This Article Full Text Full Text (PDF) All Versions of this Article: 24/6/1049    most recent 01.ATV.0000124923.95545.2cv1 Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Whitman, S. C. Articles by Daugherty, A. Search for Related Content PubMed PubMed Citation Articles by Whitman, S. C. Articles by Daugherty, A. Related Collections Animal models of human disease Genetically altered mice Mechanism of atherosclerosis/growth factors

(Arteriosclerosis, Thrombosis, and Vascular Biology. 2004;24:1049.)
© 2004 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Depletion of Natural Killer Cell Function Decreases Atherosclerosis in Low-Density Lipoprotein Receptor Null Mice

Stewart C. Whitman; Debra L. Rateri; Stephen J. Szilvassy; Wayne Yokoyama; Alan Daugherty

From the Departments of Pathology and Laboratory Medicine & Cellular and Molecular Medicine (S.C.W.), University of Ottawa Heart Institute, Ottawa, Ontario, Canada; Gill Heart Institute (D.L.R., A.D.), Division of Cardiovascular Medicine, University of Kentucky, Lexington; Amgen (S.J.S.), Thousand Oaks, Calif; and Washington University School of Medicine (W.Y.), Division of Rheumatology, St. Louis, Mo.

Correspondence to Dr Stewart C. Whitman, University of Ottawa Heart Institute, 40 Ruskin St, Room H259A, Ottawa, Ontario, Canada, K1Y 4W7. E-mail swhitman{at}ottawaheart.ca

Objective— Natural killer (NK) cells are a key component of innate immunity. Despite being identified in human and mouse atherosclerotic lesions, the role of NK cells in the disease process in unknown. To determine this role, we created chimeric atherosclerosis-susceptible low-density lipoprotein (LDL) receptor null (ldl-r^–/–) mice that were deficient in functional NK cells through expression of a transgene encoding for Ly49A.

Methods and Results— Bone marrow cells from Ly49A transgenic and nontransgenic littermates were used to repopulate the hematopoietic system of lethally-irradiated female ldl-r^–/– mice. After a recovery period to permit sufficient engraftment, mice were placed on a diet enriched in saturated fat and cholesterol. After 8 weeks, there was no difference in either serum total cholesterol concentrations or lipoprotein cholesterol distribution in mice repopulated with nontransgenic versus Ly49A transgenic marrow cells. Using immunohistochemistry, we detected NK cells in atherosclerotic lesions of both groups of mice. However, deficiency of functional NK cells significantly reduced the size of atherosclerosis by 70% (P=0.0002) in cross-sectional analysis of the aortic root and by 38% (P=0.004) in en face analysis of the intimal surface of the aortic arch.

Conclusion— These studies demonstrate that NK cells infiltrate the vessel wall and promote atherosclerotic lesion development.

Natural killer (NK) cells are found in atherosclerotic lesions, yet their role in the disease process is unknown. Using bone marrow transplantation, we created atherosclerosis-susceptible mice that were deficient in functional NK cells. NK cell deficiency did not affect serum cholesterol values but did significantly reduce (70%) atherosclerotic lesion formation.

Key Words: atherosclerosis • NK cells • LDL receptor null mice • bone marrow transplantation

This article has been cited by other articles:

				J. A. Kelly, M. E. Griffin, R. A. Fava, S. G. Wood, K. A. Bessette, E. R. Miller, S. A. Huber, C. J. Binder, J. L. Witztum, and P. M. Morganelli Inhibition of arterial lesion progression in CD16-deficient mice: evidence for altered immunity and the role of IL-10 Cardiovasc Res, September 19, 2009; (2009) cvp300v2. [Abstract] [Full Text] [PDF]

				P. Gratze, R. Dechend, C. Stocker, J.-K. Park, S. Feldt, E. Shagdarsuren, M. Wellner, F. Gueler, S. Rong, V. Gross, et al. Novel Role for Inhibitor of Differentiation 2 in the Genesis of Angiotensin II-Induced Hypertension Circulation, May 20, 2008; 117(20): 2645 - 2656. [Abstract] [Full Text] [PDF]

				P. Liu, Y.-R. A. Yu, J. A. Spencer, A. E. Johnson, C. T. Vallanat, A. M. Fong, C. Patterson, and D. D. Patel CX3CR1 Deficiency Impairs Dendritic Cell Accumulation in Arterial Intima and Reduces Atherosclerotic Burden Arterioscler Thromb Vasc Biol, February 1, 2008; 28(2): 243 - 250. [Abstract] [Full Text] [PDF]

