(Circulation. 2001;103:2753.)
© 2001 American Heart Association, Inc.
Basic Science Reports |
Liposome-Mediated Gene Transfection of Endothelial Nitric Oxide Synthase Reduces Endothelial Activation and Leukocyte Infiltration in Transplanted Hearts
From the University of Washington (A.I., R.T.), the Fred Hutchinson Cancer Research Institute (R.d.F.-H.), and the Hope Heart Institute (M.D.A.), Seattle, Wash; Tohoku University, Sendai, Japan (S.S., Y.N.); Wellesley College, Cambridge, Mass (M.C.); and the University of Minnesota, Minneapolis (J.D.).
Correspondence to Margaret D. Allen, MD, The Hope Heart Institute, 1124 Columbia St, Suite 120, Seattle, WA 98104. E-mail mallen{at}hopeheart.org
Background—During
cardiac ischemia-reperfusion injury, neutrophilic infiltration
of the myocardium is mediated by adhesion molecule
expression on activated coronary
endothelium. Nitric oxide inhibits neutrophil adhesion
to endothelium in vitro by blocking the nuclear factor
(NF)-
B–dependent transcription of adhesion molecules. We
investigated whether intraoperative gene delivery of
endothelial nitric oxide synthase (eNOS) into donor
hearts before transplantation would have a similar effect on an entire
organ.
Methods and Results—In
an allogeneic rabbit heart transplant model, liposomes complexed to the
gene encoding eNOS were infused into the donor coronary
circulation before transplantation. By 24 hours after transplantation,
calcium-dependent nitrite production was significantly higher
in eNOS-transfected donor hearts than in the 3 control groups: donor
hearts transfected with empty plasmids alone, donor hearts treated with
diluent only, and untransplanted native hearts. Intramyocardial
neutrophil and T-lymphocyte populations were halved in eNOS-transfected
hearts compared with control donor hearts
(P<0.05). Moreover, the
prevalence of NF-B activation in microvascular
endothelial cells and surrounding cardiac myocytes as
well as endothelial vascular cell adhesion molecule-1
and intracellular adhesion molecule-1 expression were all significantly
reduced in eNOS-transfected hearts compared with control donor hearts
(P<0.01). Without
immunosuppression, eNOS-transfected hearts survived longer than
controls.
Conclusions—Intraoperative
liposome-mediated gene delivery of eNOS to donor hearts can result in
early gene expression sufficient to reduce ischemia-reperfusion
injury by inhibiting NF-B activation, adhesion molecule expression,
and the early infiltration of leukocytes, all of which may improve
graft survival.
Key Words: gene therapy • nitric oxide • cell adhesion molecules • ischemia • reperfusion • transplantation
This article has been cited by other articles:
 |
|
 |
|
  G. Vassalli, M.-E. Roehrich, P. Vogt, G. B. Pedrazzini, F. Siclari, T. Moccetti, and L. K. von Segesser Modalities and future prospects of gene therapy in heart transplantation Eur. J. Cardiothorac. Surg., June 1, 2009; 35(6): 1036 - 1044. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J.-L. Balligand, O. Feron, and C. Dessy eNOS Activation by Physical Forces: From Short-Term Regulation of Contraction to Chronic Remodeling of Cardiovascular Tissues Physiol Rev, April 1, 2009; 89(2): 481 - 534. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Davis, M. V. Westfall, D. Townsend, M. Blankinship, T. J. Herron, G. Guerrero-Serna, W. Wang, E. Devaney, and J. M. Metzger Designing Heart Performance by Gene Transfer Physiol Rev, October 1, 2008; 88(4): 1567 - 1651. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Rahmani, R. P. Cruz, D. J. Granville, and B. M. McManus Allograft Vasculopathy Versus Atherosclerosis Circ. Res., October 13, 2006; 99(8): 801 - 815. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Dai, Y.H. Ding, R. Kadirvel, M.A. Danielson, D.A. Lewis, H.J. Cloft, and D.F Kallmes A longitudinal immunohistochemical study of the healing of experimental aneurysms after embolization with platinum coils. AJNR Am. J. Neuroradiol., April 1, 2006; 27(4): 736 - 741. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Tanaka, K. Sydow, F. Gunawan, J. Jacobi, P. S. Tsao, R. C. Robbins, and J. P. Cooke Dimethylarginine Dimethylaminohydrolase Overexpression Suppresses Graft Coronary Artery Disease Circulation, September 13, 2005; 112(11): 1549 - 1556. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Orlandi, A. Francesconi, M. Marcellini, A. Ferlosio, and L. G. Spagnoli Role of ageing and coronary atherosclerosis in the development of cardiac fibrosis in the rabbit Cardiovasc Res, December 1, 2004; 64(3): 544 - 552. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Kupatt, C. Dessy, R. Hinkel, P. Raake, G. Daneau, C. Bouzin, P. Boekstegers, and O. Feron Heat Shock Protein 90 Transfection Reduces Ischemia-Reperfusion-Induced Myocardial Dysfunction via Reciprocal Endothelial NO Synthase Serine 1177 Phosphorylation and Threonine 495 Dephosphorylation Arterioscler. Thromb. Vasc. Biol., August 1, 2004; 24(8): 1435 - 1441. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Ishii, Y. Suzuki, K. Takeshita, N. Miyao, H. Kudo, R. Hiraoka, K. Nishio, N. Sato, K. Naoki, T. Aoki, et al. Inhibition of c-Jun NH2-Terminal Kinase Activity Improves Ischemia/Reperfusion Injury in Rat Lungs J. Immunol., February 15, 2004; 172(4): 2569 - 2577. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Vassalli, S. Fleury, J. Li, J.-J. Goy, L. Kappenberger, and L. K. von Segesser Gene transfer of cytoprotective and immunomodulatory molecules for prevention of cardiac allograft rejection Eur. J. Cardiothorac. Surg., November 1, 2003; 24(5): 794 - 806. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Li, H. Chen, F. Romeo, T. Sawamura, T. Saldeen, and J. L. Mehta Statins Modulate Oxidized Low-Density Lipoprotein-Mediated Adhesion Molecule Expression in Human Coronary Artery Endothelial Cells: Role of LOX-1 J. Pharmacol. Exp. Ther., August 1, 2002; 302(2): 601 - 605. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. A. Santizo, H.-L. Xu, E. Galea, S. Muyskens, V. L. Baughman, and D. A. Pelligrino Combined Endothelial Nitric Oxide Synthase Upregulation and Caveolin-1 Downregulation Decrease Leukocyte Adhesion in Pial Venules of Ovariectomized Female Rats Stroke, February 1, 2002; 33(2): 613 - 616. [Abstract] [Full Text] [PDF]
|
|