocyte proliferation by both low-density receptor-dependent and -independent mechanisms. J Biol Chem 1989; 264: 13468-74.
    PubMedGoogle Scholar
  • 10 Favre G, Blancy E, Tournier JF, Soula G. Proliferative effect of high density lipoprotein (HDL) and HDL fractions (HDL1,2, HDL3) on virus-transformed lymphoblastoid cells. Biochim Biophys Acta 1989; 1013: 118-24.
    CrossrefPubMedGoogle Scholar
  • 11 Boyd NF, McGuire V. Evidence of association between plasma high-density lipoprotein cholesterol and risk factors for breast cancer. J Natl Cancer Inst 1990; 82: 460-8.
    CrossrefPubMedGoogle Scholar
  • 12 Favre G, Tazi KA, Le Gaillard F, Bennis F, Hachem H, Soula G. High density lipoprotein 3 binding sites are related to DNA biosynthesis in the adrenocarcinoma cell line A549. J Lipid Res 1993; 34: 1093-106.
    PubMedGoogle Scholar
  • 13 Walter M, Reinecke H, Nofer J-R, Seedorf U, Assmann G. HDL3 stimulates multiple signaling pathways in human skin fibroblasts. Arterioscler Thromb Vasc Biol 1995; 15: 1975-86.
    CrossrefPubMedGoogle Scholar
  • 14 Walter M, Reinecke H, Gerdes U, Nofer J-R, Höbbel G, Seedorf U, Ass-mann G. Defective regulation of phosphatidylcholine-specific phospholipases C and D in a kindred with Tangier disease. Evidence for the involvement of the phosphatidylcholine breakdown in HDL-mediated cholesterol efflux mechanisms. J Clin Invest 1996; 98: 2315-23.
    CrossrefPubMedGoogle Scholar
  • 15 Drobnik W, Mollers C, Resink T, Schmitz G. Activation of phosphatidylinositol-specific phospholipase C in response to HDL3 and LDL is markedly reduced in cultured fibroblasts from Tangier patients. Arterioscl Thromb Vasc Biol 1995; 15: 1369-77.
    CrossrefPubMedGoogle Scholar
  • 16 Nofer J-R, Walter M, Kehrel B, Seedorf U, Assmann G. HDL3 activates phospholipase D in normal but not in glycoprotein IIb/IIIa-deficient platelets. Biochem Biophys Res Commun 1995; 207: 148-54.
    CrossrefPubMedGoogle Scholar
  • 17 Mendez AJ, Oram JF, Biermann EL. Protein kinase C as mediator of high-density lipoprotein receptor-dependent efflux of intracellular cholesterol. J Biol Chem 1991; 266: 10104-111.
    PubMedGoogle Scholar
  • 18 Theret N, Delbart C, Aguie G, Fruchart JD, Vassaux G, Ailhaud G. Cholesterol efflux from adipose cells is coupled to diacylglycerol production and protein kinase C activation. Biochem Biophys Res Commun 1990; 173: 1361-8.
    CrossrefPubMedGoogle Scholar
  • 19 Nofer JR, Walter M, Kehrel B, Wierwille S, Tepel M, Seedorf U, Assmann G. HDL3-mediated inhibition of thrombin-induced platelet aggregation and fibrinogen binding occurs vie decreased production of phosphoinositide-derived second messengers 1,2-diacylglycerol and inositol 1,4,5-tris-phosphate. Arterioscler Thromb Vasc Biol 1998; 18: 861-9.
    CrossrefPubMedGoogle Scholar
  • 20 Deeg MA, Bowen RF, Oram JF, Bierman ED. High density lipoproteins stimulate mitogen-activated protein kinases in human skin fibroblasts. Arterioscler Thromb Vasc Biol 1997; 17: 1667-74.
    CrossrefPubMedGoogle Scholar
  • 21 Pörn MI, Ackermann KEO, Slotte JP. High-density lipoprotein induces rapid and transient release of Ca2+ in cultured fibroblasts. Biochem J 1991; 279: 29-33.
    CrossrefPubMedGoogle Scholar
  • 22 Garver WS, Deeg MA, Boen RF, Culala MM, Bierman EL, Oram JF. Phosphoproteins regulated by the interaction of high density lipoproteins with human skin. Arterioscler Thromb Vasc Biol 1997; 17: 2698-706.
    CrossrefPubMedGoogle Scholar
  • 23 Havel RJ, Eder H, Bragdon JH. The distribution and chemical composition of ultracentrifugally separated lipoproteins in human serum. J Clin Invest 1955; 3: 1345-53.
    PubMedGoogle Scholar
  • 24 von Eckardstein A, Funke H, Walter M, Altland K, Benninghoven A, Ass-mann G. Structural analysis of human apolipoprotein A-I variants: amino acid substitutions are nonrandomly distributed throughout the apolipoprotein A-I primary structure. J Biol Chem 1990; 265: 8610-7.
    PubMedGoogle Scholar
  • 25 Jonas A, von Eckardstein A, Kezdy KE, Steimentz A, Assmann G. Structural and functional properties of reconstituted high density lipoprotein discs prepared with six apolipoprotein A-I variants. J. Lipid Res 1991; 32: 97-106.
