Summary
Accurate diagnosis and prevention of graft arteriosclerosis, known as chronic rejection, is critical to the success of cardiac transplantation, but often is difficult to attain. Expression of cell division cycle (cdc) 2 kinase, which plays a critical role in cell transition through the G2/M phase, is critical to the proliferation of vascular smooth muscle cells. To evaluate the usefulness of cdc2 kinase expression for pathophysiological analysis of chronic rejection, heterotopic cardiac transplantation was performed in Japanese monkeys (n=7). Standard reverse transcriptase-polymerase chain reaction (RT-PCR) and in situ RT-PCR were performed to evaluate the expression. In the coronary arteries of chronically rejected allografts, enhanced cdc2 kinase expression was observed in thickened intima and media, while none was expressed in native hearts. The cdc2 kinase was also expressed before the intimal thickening occurred. These results indicate that enhanced expression of cdc2 kinase is a sensitive indicator for chronic cardiac rejection; targeting cdc2 kinase may be a viable gene therapy for prevention of this vasculopathy.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Kaye MP (1992) The registry of the International Society for Heart and Lung Transplantation: 9th official report. J Heart Lung Transplant 11:599–606
Johnson DE, Alderman EL, Schroeder JS, Gao SZ, Hunt S, DeCampi WM, Stinson E, Billingham M (1991) Transplant coronary artery disease: histopathologic correlations with angiographic morphology. J Am Coll Cardiol 17:449–457
Botas J, Pinto FJ, Chenzbraun A, Liang D, Schroeder JS, Oesterle SN, Alderman EL, Popp RL, Yeung AC (1995) Influence of preexistent donor coronary artery disease on the progression of transplant vasculopathy. An intravascular ultrasound study. Circulation 92:1126–1132
Uretsky BF, Murali S, Reddy S, Rabin B, Lee A, Griffith BP, Hardesty RL, Trento A, Bahnson HT (1987) Development of coronary artery disease in cardiac transplanted patients receiving immunosuppressive therapy with cyclosporine and predonisolone. Circulation 76:827–834
Seo K, Imamura S, Ohta Y, Nishikawa T, Imai Y (1993) Longer transplanted heart allograft survival in rats without immunosuppressants after intrathymic myocardial cell inoculation in the neonatal period. Heart Vessels 8:67–70
Isobe M, Suzuki J (1998) New approaches to the management of acute and chronic cardiac allograft rejection. Jpn Circ J 62:315–317
Morishita R, Gibbons GH, Ellison KE, Nakajima M, Leyen H, Zhang L, Kaneda Y, Ogihara T, Dzau VJ (1994) Intimal hyperplasia after vascular injury is inhibited by antisense cdk2 kinase oligonucleotides. J Clin Invest 93:1458–1464
Morishita R, Gibbons GH, Ellison KE, Nakajima M, Zhang L, Kaneda Y, Ogihara T, Dzau VJ (1993) Single intraluminal delivery of antisense cdc2 kinase and PCNA oligonucleotides results in chronic inhibition of neointimal hyperplasia. Proc Natl Acad Sci USA 90:8474–8478
Ono K, Lindsey E (1969) Improved technique of heart transplantation in rats. J Thorac Cardiovasc Surg 547:225–229
Kawauchi M, Yazaki Y, Oka T, Okabe H, Mathison M, Nakajima J, Morisugi O, Kawaguchi G, Koseni K, Takeda M, Chikada M, Furuse A (1990) Diagnosis of cardiac allograft rejection by the detection of circulating plasma cardiac myosin light chains. Jpn J Surg 20:212–216
Suzuki J, Isobe M, Aikawa M, Kawauchi M, Shiojima I, Kobayashi N, Tojo A, Kimura K, Nishikawa T, Sakai T, Sekiguchi M, Yazaki Y, Nagai R (1996) Nonmuscle and smooth muscle myosin heavy chain expression in rejected cardiac allograft. A study in rat and monkey models. Circulation 94:1118–1124
Patel GV, Shum-siu A, Henifold BW, Wieman TJ, Hendler FJ (1994) Detection of epidermal growth factor receptor mRNA in tissue sections from biopsy specimens using in situ polymerase chain reaction. Am J Pathol 144:7–14
Nuovo GJ, Gallery F, MacConnell P, Braun A (1994) In situ detection of polymerase chain reaction-amplified HIV-1 nucleic acids and tumor necrosis factor-α RNA in the central nervous system. Am J Pathol 144:659–666
Suzuki J, Isobe M, Yamazaki S, Sekiguchi M (1997) Inhibition of accelerated coronary atherosclerosis with short-term blockade of intercellular adhesion molecule-1 and lymphocyte function-associated antigen-1 in a heterotopic murine model of heart transplantation. J Heart Lung Transplant 16:1141–1148
Hosenpud JD (1993) Immune mechanism of cardiac allograft vasculopathy: an update. Transplant Immunol 1:237–249
Osborn L (1990) Leukocyte adhesion to endothelium in inflammation. Cell 62:3–6
Russell PS, Chase CM, Winn HJ, Colvin RB (1994) Coronary arteriosclerosis in transplanted mouse hearts, 1. Time course and immunogeneic considerations. Am J Pathol 144:260–274
Cybulsky MI, Gimbrone MA Jr (1991) Endothelial expression of monnuclear leukocyte adhesion molecule during atherogenesis. Science 251:788–791
Suzuki J, Isobe M, Morishita R, Aoki M, Horie S, Okubo Y, Kaneda Y, Sawa Y, Matsuda H, Ogihara T, Sekiguchi M (1997) Prevention of graft coronary arteriosclerosis by antisense cdk2 kinase oligonucleotide. Nature Med 3:900–903
Author information
Authors and Affiliations
Additional information
This study was supported by a Grant-in-Aid from the Ministry of Education, Science and Culture, Ministry of Health and Welfare, and by the Uehara Memorial Foundation, Japan Medical Foundation, Shinshu Medical Foundation, and Tokyo Biochemical Research Foundation.
Rights and permissions
About this article
Cite this article
Schoenbeck, A., Isobe, M., Suzuki, Ji. et al. Expression of cell division cycle 2 kinase transcription in chronically rejected cardiac allografts of nonhuman primates. Heart Vessels 12, 275–279 (1997). https://doi.org/10.1007/BF02766803
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF02766803