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Progenitor cell mobilizing treatments prevent experimental transplant arteriosclerosis
j o u r n a l o f s u r g i c a l r e s e a r c h 1 8 1 ( 2 0 1 3 ) 6 9 e7 0
Available online at www.sciencedirect.com
journal homepage: www.JournalofSurgicalResearch.com
Commentary
Progenitor cell mobilizing treatments prevent experimental transplant arteriosclerosis Christopher W. Macomber, and Shimul A. Shah* Division of Solid Organ Transplantation, Department of Surgery, University of Massachusetts Medical School, 55 Lake Avenue North, S6-432, Worcester, Massachusetts 01655
article info Article history: Received 4 January 2012 Received in revised form 4 January 2012 Accepted 5 January 2012 Available online 1 April 2012
Transplant arteriosclerosis (TA) is a significant causative factor in the long-term failure of transplantation, specifically cardiac allograft transplantation. The authors of this study have contributed additional valuable information related to the mechanisms of TA and methods to limit or prevent its development using existing pharmacologic interventions [1]. In the current paper, Roux et al [1] investigate the use of three pharmacologic interventions known to affect mobilization of progenitor cells and subsequently assist in early endothelial repair. The C57Bl/6 mouse model is ideal for the study of atherosclerosis, and the use of orthotopic arterial transplant is an acceptable method for reliably demonstrating intimal hyperplasia [2]. The authors have previously demonstrated the use of bone marrowederived progenitor cells as a possible treatment for intimal proliferation and demonstrate in the current report that they were able to pharmacologically enhance mobilization of those cells [3]. Interestingly, they were unable to demonstrate protection of the medial smooth muscle cells (SMCs) or inflammation of the adventitia. The importance of progenitor cells in non-transplanterelated
atherosclerotic changes has been well documented, and their importance in TA is clear [4]. Transplant arteriosclerosis has many parallels to nontransplanteassociated atherosclerosis and hyperlipidemia, specifically in relation to the initiating infiltration of mononuclear cells and subsequent intimal accumulation of SMCs [2,5]. Specifically in the case of transplantation, vascular injury resulting from a necessary vascular anastomosis serves as an inciting injury to the vessel wall. There has been a longstanding search to understand the origin of the cells involved in the formation of the neointima. Over the past several years, the recipient has been proposed as the source of the endothelial cells that invade the intima [5,6]. The most exciting aspect of this study is the exploration of new applications of several existing medications. In this case, statins and low-molecular-weight heparin have been used with great success in humans for decades and have known safety profiles. Specifically in the case of statins, there has been a large amount of research regarding their use as an adjunct therapy in transplantation [7e10]. In addition, their effects on SMC migration, progenitor cell mobilization, and progression
* Corresponding author. Associate Professor of Surgery, Solid Organ Transplantation, University of Massachusetts Medical School, 55 Lake Avenue North, S6-432, Worcester, MA 01655. Tel.: þ1 508 334 2023; fax: þ1 508 856 1102. E-mail address: [email protected] (S.A. Shah). 0022-4804/$ e see front matter ª 2013 Elsevier Inc. All rights reserved. doi:10.1016/j.jss.2012.01.013
70
j o u r n a l o f s u r g i c a l r e s e a r c h 1 8 1 ( 2 0 1 3 ) 6 9 e7 0
of atheromatous lesions are well known [7,11]. Although the authors were unable to find improvements in pathologic changes of the medial layer, the possible addition of cyclosporine to their model may provide additional improvements. Cyclosporine is a mainstay of cardiac transplantation immunosuppression and has been shown to assist in preservation of the vascular media in aortic allografts, in addition to preventing neointimal formation [12]. Wenke et al [9,10] have repeatedly reported on the long-term benefits of statins in heart transplant and their potential ability to improve long-term graft survival and decrease the severity of graft rejection. They have also suggested synergistic effects of cyclosporine and statins and the ensuing immunomodulation effects. There is significant published research indicating the potential benefits of existing medications in the treatment of TA, specifically those explored by Roux et al [1]. These drugs have been used in humans for years and have welldocumented safety profiles. The research presented in the current report demonstrates not only the potential for these medications to have an impact on transplant outcomes, but also the value of exploring the use of existing medications for new indications. In the age of rising health care expenditures, this is a cost-effective way to address unmet medical needs.
references
[1] Roux N, Brakenhielm E, Freguin-Bouillant C, et al. Progenitor cell mobilizing treatments prevent experimental transplant arteriosclerosis. J Surg Res 2012;176:657.
