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(Circulation Research. 2004;94:269.)
© 2004 American Heart Association, Inc.

Editorials

Apoptosis of Vascular Cells by Oxidized LDL

Involvement of Caspases and LOX-1 and Its Implication in Atherosclerotic Plaque Rupture

Noriaki Kume, Toru Kita

From the Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Correspondence to Noriaki Kume, MD, PhD, Department of Cardio-vascular Medicine, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan. E-mail nkume{at}kuhp.kyoto-u.ac.jp

Key Words: oxidized LDL • caspases • apoptosis

A therosclerotic plaque rupture followed by thrombus formation is a key event in the onset of acute coronary syndrome.¹ Apoptotic death of smooth muscle cells in the fibrous cap of the atherosclerotic plaque, in addition to degradation of extracellular matrix proteins by matrix metalloproteinases (MMPs), appears to be involved in atherosclerotic plaque rupture.¹ Oxidized LDL (Ox-LDL) has been implicated in the pathogenesis of atherosclerosis and atherosclerotic plaque rupture by promoting lipid accumulation, proinflammatory responses, and apoptotic cell death.^2–4 In fact, apoptotic cells are present in atherosclerotic lesions.^4,5 These biological effects, including proapoptotic effects, of Ox-LDL appear to be, at least in part, mediated by cell-surface receptors for Ox-LDL.⁶

Among several different classes of oxidized LDL receptors (also designated scavenger receptors) most of which are expressed mainly by macrophages, lectin-like oxidized LDL receptor-1 (LOX-1) is a type II membrane glycoprotein and expressed by activated vascular endothelial and smooth muscle cells, as well as macrophages.^7–10 LOX-1 expression can dynamically be induced by proinflammatory and other pathological stimuli relevant to atherogenesis.^11–14 Particularly, LOX-1 is induced by its ligand Ox-LDL,^15,16 as well as proinflammatory cytokines,^11,12 thus making a positive-feedback loop to enhance the effect of Ox-LDL on vascular cells. Uptake of Ox-LDL through LOX-1 induces reactive oxygen species (ROS), reduces nitric oxide, activates NF-B, ^17,18 and thereby upregulates expression of monocyte chemoattractant protein-1 (MCP-1) and MMPs.^19–21 LOX-1-dependent uptake of Ox-LDL also induces expression of a proapoptotic factor Bax, downregulates an antiapoptotic factor Bcl-2, and induces apoptosis of cultured vascular smooth muscle cells,¹⁵ as well as endothelial cells.¹⁶

In human advanced atherosclerotic lesions, but not in normal arterial walls, macrophages and smooth muscle cells in the intima, in addition to vascular endothelial cells, dominantly express LOX-1,²² which is colocalized with Bax.¹⁵ In the early stages of atherogenesis, LOX-1 expression is prominent in vascular endothelial cells,^22,23 and apoptosis of endothelial cells also are detected, which may be implicated in endothelial dysfunction.⁴ Thus, evidence has been accumulated to indicate that vascular cell apoptosis is mediated by Ox-LDL and its receptor LOX-1, and it may be crucial for atherosclerotic plaque rupture in the advanced stage, as well as endothelial dysfunction in the early stage.

However, molecular mechanisms involved in cell apoptosis by Ox-LDL and LOX-1 interactions have not been fully understood. In this issue of Circulation Research, Chen et al²⁴ have explored the involvement of caspases and the related molecules, such as Bcl-2 and c-IAP-2, and report that activation of caspase-9 and subsequent activation of caspase-3 are responsible for Ox-LDL-induced apoptosis of cultured vascular endothelial cells through its receptor LOX-1. In addition, release of mitochondrial apoptotic proteins, such as cytochrome c and Smac, was associated with Ox-LDL-induced caspase activation and apoptosis. Because Ox-LDL-induced release of cytochrome c or Smac was blocked by antisense oligonucleotides for LOX-1 but not affected by caspase inhibitors, cytochrome c and Smac appear to be upstream of caspase 9 and caspase 3 or might alternatively be independent of these caspases, although LOX-1 mediates the both pathways.

Chen et al²⁴ have confirmed that caspase 9 is upstream of caspase 3²⁵ in the Ox-LDL-induced apoptosis, as shown in cytochrome c-dependent apoptosis by other stimuli.²⁶ In addition, LOX-1-dependent downregulation of Bcl-2 by Ox-LDL is also shown in this study, as shown in cultured vascular smooth muscle cells.¹⁵ Bcl-2 appears to be the upstream of cytochrome c and Smac and thus may inhibit their mitochondrial release. Furthermore, c-IAP-1, an inhibitor of caspase activation, has been shown to be downregulated by Ox-LDL, depending on LOX-1, in this study (Figure). LOX-1-dependent downregulation of Bcl-2 and c-IAP-1 may depend on ROS and its downstream signals; however, these points remain to be determined. Because activation of protein kinase C,²⁰ mitogen-activated protein (MAP) kinases,¹⁹ and nuclear factor-B (NF-B)¹⁷ and inhibition of phosphatidylinositol 3-kinase (PI3K)/Akt,²⁷ as well as production of ROS,¹⁷ are involved in Ox-LDL and LOX-1-mediated cellular events, roles of these signal transduction cascades and transcription factors in Ox-LDL-induced downregulation of Bcl-2 and c-IAP-1, as well as cell apoptosis, should also be explored. In fact, PI3K/Akt has been implicated in Ox-LDL/LOX-1-induced apoptosis.^27,28 In addition, Bax is also the upstream of cytochrome c and Smac release and is upregulated by Ox-LDL-LOX-1 interactions,¹⁵ signal transduction cascades, and transcription factors involved in Ox-LDL-induced upregulation of Bax should also be examined. More importantly, future studies should be conducted to determine the effect of vascular cell apoptosis in the pathogenesis of atherosclerotic plaque rupture, thrombus formation, and the onset of acute coronary syndrome in humans or suitable animal models in vivo.

