From the Cardiovascular Biology Laboratory, Harvard School of Public
Health (J.K., T.G.-J., M.E.R.), Cardiovascular Medicine Division, Brigham and
Women's Hospital (M.E.R.), and Harvard Medical School (M.E.R.), Boston,
Mass, and Merck Research Laboratories, Rahway, NJ (J.S.M.).
Correspondence to Mary E. Russell, MD, Cardiovascular Biology Laboratory, Harvard School of Public Health, 677 Huntington Ave, Boston, MA 02115. E-mail russell{at}cvlab.harvard.edu
Background—Inducible NO synthase
(NOS2, or iNOS) is upregulated in grafts with transplant
arteriosclerosis. However, the functional role of
NOS2 in the pathogenesis of transplant
arteriosclerosis remains unclear. NOS2 may regulate
lesion development by modulating the early alloimmune response and/or
late myointimal thickening.
Methods and Results—To determine whether NOS2-mediated pathways
protect against or promote transplant
arteriosclerosis, we used NOS2-deficient mice as
recipients in our vascularized chronic cardiac rejection model. The
severity of vascular thickening in 55-day grafts placed into NOS2 -/-
recipients (n=13) was compared with that in wild-type recipients
(n=15). Computer-assisted analysis of all elastin-stained
vessels (n=283) showed significantly increased luminal occlusion
(77.1±9.4% versus 40.8±13.6%, P<.0001) and
intima/media ratios in allografts from NOS2 -/- recipients (1.9±1.3
versus 0.4±0.3, P=.0002). To elucidate potential
mechanisms, we studied NOS2 effects on T-cell differentiation
(Th1/Th2) and neointimal smooth
muscle cell accumulation. Normalized mRNA levels for Th1-
(signal transducer and activator of transcription [STAT]
4, interleukin [IL]-2, interferon-
Conclusions—NOS2 plays a protective role in the development of
transplant arteriosclerosis, suppressing
neointimal smooth muscle cell accumulation.
© 1998 American Heart Association, Inc.
Basic Science Reports
Exacerbated Transplant Arteriosclerosis in Inducible Nitric Oxide–Deficient Mice
) and Th2- (STAT 6,
IL-4, and IL-5) associated factors were comparable in both groups. In
contrast, quantitative analysis of the 
-actin–positive area
showed a significant increase in the contribution of smooth muscle
cells within the neointima in allografts from NOS2 -/-
recipients (28.2±2.0%) compared with wild-type controls (13.2±2.3%;
P<.0001).
Key Words: transplantation • immunology • lymphocytes • remodeling • muscle, smooth
This article has been cited by other articles:
 |
|
 |
|
  S. Nakata, M. Tsutsui, H. Shimokawa, T. Yamashita, A. Tanimoto, H. Tasaki, K. Ozumi, K. Sabanai, T. Morishita, O. Suda, et al. Statin Treatment Upregulates Vascular Neuronal Nitric Oxide Synthase Through Akt/NF-{kappa}B Pathway Arterioscler. Thromb. Vasc. Biol., January 1, 2007; 27(1): 92 - 98. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Ferlito, K. Irani, N. Faraday, and C. J. Lowenstein Nitric oxide inhibits exocytosis of cytolytic granules from lymphokine-activated killer cells PNAS, August 1, 2006; 103(31): 11689 - 11694. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 U. Mayr, Y. Zou, Z. Zhang, H. Dietrich, Y. Hu, and Q. Xu Accelerated Arteriosclerosis of Vein Grafts in Inducible NO Synthase-/- Mice Is Related to Decreased Endothelial Progenitor Cell Repair Circ. Res., February 17, 2006; 98(3): 412 - 420. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Hofmann, R. Feil, T. Kleppisch, and J. Schlossmann Function of cGMP-Dependent Protein Kinases as Revealed by Gene Deletion Physiol Rev, January 1, 2006; 86(1): 1 - 23. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Nakata, M. Tsutsui, H. Shimokawa, M. Tamura, H. Tasaki, T. Morishita, O. Suda, S. Ueno, Y. Toyohira, Y. Nakashima, et al. Vascular Neuronal NO Synthase Is Selectively Upregulated by Platelet-Derived Growth Factor: Involvement of the MEK/ERK Pathway Arterioscler. Thromb. Vasc. Biol., December 1, 2005; 25(12): 2502 - 2508. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. W. Q. Moore and D. Y. Hui Apolipoprotein E inhibition of vascular hyperplasia and neointima formation requires inducible nitric oxide synthase J. Lipid Res., October 1, 2005; 46(10): 2083 - 2090. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. M. Tesar, G. Chalasani, L. Smith-Diggs, F. K. Baddoura, F. G. Lakkis, and D. R. Goldstein Direct Antigen Presentation by a Xenograft Induces Immunity Independently of Secondary Lymphoid Organs J. Immunol., October 1, 2004; 173(7): 4377 - 4386. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Hayashi, Y. Sawa, N. Fukuyama, Y. Miyamoto, T. Takahashi, H. Nakazawa, and H. Matsuda Leukocyte-depleted terminal blood cardioplegia provides superior myocardial protective effects in association with myocardium-derived nitric oxide and peroxynitrite production for patients undergoing prolonged aortic crossclamping for more than 120 minutes J. Thorac. Cardiovasc. Surg., December 1, 2003; 126(6): 1813 - 1821. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Feil, S. M. Lohmann, H. de Jonge, U. Walter, and F. Hofmann Cyclic GMP-Dependent Protein Kinases and the Cardiovascular System: Insights From Genetically Modified Mice Circ. Res., November 14, 2003; 93(10): 907 - 916. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Dixit, D. Zhuang, B. Ceacareanu, and A. Hassid Treatment With Insulin Uncovers the Motogenic Capacity of Nitric Oxide in Aortic Smooth Muscle Cells: Dependence on Gab1 and Gab1-SHP2 Association Circ. Res., November 14, 2003; 93 (10): e113 - e123. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Vassalli, A. Gallino, M. Weis, W. von Scheidt, L. Kappenberger, L.K. von Segesser, J.-J. Goy, and on behalf of the Working Group Microcirculation of Alloimmunity and nonimmunologic risk factors in cardiac allograft vasculopathy Eur. Heart J., July 1, 2003; 24(13): 1180 - 1188. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Weis and J. P. Cooke Cardiac Allograft Vasculopathy and Dysregulation of the NO Synthase Pathway Arterioscler. Thromb. Vasc. Biol., April 1, 2003; 23(4): 567 - 575. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Minamoto and D. J. Pinsky Recipient iNOS but Not eNOS Deficiency Reduces Luminal Narrowing in Tracheal Allografts J. Exp. Med., November 18, 2002; 196(10): 1321 - 1333. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Hayashi, Y. Sawa, N. Fukuyama, H. Nakazawa, and H. Matsuda Preoperative Glutamine Administration Induces Heat-Shock Protein 70 Expression and Attenuates Cardiopulmonary Bypass-Induced Inflammatory Response by Regulating Nitric Oxide Synthase Activity Circulation, November 12, 2002; 106(20): 2601 - 2607. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C.A. Gunnett, D.D. Lund, M.A. Howard III, Y. Chu, F.M. Faraci, and D.D. Heistad Gene Transfer of Inducible Nitric Oxide Synthase Impairs Relaxation in Human and Rabbit Cerebral Arteries Stroke, September 1, 2002; 33(9): 2292 - 2296. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Tolbert, J. A. Thompson, P. Bouchard, and S. Oparil Estrogen-Induced Vasoprotection Is Independent of Inducible Nitric Oxide Synthase Expression: Evidence From the Mouse Carotid Artery Ligation Model Circulation, November 27, 2001; 104(22): 2740 - 2745. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Qian, R. Gelzer-Bell, S.-x. Yang, W. Cao, T. Ohnishi, B. A. Wasowska, R. H. Hruban, E. R. Rodriguez, W. M. Baldwin III, and C. J. Lowenstein Inducible Nitric Oxide Synthase Inhibition of Weibel-Palade Body Release in Cardiac Transplant Rejection Circulation, November 6, 2001; 104(19): 2369 - 2375. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. M. Wildhirt, M. Weis, C. Schulze, N. Conrad, S. Pehlivanli, G. Rieder, G. Enders, W. von Scheidt, and B. Reichart Expression of Endomyocardial Nitric Oxide Synthase and Coronary Endothelial Function in Human Cardiac Allografts Circulation, September 18, 2001; 104(90001): I-336 - 343. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Hayashi, Y. Sawa, N. Fukuyama, H. Nakazawa, and H. Matsuda Inducible nitric oxide production is an adaptation to cardiopulmonary bypass-induced inflammatory response Ann. Thorac. Surg., July 1, 2001; 72(1): 149 - 155. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. J. Kuhlencordt, J. Chen, F. Han, J. Astern, and P. L. Huang Genetic Deficiency of Inducible Nitric Oxide Synthase Reduces Atherosclerosis and Lowers Plasma Lipid Peroxides in Apolipoprotein E-Knockout Mice Circulation, June 26, 2001; 103(25): 3099 - 3104. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. E. von der Leyen and V. J. Dzau Therapeutic Potential of Nitric Oxide Synthase Gene Manipulation Circulation, June 5, 2001; 103(22): 2760 - 2765. [Full Text] [PDF]
|
|
|
|
 |
|
