Published online before print April 4, 2005, doi: 10.1161/01.CIR.0000160864.31351.C1
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Circulation. 2005;111:1814-1821.)
© 2005 American Heart Association, Inc.
Molecular Cardiology |
Activation of the Unfolded Protein Response Occurs at All Stages of Atherosclerotic Lesion Development in Apolipoprotein E–Deficient Mice
árka Lhoták, PhD*From the Department of Pathology and Molecular Medicine, McMaster University, and the Henderson Research Centre, Hamilton, Ontario, Canada.
Correspondence to Richard C. Austin, PhD, Henderson Research Centre, 711 Concession St, Hamilton, Ontario L8V 1C3, Canada. E-mail raustin{at}thrombosis.hhscr.org
Received July 12, 2004; revision received November 9, 2004; accepted December 1, 2004.
Background— Apoptotic cell death contributes to atherosclerotic lesion instability, rupture, and thrombogenicity. Recent findings suggest that free cholesterol (FC) accumulation in macrophages induces endoplasmic reticulum (ER) stress/unfolded protein response (UPR) and apoptotic cell death; however, it is not known at what stage of lesion development the UPR is induced in macrophages or whether a correlation exists between UPR activation, FC accumulation, and apoptotic cell death.
Methods and Results— Aortic root sections from apolipoprotein E–deficient (apoE–/–) mice at 9 weeks of age (early-lesion group) or 23 weeks of age (advanced-lesion group) fed a standard chow diet were examined for markers of UPR activation (GRP78, phospho-PERK, CHOP, and TDAG51), apoptotic cell death (TUNEL and cleaved caspase-3), and lipid accumulation (filipin and oil red O). UPR markers were dramatically increased in very early intimal macrophages and in macrophage foam cells from fatty streaks and advanced atherosclerotic lesions. Although accumulation of FC was observed in early-lesion–resident macrophage foam cells, no evidence of apoptotic cell death was observed; however, UPR activation, FC accumulation, and apoptotic cell death were observed in a small percentage of advanced-lesion–resident macrophage foam cells.
Conclusions— UPR activation occurs at all stages of atherosclerotic lesion development. The additional finding that macrophage apoptosis did not correlate with UPR activation and FC accumulation in early-lesion–resident macrophages suggests that activation of other cellular mediators and/or pathways are required for apoptotic cell death.
Key Words: immunohistochemistry • atherosclerosis • cholesterol • apoptosis
This article has been cited by other articles:
 |
|
 |
|
  J. G. Dickhout, S. Basseri, and R. C. Austin Macrophage Function and Its Impact on Atherosclerotic Lesion Composition, Progression, and Stability: The Good, the Bad, and the Ugly Arterioscler. Thromb. Vasc. Biol., August 1, 2008; 28(8): 1413 - 1415. [Full Text] [PDF]
|
|
|
|
|
|
R. E. Feaver, N. E. Hastings, A. Pryor, and B. R. Blackman GRP78 Upregulation by Atheroprone Shear Stress Via p38-, {alpha}2{beta}1-Dependent Mechanism in Endothelial Cells Arterioscler. Thromb. Vasc. Biol., August 1, 2008; 28(8): 1534 - 1541. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O. V. Oskolkova, T. Afonyushkin, A. Leitner, E. von Schlieffen, P. S. Gargalovic, A. J. Lusis, B. R. Binder, and V. N. Bochkov ATF4-dependent transcription is a key mechanism in VEGF up-regulation by oxidized phospholipids: critical role of oxidized sn-2 residues in activation of unfolded protein response Blood, July 15, 2008; 112(2): 330 - 339. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J.-C. Chen, M.-L. Wu, K.-C. Huang, and W.-W. Lin HMG-CoA reductase inhibitors activate the unfolded protein response and induce cytoprotective GRP78 expression Cardiovasc Res, July 2, 2008; (2008) cvn160v2. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Zhou, G. H. Werstuck, S. Lhotak, Y. Y. Shi, V. Tedesco, B. Trigatti, J. Dickhout, A. K. Majors, P. M. DiBello, D. W. Jacobsen, et al. Hyperhomocysteinemia induced by methionine supplementation does not independently cause atherosclerosis in C57BL/6J mice FASEB J, July 1, 2008; 22(7): 2569 - 2578. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Herrmann, S. M. Soares, L. O. Lerman, and A. Lerman Potential Role of the Ubiquitin-Proteasome System in Atherosclerosis: Aspects of a Protein Quality Disease J. Am. Coll. Cardiol., May 27, 2008; 51(21): 2003 - 2010. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Mayr, A. Zampetaki, A. Sidibe, U. Mayr, X. Yin, A. I. De Souza, Y.-L. Chung, B. Madhu, P. H. Quax, Y. Hu, et al. Proteomic and Metabolomic Analysis of Smooth Muscle Cells Derived From the Arterial Media and Adventitial Progenitors of Apolipoprotein E-Deficient Mice Circ. Res., May 9, 2008; 102(9): 1046 - 1056. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Kuchibhotla, D. Vanegas, D. J. Kennedy, E. Guy, G. Nimako, R. E. Morton, and M. Febbraio Absence of CD36 protects against atherosclerosis in ApoE knock-out mice with no additional protection provided by absence of scavenger receptor A I/II Cardiovasc Res, April 1, 2008; 78(1): 185 - 196. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. J. Gregory, R. Sladek, M. Olivier, and G. Matlashewski Comparison of the Effects of Leishmania major or Leishmania donovani Infection on Macrophage Gene Expression Infect. Immun., March 1, 2008; 76(3): 1186 - 1192. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W.-S. Lim, J. M. Timmins, T. A. Seimon, A. Sadler, F. D. Kolodgie, R. Virmani, and I. Tabas Signal Transducer and Activator of Transcription-1 Is Critical for Apoptosis in Macrophages Subjected to Endoplasmic Reticulum Stress In Vitro and in Advanced Atherosclerotic Lesions In Vivo Circulation, February 19, 2008; 117(7): 940 - 951. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Cui, E. Thorp, Y. Li, N. Wang, L. Yvan-Charvet, A. R. Tall, and I. Tabas Pivotal Advance: Macrophages become resistant to cholesterol-induced death after phagocytosis of apoptotic cells J. Leukoc. Biol., November 1, 2007; 82(5): 1040 - 1050. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. G. Dickhout, S. M. Colgan, S. Lhotak, and R. C. Austin Increased Endoplasmic Reticulum Stress in Atherosclerotic Plaques Associated With Acute Coronary Syndrome: A Balancing Act Between Plaque Stability and Rupture Circulation, September 11, 2007; 116(11): 1214 - 1216. [Full Text] [PDF]
|
|
|
|
|
|
M. Myoishi, H. Hao, T. Minamino, K. Watanabe, K. Nishihira, K. Hatakeyama, Y. Asada, K.-i. Okada, H. Ishibashi-Ueda, G. Gabbiani, et al. Increased Endoplasmic Reticulum Stress in Atherosclerotic Plaques Associated With Acute Coronary Syndrome Circulation, September 11, 2007; 116(11): 1226 - 1233. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. S. Gargalovic, N. M. Gharavi, M. J. Clark, J. Pagnon, W.-P. Yang, A. He, A. Truong, T. Baruch-Oren, J. A. Berliner, T. G. Kirchgessner, et al. The Unfolded Protein Response Is an Important Regulator of Inflammatory Genes in Endothelial Cells Arterioscler. Thromb. Vasc. Biol., November 1, 2006; 26(11): 2490 - 2496. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Arabzadeh, T.-C. Troy, and K. Turksen Role of the Cldn6 Cytoplasmic Tail Domain in Membrane Targeting and Epidermal Differentiation In Vivo Mol. Cell. Biol., August 1, 2006; 26(15): 5876 - 5887. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Gotoh and M. Mori Nitric Oxide and Endoplasmic Reticulum Stress Arterioscler. Thromb. Vasc. Biol., July 1, 2006; 26(7): 1439 - 1446. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. G. Dickhout, G. S. Hossain, L. M. Pozza, J. Zhou, S. Lhotak, and R. C. Austin Peroxynitrite Causes Endoplasmic Reticulum Stress and Apoptosis in Human Vascular Endothelium: Implications in Atherogenesis Arterioscler. Thromb. Vasc. Biol., December 1, 2005; 25(12): 2623 - 2629. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Tabas Consequences and Therapeutic Implications of Macrophage Apoptosis in Atherosclerosis: The Importance of Lesion Stage and Phagocytic Efficiency Arterioscler. Thromb. Vasc. Biol., November 1, 2005; 25(11): 2255 - 2264. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Bhattacharjee, J. Ahamed, B. Pedersen, A. El-Sheikh, N. Mackman, W. Ruf, C. Liu, and T. S. Edgington Regulation of Tissue Factor-Mediated Initiation of the Coagulation Cascade by Cell Surface Grp78 Arterioscler. Thromb. Vasc. Biol., August 1, 2005; 25(8): 1737 - 1743. [Abstract] [Full Text] [PDF]
|
|