View larger version (18K): [in this window] [in a new window]   Molecular cascades involved in apoptosis by Ox-LDL-LOX-1 interactions.

Footnotes

The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.

See related article, pages 370–376

References

1. Libby P. Current concepts of the pathogenesis of the acute coronary syndromes. Circulation. 2001; 104: 365–372.[Free Full Text]
2. Ross R. Atherosclerosis: an inflammatory disease. N Engl J Med. 1999; 1340: 115–126.
3. Steinberg D. Lewis A. Conner Memorial Lecture: oxidative modification of LDL and atherogenesis. Circulation. 1997; 95: 1062–1071.[Free Full Text]
4. Norata GD, Tonti L, Roma P, Catapano AL. Apoptosis and proliferation of endothelial cells in early atherosclerotic lesions: possible role of oxidised LDL. Nutr Metab Cardiovasc Dis. 2002; 12: 297–305.[Medline] [Order article via Infotrieve]
5. Kockx MM, De Meyer GR, Muhring J, Jacob W, Bult H, Herman AG. Apoptosis and related proteins in different stages of human atherosclerosis and restenosis. Circulation. 1998; 97: 2307–2315.[Abstract/Free Full Text]
6. Krieger M, Acton S, Ashkenas J, Pearson A, Penman M, Resnick D. Molecular flypaper, host defense, and atherosclerosis: structure, binding properties, and functions of macrophage scavenger receptors. J Biol Chem. 1993; 268: 4569–4572.[Free Full Text]
7. Sawamura T, Kume N, Aoyama T, Moriwaki H, Hoshikawa H, Aiba Y, Tanaka T, Miwa S, Katsura Y, Kita T, Masaki T. A novel endothelial receptor for oxidised low density lipoprotein. Nature. 1997; 386: 73–77.[CrossRef][Medline] [Order article via Infotrieve]
8. Moriwaki H, Kume N, Sawamura T, Aoyama T, Hoshikawa H, Ochi H, Nishi E, Masaki T, Kita T. Ligand specificity of LOX-1, a novel receptor for oxidized low-density lipoprotein. Arterioscler Thromb Vasc Biol. 1998; 18: 1541–1547.[Abstract/Free Full Text]
9. Kataoka H, Kume N, Miyamoto S, Murase T, Minami M, Sawamura T, Masaki T, Hashimoto N, Kita T. Biosynthesis and posttranslational processing of lectin-like oxidized LDL receptor-1 (LOX-1): N-linked glycosylation affects the cell-surface expression and the ligand binding. J Biol Chem. 2000; 275: 6573–6579.[Abstract/Free Full Text]
10. Kume N, Kita T. Roles of lectin-like oxidized low density lipoprotein receptor-1 (LOX-1) and its soluble forms in atherogenesis. Curr Opin Lipidol. 2001; 12: 419–423.[CrossRef][Medline] [Order article via Infotrieve]
11. Kume N, Murase T, Moriwaki H, Aoyama T, Sawamura T, Masaki T, Kita T. Inducible expression of lectin-like oxidized low density lipoprotein receptor-1 in vascular endothelial cells. Circ Res. 1998; 83: 322–327.[Abstract/Free Full Text]
12. Minami M, Kume N, Kataoka H, Morimoto M, Hayashida K, Sawamura T, Masaki T, Kita T. Transforming growth factor-ß1 increases the expression of lectin-like oxidized low density lipoprotein receptor-1. Biochem Biophys Res Commun. 2000; 272: 357–361.[CrossRef][Medline] [Order article via Infotrieve]
13. Moriwaki H, Kume N, Kataoka H, Murase T, Nishi E, Sawamura T, Masaki T, Kita T. Expression of lectin-like oxidized low density lipoprotein receptor-1 in human and murine macrophages-upregulated expression by TNF-. FEBS Lett. 1998; 440: 29–32.[CrossRef][Medline] [Order article via Infotrieve]
14. Kita T. LOX-1, a possible clue to the missing link between hypertension and atherogenesis. Circ Res. 1999; 84: 1113–1115.[Free Full Text]
15. Kataoka H, Kume N, Miyamoto S, Minami M, Morimoto M, Hayashida K, Hashimoto N, Kita T. Oxidized low density lipoprotein (Ox-LDL) modulates Bax/Bcl-2 through lectin-like Ox-LDL receptor-1 in vascular smooth muscle cells. Arterioscler Thromb Vasc Biol. 2001; 21: 955–960.[Abstract/Free Full Text]