    PubMedGoogle Scholar
  • 26 Chacko GK, Lund-Katz S, Johnson WJ, Karlin JB. Tetranitromethane modification of human high density lipoprotein (HDL3): inactivation of high density lipoprotein binding is not related to cross-linking of phospholipids to apoproteins. J Lipid Res 1987; 29: 332-40.
    PubMedGoogle Scholar
  • 27 Chomczynski P, Sacchi N. Single step method of RNA isolation by acid guanidium thiocyanate/phenol-chloroform extraction. Anal Biochem 1987; 162: 156-9.
    PubMedGoogle Scholar
  • 28 Michaelides RJAM. Cell cycle regulators: mechanisms and their role in aetiology, prognosis, and treatment of cancer. J Clin Pathol 1999; 52: 555-68.
    CrossrefPubMedGoogle Scholar
  • 29 Daum G, Eisenmann-Tappe I, Fries HW, Troppmair J, Rapp UR. The ins and outs of Raf kinases. Trends Biochem Sci 1994; 19: 474-80.
    CrossrefPubMedGoogle Scholar
  • 30 Lavoie JN, L‘Allemain G, Brunet A, Muller P, Poussegur J. Cyclin D1 expression is regulated positively by the p42/p44MAPK and negatively by the p38/HOGMAPK pathway. J Biol Chem 1996; 271: 20608-16.
    CrossrefPubMedGoogle Scholar
  • 31 Robinson MJ, Cobb M. Mitogen-activated protein kinase pathways. Curr Opin Cell Biol 1997; 9: 180-6.
    CrossrefPubMedGoogle Scholar
  • 32 Gille H, Kortenjann M, Thomae O, Moomaw C, Slaughter C, Cobb MH, Shaw PE. ERK phosphorylation potentiates Elk-1-mediated ternary complex formation and transactivation. EMBO J 1995; 14: 951-62.
    CrossrefPubMedGoogle Scholar
  • 33 Kolch W, Heidecker G, Kochs G, Hummel R, Vahidi H, Mischak H, Finkenzeller G, Marme D, Rapp UR. Protein kinase C alpha activates RAF-1 by direct phosphorylation. Nature 1993; 364: 249-52.
    CrossrefPubMedGoogle Scholar
  • 34 Hordijk PL, Verlaan L, van Corven EJ, Moolenaar WH. Pertussis toxin-sensitive activation of p21ras by G protein-coupled receptor agonists in fibroblasts. J Biol Chem 1994; 269: 645-51.
    PubMedGoogle Scholar
  • 35 Faure M, Voyno-Yasenetskaya T, Bourne H. cAMP and beta gamma subunits of heterotrimeric G proteins stimulate the mitogen-activated protein kinase pathway in COS-7 cells. J Biol Chem 1994; 269: 7851-4.
    PubMedGoogle Scholar
  • 36 Chai Y-C, Howe PH, DiCoroleto PE, Chisolm GM. Oxidized low density lipoprotein and phosphatidylcholine stimulate cell cycle entry in vascular smooth muscle cells. J Biol Chem 1996; 271: 17791-7.
    CrossrefPubMedGoogle Scholar
  • 37 Gordon D, Reidy M, Benditt E, Schwartz S. Cell proliferation in human coronary arteries. Proc Natl Acad Sci 1990; 87: 4600-4.
    CrossrefPubMedGoogle Scholar
  • 38 Ferns GAA, Raines EW, Sprugel KH, Motani AS, Reidy MA, Ross R. Inhibition of neointimal smooth muscle accmulation after angioplasty by an antibody to PDGF. Science 1991; 253: 1129-32.
    CrossrefPubMedGoogle Scholar
  • 39 Lindner V, Reidy MA. Proliferation of smooth muscle cells after vascular injury is inhibited by an antibody against basic fibroblast growth factor. Proc Natl Acad Sci 1991; 88: 3739-43.
    CrossrefPubMedGoogle Scholar
  • 40 Björkerud B, Björkerud S. Contrary effects of lightly and strongly oxidized LDL with potent promotion on growth versus apoptosis on arterial smooth muscle cells, macrophages, and fibroblasts in vitro. Arterioscler Thromb Vasc Biol 1996; 16: 416-24.
    CrossrefPubMedGoogle Scholar
  • 41 Reichl D. Lipoproteins of human peripheral lymph. Eur Heart J 1990; Suppl. E: 230-6.
    PubMedGoogle Scholar
  • 42 Nazih H, Nazih-Sanderson F, Magret V, Caron B, Goudement J, Fruchart JC, Delbart C. Protein kinase C-dependent desensitization of HDL3 activated phospholipase C in human platelets. Arterioscler Thromb 1994; 14: 1321-6.
    CrossrefPubMedGoogle Scholar
  • 43 O’Brien ER, Alpers CE, Stewart DK, Fergusson M, Tran N, Gordon D, Benditt EP, Hinokara T, Simpson JB, Schwarz SM. Proliferation in primary and restenotic coronary atherectomy tissue. Implications for antiproliferative therapy. Circ Res 1993; 73: 223-31.
    CrossrefPubMedGoogle Scholar
  • 44 Bennett M. Apoptosis of vascular smooth muscle cells in vascular remodelling and atherosclerotic plaque rupture. Cardiovasc Res 1999; 41: 361-8.
    CrossrefPubMedGoogle Scholar