[2] Rahmani M, Cruz RP, Granville DJ, et al. Allograft vasculopathy versus atherosclerosis. Circ Res 2006;99:801. [3] Alkhatib B, Freguin-Bouilland C, Lallemand F, et al. Low molecular weight fucan prevents transplant coronaropathy in rat cardiac allograft model. Transplant Immunol 2006; 16:14. [4] Rauscher FM, Goldschmidt-Clermont PJ, Davis BH, et al. Aging, progenitor cell exhaustion, and atherosclerosis. Circulation 2003;108:457. [5] Hu Y, Davison F, Ludewig B, et al. Smooth muscle cells in transplant atherosclerotic lesions are originated from recipients, but not bone marrow progenitor cells. Circulation 2002;106:1834. [6] Lagaaij EL, Cramer-Knijnenburg GF, van Kemenade FJ, et al. Endothelial cell chimerism after renal transplantation and vascular rejection. Lancet 2001;357:33. [7] Stein W, Schrepfer S, Itoh S, et al. Prevention of transplant coronary artery disease by prenylation inhibitors. J Heart Lung Transplant 2011;30:761. [8] Schroeter MR, Humboldt T, Scha¨fer K, et al. Rosuvastatin reduces atherosclerotic lesions and promotes progenitor cell mobilisation and recruitment in apolipoprotein E knockout mice. Atherosclerosis 2009;205:63. [9] Wenke K, Meiser B, Thiery J, et al. Simvastatin initiated early after heart transplantation: 8-year prospective experience. Circulation 2003;107:93. [10] Wenke K, Meiser B, Thiery J, et al. Impact of simvastatin therapy after heart transplantation an 11-year prospective evaluation. Herz 2005;30:431. [11] Ma FX, Han ZC. Statins, nitric oxide and neovascularization. Cardiovasc Drug Rev 2005;23:281. [12] Hillebrands JL, Klatter FA, van den Hurk BM, et al. Origin of neointimal endothelium and alpha-actin-positive smooth muscle cells in transplant arteriosclerosis. J Clin Invest 2001; 107:1411.
Available online at www.sciencedirect.com
journal homepage: www.JournalofSurgicalResearch.com
Commentary
Progenitor cell mobilizing treatments prevent experimental transplant arteriosclerosis Christopher W. Macomber, and Shimul A. Shah* Division of Solid Organ Transplantation, Department of Surgery, University of Massachusetts Medical School, 55 Lake Avenue North, S6-432, Worcester, Massachusetts 01655
article info Article history: Received 4 January 2012 Received in revised form 4 January 2012 Accepted 5 January 2012 Available online 1 April 2012
Transplant arteriosclerosis (TA) is a significant causative factor in the long-term failure of transplantation, specifically cardiac allograft transplantation. The authors of this study have contributed additional valuable information related to the mechanisms of TA and methods to limit or prevent its development using existing pharmacologic interventions [1]. In the current paper, Roux et al [1] investigate the use of three pharmacologic interventions known to affect mobilization of progenitor cells and subsequently assist in early endothelial repair. The C57Bl/6 mouse model is ideal for the study of atherosclerosis, and the use of orthotopic arterial transplant is an acceptable method for reliably demonstrating intimal hyperplasia [2]. The authors have previously demonstrated the use of bone marrowederived progenitor cells as a possible treatment for intimal proliferation and demonstrate in the current report that they were able to pharmacologically enhance mobilization of those cells [3]. Interestingly, they were unable to demonstrate protection of the medial smooth muscle cells (SMCs) or inflammation of the adventitia. The importance of progenitor cells in non-transplanterelated
atherosclerotic changes has been well documented, and their importance in TA is clear [4]. Transplant arteriosclerosis has many parallels to nontransplanteassociated atherosclerosis and hyperlipidemia, specifically in relation to the initiating infiltration of mononuclear cells and subsequent intimal accumulation of SMCs [2,5]. Specifically in the case of transplantation, vascular injury resulting from a necessary vascular anastomosis serves as an inciting injury to the vessel wall. There has been a longstanding search to understand the origin of the cells involved in the formation of the neointima. Over the past several years, the recipient has been proposed as the source of the endothelial cells that invade the intima [5,6]. The most exciting aspect of this study is the exploration of new applications of several existing medications. In this case, statins and low-molecular-weight heparin have been used with great success in humans for decades and have known safety profiles. Specifically in the case of statins, there has been a large amount of research regarding their use as an adjunct therapy in transplantation [7e10]. In addition, their effects on SMC migration, progenitor cell mobilization, and progression