16. Li D, Mehta JL. Upregulation of endothelial receptor for oxidized LDL (LOX-1) by oxidized LDL and implications in apoptosis of human coronary artery endothelial cells: evidence from use of antisense LOX-1 mRNA and chemical inhibitors. Arterioscler Thromb Vasc Biol. 2000; 20: 1116–1122.[Abstract/Free Full Text]
17. Cominacini L, Pasini AF, Garbin U, Davoli A, Tosetti ML, Campagnola M, Rigioni A, Pastorino AM, Lo Cascio V, Sawamura T. Oxidized low-density lipoprotein binding to LOX-1 in endothelial cells induces the activation of NF-B through an increased production of intracellular reactive oxygen species. J Biol Chem. 2000; 275: 633–638.
18. Cominacini L, Rigoni A, Pasini AF, Garbin U, Davoli A, Campagnola M, Pastorino AM, Lo Cascio V, Sawamura T. The binding of oxidized low-density lipoprotein (ox-LDL) to ox-LDL receptor-1 reduces the intracellular concentration of nitric oxide in endothelial cells through an increased production of superoxide. J Biol Chem. 2001; 276: 13750–13755.[Abstract/Free Full Text]
19. Li D, Mehta JL. Antisense to LOX-1 inhibits oxidized LDL-mediated upregulation of monocyte chemoattractant protein-1 and monocyte adhesion to human coronary artery endothelial cells. Circulation. 2000; 101: 2889–2895.[Abstract/Free Full Text]
20. Li D, Liu L, Chen H, Sawamura T, Ranganathan S, Mehta JL. LOX-1 mediates oxidized low-density lipoprotein-induced expression of matrix metalloproteinases in human coronary artery endothelial cells. Circulation. 2003; 107: 612–617.[Abstract/Free Full Text]
21. Li D, Williams V, Liu L, Chen H, Sawamura T, Antakli T, Mehta JL. LOX-1 inhibition in myocardial ischemia-reperfusion injury: modulation of MMP-1 and inflammation. Am J Physiol. 2002; 283: H1795–H1801.
22. Kataoka H, Kume N, Miyamoto S, Minami M, Moriwaki H, Sawamura T, Masaki T, Hashimoto N, Kita T. Expression of lectin-like oxidized low density lipoprotein receptor-1 in human atherosclerotic lesions. Circulation. 1999; 99: 3110–3117.[Abstract/Free Full Text]
23. Chen M, Kakutani M, Minami M, Kataoka H, Kume N, Narumiya S, Kita T, Masaki T, Sawamura T. Increased expression of lectin-like oxidized low density lipoprotein receptor-1 in initial atherosclerotic lesions of Watanabe heritable hyperlipidemic rabbits. Arterioscler Thromb Vasc Biol. 2000; 20: 1107–1115.[Abstract/Free Full Text]
24. Chen J, Mehta JL, Haider N, Zhang X, Narula J, Li D. Role of caspases in Ox-LDL-induced apoptotic cascade in human coronary artery endothelial cells. Circ Res. 2004; 94: 370–376.[Abstract/Free Full Text]
25. Dimmeler S, Haendeler J, Galle J, Zeiher AM. Oxidized low-density lipoprotein induces apoptosis of human endothelial cells by activation of CPP32-like proteases. Circulation. 1997; 95: 1760–1763.[Abstract/Free Full Text]
26. Slee EA, Harte MT, Kluck RM, Wolf BB, Casiano CA, Newmeyer DD, Wang HG, Reed JC, Nicholson DW, Alnemri ES, Green DR, Martin SJ. Ordering the cytochromec-initiated caspase cascade: hierarchical activation of caspases-2, -3, -6, -7, -8, and -10 in a capase-9-dependent manner. J Cell Biol. 1999; 144: 281–292.[Abstract/Free Full Text]
27. Nakagawa T, Yasuda T, Hoshokawa H, Shimizu M, Kakinuma T, Chen M, Masaki T, Nakamura T, Sawamura T. LOX-1 expressed in cultured rat chondrocytes mediates oxidized LDL-induced cell death-possible role of dephosphorylation of Akt. Biochem Biophys Res Commun. 2002; 299: 91–97.[CrossRef][Medline] [Order article via Infotrieve]
28. Li Y, Higashi Y, Itabe H, Song Y-H, Du J, Delafontaine P. Insulin-like growth factor-1 receptor activation inhibits oxidized LDL-induced cytochromec release and apoptosis via the phosphatidylinositol 3 kinase/Akt signaling pathway. Arterioscler Thromb Vasc Biol. 2003; 23: 2178–2184.[Abstract/Free Full Text]

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