 S. M. Wildhirt, M. Weis, C. Schulze, N. Conrad, S. Pehlivanli, G. Rieder, G. Enders, W. von Scheidt, and B. Reichart Coronary flow reserve and nitric oxide synthases after cardiac transplantation in humans Eur. J. Cardiothorac. Surg., June 1, 2001; 19(6): 840 - 847. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Sasu, A. L. Cooper, and D. Beasley Juxtacrine effects of IL-1{alpha} precursor promote iNOS expression in vascular smooth muscle cells Am J Physiol Heart Circ Physiol, April 1, 2001; 280(4): H1615 - H1623. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X.-L. Niu, X. Yang, K. Hoshiai, K. Tanaka, S. Sawamura, Y. Koga, and H. Nakazawa Inducible Nitric Oxide Synthase Deficiency Does Not Affect the Susceptibility of Mice to Atherosclerosis but Increases Collagen Content in Lesions Circulation, February 27, 2001; 103(8): 1115 - 1120. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. F. Halloran, M. Afrouzian, V. Ramassar, J. Urmson, L.-F. Zhu, L. M. H. Helms, K. Solez, and N. M. Kneteman Interferon-{{gamma}} Acts Directly on Rejecting Renal Allografts to Prevent Graft Necrosis Am. J. Pathol., January 1, 2001; 158(1): 215 - 226. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Yogo, H. Shimokawa, H. Funakoshi, T. Kandabashi, K. Miyata, S. Okamoto, K. Egashira, P. Huang, T. Akaike, and A. Takeshita Different Vasculoprotective Roles of NO Synthase Isoforms in Vascular Lesion Formation in Mice Arterioscler. Thromb. Vasc. Biol., November 1, 2000; 20 (11): e96 - e100. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Muniyappa, R. Xu, J. L. Ram, and J. R. Sowers Inhibition of Rho protein stimulates iNOS expression in rat vascular smooth muscle cells Am J Physiol Heart Circ Physiol, June 1, 2000; 278(6): H1762 - H1768. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Y. Wang, I. Aronson, S. Takuma, S. Homma, Y. Naka, T. Alshafie, V. Brovkovych, T. Malinski, M. C. Oz, and D. J. Pinsky cAMP Pulse During Preservation Inhibits the Late Development of Cardiac Isograft and Allograft Vasculopathy Circ. Res., May 12, 2000; 86(9): 982 - 988. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Koglin, T. Glysing-Jensen, S. Gadiraju, and M. E. Russell Attenuated Cardiac Allograft Vasculopathy in Mice With Targeted Deletion of the Transcription Factor STAT4 Circulation, March 7, 2000; 101(9): 1034 - 1039. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. M Shah Inducible nitric oxide synthase and cardiovascular disease Cardiovasc Res, January 1, 2000; 45(1): 148 - 155. [Full Text] [PDF]
|
|
|
|
|
|
J. Y. Jeremy, D. Rowe, A. M. Emsley, and A. C. Newby Nitric oxide and the proliferation of vascular smooth muscle cells Cardiovasc Res, August 15, 1999; 43(3): 580 - 594. [Full Text] [PDF]
|
|
|
|
|
|
M. Kibbe, T. Billiar, and E. Tzeng Inducible nitric oxide synthase and vascular injury Cardiovasc Res, August 15, 1999; 43(3): 650 - 657. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. J. Lefer, S. P. Jones, W. G. Girod, A. Baines, M. B. Grisham, A. S. Cockrell, P. L. Huang, and R. Scalia Leukocyte-endothelial cell interactions in nitric oxide synthase-deficient mice Am J Physiol Heart Circ Physiol, June 1, 1999; 276(6): H1943 - H1950. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Wever, P. Boer, M. Hijmering, E. Stroes, M. Verhaar, J. Kastelein, K. Versluis, F. Lagerwerf, H. van Rijn, H. Koomans, et al. Nitric Oxide Production Is Reduced in Patients With Chronic Renal Failure Arterioscler. Thromb. Vasc. Biol., May 1, 1999; 19(5): 1168 - 1172. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Koglin, D. J. Granville, T. Glysing-Jensen, J. S. Mudgett, C. M. Carthy, B. M. McManus, and M. E. Russell Attenuated Acute Cardiac Rejection in NOS2 -/- Recipients Correlates With Reduced Apoptosis Circulation, February 16, 1999; 99(6): 836 - 842. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Koglin, T. Glysing-Jensen, J. S. Mudgett, and M. E. Russell NOS2 Mediates Opposing Effects in Models of Acute and Chronic Cardiac Rejection : Insights from NOS2-Knockout Mice Am. J. Pathol., November 1, 1998; 153(5): 1371 - 1376. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Koglin, T. Glysing-Jensen, A. Raisanen-Sokolowski, and M. E. Russell Immune Sources of Transforming Growth Factor-ß1 Reduce Transplant Arteriosclerosis : Insight Derived From a Knockout Mouse Model Circ. Res., September 21, 1998; 83(6): 652 - 660. [Abstract] [Full Text] [PDF]
|
|