* Corresponding author. Associate Professor of Surgery, Solid Organ Transplantation, University of Massachusetts Medical School, 55 Lake Avenue North, S6-432, Worcester, MA 01655. Tel.: þ1 508 334 2023; fax: þ1 508 856 1102. E-mail address: [email protected] (S.A. Shah). 0022-4804/$ e see front matter ª 2013 Elsevier Inc. All rights reserved. doi:10.1016/j.jss.2012.01.013
70
j o u r n a l o f s u r g i c a l r e s e a r c h 1 8 1 ( 2 0 1 3 ) 6 9 e7 0
of atheromatous lesions are well known [7,11]. Although the authors were unable to find improvements in pathologic changes of the medial layer, the possible addition of cyclosporine to their model may provide additional improvements. Cyclosporine is a mainstay of cardiac transplantation immunosuppression and has been shown to assist in preservation of the vascular media in aortic allografts, in addition to preventing neointimal formation [12]. Wenke et al [9,10] have repeatedly reported on the long-term benefits of statins in heart transplant and their potential ability to improve long-term graft survival and decrease the severity of graft rejection. They have also suggested synergistic effects of cyclosporine and statins and the ensuing immunomodulation effects. There is significant published research indicating the potential benefits of existing medications in the treatment of TA, specifically those explored by Roux et al [1]. These drugs have been used in humans for years and have welldocumented safety profiles. The research presented in the current report demonstrates not only the potential for these medications to have an impact on transplant outcomes, but also the value of exploring the use of existing medications for new indications. In the age of rising health care expenditures, this is a cost-effective way to address unmet medical needs.
references
[1] Roux N, Brakenhielm E, Freguin-Bouillant C, et al. Progenitor cell mobilizing treatments prevent experimental transplant arteriosclerosis. J Surg Res 2012;176:657.
[2] Rahmani M, Cruz RP, Granville DJ, et al. Allograft vasculopathy versus atherosclerosis. Circ Res 2006;99:801. [3] Alkhatib B, Freguin-Bouilland C, Lallemand F, et al. Low molecular weight fucan prevents transplant coronaropathy in rat cardiac allograft model. Transplant Immunol 2006; 16:14. [4] Rauscher FM, Goldschmidt-Clermont PJ, Davis BH, et al. Aging, progenitor cell exhaustion, and atherosclerosis. Circulation 2003;108:457. [5] Hu Y, Davison F, Ludewig B, et al. Smooth muscle cells in transplant atherosclerotic lesions are originated from recipients, but not bone marrow progenitor cells. Circulation 2002;106:1834. [6] Lagaaij EL, Cramer-Knijnenburg GF, van Kemenade FJ, et al. Endothelial cell chimerism after renal transplantation and vascular rejection. Lancet 2001;357:33. [7] Stein W, Schrepfer S, Itoh S, et al. Prevention of transplant coronary artery disease by prenylation inhibitors. J Heart Lung Transplant 2011;30:761. [8] Schroeter MR, Humboldt T, Scha¨fer K, et al. Rosuvastatin reduces atherosclerotic lesions and promotes progenitor cell mobilisation and recruitment in apolipoprotein E knockout mice. Atherosclerosis 2009;205:63. [9] Wenke K, Meiser B, Thiery J, et al. Simvastatin initiated early after heart transplantation: 8-year prospective experience. Circulation 2003;107:93. [10] Wenke K, Meiser B, Thiery J, et al. Impact of simvastatin therapy after heart transplantation an 11-year prospective evaluation. Herz 2005;30:431. [11] Ma FX, Han ZC. Statins, nitric oxide and neovascularization. Cardiovasc Drug Rev 2005;23:281. [12] Hillebrands JL, Klatter FA, van den Hurk BM, et al. Origin of neointimal endothelium and alpha-actin-positive smooth muscle cells in transplant arteriosclerosis. J Clin Invest 2001; 107:1411.