				V. van Weel, R.E.M. Toes, L. Seghers, M.M.L. Deckers, M.R. de Vries, P.H. Eilers, J. Sipkens, A. Schepers, D. Eefting, V.W.M. van Hinsbergh, et al. Natural Killer Cells and CD4+ T-Cells Modulate Collateral Artery Development Arterioscler Thromb Vasc Biol, November 1, 2007; 27(11): 2310 - 2318. [Abstract] [Full Text] [PDF]

				K. Y. Stokes, S. Gurwara, and D. N. Granger T-Cell-Derived Interferon-{gamma} Contributes to Arteriolar Dysfunction During Acute Hypercholesterolemia Arterioscler Thromb Vasc Biol, September 1, 2007; 27(9): 1998 - 2004. [Abstract] [Full Text] [PDF]

				L. A. Cassis, D. L. Rateri, H. Lu, and A. Daugherty Bone Marrow Transplantation Reveals That Recipient AT1a Receptors Are Required to Initiate Angiotensin II-Induced Atherosclerosis and Aneurysms Arterioscler Thromb Vasc Biol, February 1, 2007; 27(2): 380 - 386. [Abstract] [Full Text] [PDF]

				C D Schwindt, F Zaldivar, L Wilson, S-Y Leu, J Wang-Rodriguez, P J Mills, and D M Cooper Do circulating leucocytes and lymphocyte subtypes increase in response to brief exercise in children with and without asthma? Br. J. Sports Med., January 1, 2007; 41(1): 34 - 40. [Abstract] [Full Text] [PDF]

				L. R. Tannock, E. A. Kirk, V. L. King, R. LeBoeuf, T. N. Wight, and A. Chait Glucosamine Supplementation Accelerates Early but Not Late Atherosclerosis in LDL Receptor-Deficient Mice J. Nutr., November 1, 2006; 136(11): 2856 - 2861. [Abstract] [Full Text] [PDF]

				A.-K. L. Robertson and G. K Hansson T Cells in Atherogenesis: For Better or For Worse? Arterioscler Thromb Vasc Biol, November 1, 2006; 26(11): 2421 - 2432. [Abstract] [Full Text] [PDF]

				E. Galkina, A. Kadl, J. Sanders, D. Varughese, I. J. Sarembock, and K. Ley Lymphocyte recruitment into the aortic wall before and during development of atherosclerosis is partially L-selectin dependent J. Exp. Med., May 15, 2006; 203(5): 1273 - 1282. [Abstract] [Full Text] [PDF]

				A.D. Hauer, C. Uyttenhove, P. de Vos, V. Stroobant, J.C. Renauld, T.J.C. van Berkel, J. van Snick, and J. Kuiper Blockade of Interleukin-12 Function by Protein Vaccination Attenuates Atherosclerosis Circulation, August 16, 2005; 112(7): 1054 - 1062. [Abstract] [Full Text] [PDF]

				R. Wessely Interference by interferons: Janus faces in vascular proliferative diseases Cardiovasc Res, June 1, 2005; 66(3): 433 - 443. [Abstract] [Full Text] [PDF]

				P. A. VanderLaan and C. A. Reardon Thematic review series: The Immune System and Atherogenesis. The unusual suspects:an overview of the minor leukocyte populations in atherosclerosis J. Lipid Res., May 1, 2005; 46(5): 829 - 838. [Abstract] [Full Text] [PDF]

				G. Caligiuri, S. Kaveri, and A. Nicoletti When Interleukin-18 Conducts, the Preludio Sounds the Same no Matter Who Plays Arterioscler Thromb Vasc Biol, April 1, 2005; 25(4): 655 - 657. [Full Text] [PDF]

				G. S. Getz Thematic review series: The Immune System and Atherogenesis. Immune function in atherogenesis J. Lipid Res., January 1, 2005; 46(1): 1 - 10. [Abstract] [Full Text] [PDF]

				M. F. Linton, A. S. Major, and S. Fazio Proatherogenic Role for NK Cells Revealed Arterioscler Thromb Vasc Biol, June 1, 2004; 24(6): 992 - 994. [Full Text] [PDF]