International Journal of Cardiology 187 (2015) 31–32
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Letter to the Editor
Blockade of mTOR pathway inhibition in the neointimal hyperplasia and promoting macrophage autophagy — Effect of statin-eluting stents to reduce in-stent restenosis Heng-Jing Hu, Sheng-Hua Zhou, Qi-Ming Liu ⁎ Department of Cardiology/Cardiac Catheterisation Lab, Second Xiangya Hospital, Central South University, Changsha City, Hunan Province 410011, China
a r t i c l e
i n f o
Article history: Received 5 January 2015 Accepted 7 March 2015 Available online 20 March 2015 Keywords: Statins-eluting stents In-stent restenosis Mammalian target of rapamycin
To the editor, Nowadays stent surgery, which can save a great number of patients by choosing percutaneous coronary intervention (PCI) treatment in the endarterium of the arteria coronaria by delivery of stent implantation, is emerging as a new, effective and safe approach to achieve sustained dilatation stenosis or occlusion of arteria coronaria reduction in patients with unstable angina pectoris. Unfortunately, in-stent restenosis (ISR) has occurred frequently at a ratio as high as 20–30% 6 months after the surgery, which has become a major problem in stent implantation practice [1]. ISR has been characterized by a process called neointimal hyperplasia, a sequential event of inflammation, granulation, extracellular matrix remodeling, and vascular smooth muscle cell (VSMC) proliferation and migration. The drug-eluting stents (DES) indeed improve the performance of conventional bare-metal stents (BMS) to reduce ISR. However, ISR caused by DES has also been reported, and it has been attributed partially to the impairment of the arterial healing process characterized by neointimal hyperplasia and macrophage infiltration [2]. To achieve an effective inhibition of macrophage infiltration and neointimal hyperplasia that reduce of ISR form, a novel metallic material for stent applications has been developed extensively. ⁎ Corresponding author at: Department of Cardiology/Cardiac Catheterisation Lab, Second Xiangya Hospital, Central South University, 139 W Middle Renmin Road Changsha, 410011 Hunan, China. E-mail address: [email protected] (Q.-M. Liu).
http://dx.doi.org/10.1016/j.ijcard.2015.03.286 0167-5273/© 2015 Elsevier Ireland Ltd. All rights reserved.
Autophagy (also referred to as macroautophagy) is an evolutionarily conserved controlled living cell catabolic process involving the delivery of cytoplasmic contents to the machinery for ultimate degradation and recycling [3]. This process removes damaged or redundant organelles such as dysfunction mitochondria and excess peroxisomes by degrading long-lived cytoplasmic macromolecules during periods of anaerobic glycolysis, and promotes cell survival. Macrophage autophagy promoted reduction of plaque area via lower lesional macrophage apoptosis, smaller oxidative stress index and alleviated inflammatory response [4]. Autophagy has effects on reduction of neointimal hyperplasia, however; the molecular basis and correlation between autophagy and neointimal hyperplasia remain unclear [5]. Mammalian target of rapamycin (mTOR) is an evolutionarily conserved protein kinase regulating autophagy, which is also critical in the regulation of embryonic cardiovascular development and in the control of vital cellular processes necessary for normal arteria coronaria growth and maintenance of cardiac function [6]. Recent reports have confirmed that mTOR can inhibit autophagy, and rapamycin or everolimus (both are specific inhibitors of the mTOR pathway) can selectively promote moderate autophagy of macrophage [7] and improve the performance of conventional BMS to reduce ISR [8,9]. However, rapamycin is effective in inhibiting neointimal hyperplasia , but neointimal hyperplasia still persisted after rapamycin-eluting stent implantation in the porcine aortic intima, which may be partly related to an exaggerated inflammatory response (for example TNF-α, IL-1β and IL-6) within the blood vessel wall [10]. Adverse effects correlated with rapamycin or everolimus such as dyslipidemia and hyperglycemia also have recently been identified. Developing novel metallic material for stent applications improve the impaired autophagy of macrophage and inhibit the neointimal hyperplasia after stenting has been extensively explored. Currently, statins as a novel metallic material for stent applications have been found [11]; they have pleiotropic effects, which include the inhibition of neointima hyperplasia [11], the inhibition of mTOR [12], and macrophage autophagy enhancement [13]. In additional, statins are potent cardiovascular protective agents that have been shown to reduce inflammatory response and oxidative stress, and inhibit platelet aggregation. Dyslipidemia is manageable via statins treatment; they also prevent hyperglycemia. Because statins has beneficial macrovascular effects, this drug in combination with an mTOR inhibitor might have significant promise to treat patients with unstable plaques. Moreover, statins are known to inhibit mTOR via AMPK activation so
32
H.-J. Hu et al. / International Journal of Cardiology 187 (2015) 31–32
that it would fully exploit the beneficial effects of mTOR inhibition in atherosclerosis (AS). Therefore, we can deduce that statin-eluting stents' selective inhibition of the mTOR signal transduction pathway can reduce neointima hyperplasia and reduce the AS plaque area by promoting macrophage autophagy, consequently improving the ISR in stent implantation without having adverse effects in both cholesterol and glucose metabolism by rapamycin or everolimus. In conclusion, we hypothesize that the mTOR mediates the neointimal hyperplasia efficacy and autophagy in ISR after stent implantation. Statin-eluting stents by regulating and controlling mTOR can reduce neointima hyperplasia and reduce the AS plaque area by promoting macrophage autophagy, consequently improving the ISR in stent implantation and reducing the occurrence of clinical events. Conflict of interest The authors report no relationships that could be construed as a conflict of interest. References [1] C. Bauters, J.L. Banos, E. Van Belle, E.P. Mc Fadden, J.M. Lablanche, M.E. Bertrand, Six-month angiographic outcome after successful repeat percutaneous intervention for in-stent restenosis, Circulation 97 (1998) 318–321. [2] S. Garg, P. Serruys, Benefits of and safety concerns associated with drug-eluting coronary stents, Expert. Rev. Cardiovasc. Ther. 8 (2010) 449–470.
[3] J.M. Vicencio, L. Galluzzi, N. Tajeddine, C. Ortiz, A. Criollo, E. Tasdemir, et al., Senescence, apoptosis or autophagy? When a damaged cell must decide its path — a mini-review, Gerontology 54 (2008) 92–99. [4] X. Liao, J.C. Sluimer, Y. Wang, M. Subramanian, K. Brown, J.S. Pattison, et al., Macrophage autophagy plays a protective role in advanced atherosclerosis, Cell Metab. 15 (2012) 545–553. [5] L. Li, S. Pan, X. Zhou, X. Meng, X. Han, Y. Ren, et al., Reduction of in-stent restenosis risk on nickel-free stainless steel by regulating cell apoptosis and cell cycle, PLoS One 8 (2013) e62193. [6] S. Sciarretta, M. Volpe, J. Sadoshima, Mammalian target of rapamycin signaling in cardiac physiology and disease, Circ. Res. 114 (2014) 549–564. [7] S. Verheye, W. Martinet, M.M. Kockx, M.W. Knaapen, K. Salu, J.P. Timmermans, et al., Selective clearance of macrophages in atherosclerotic plaques by autophagy, J. Am. Coll. Cardiol. 49 (2007) 706–715. [8] Y.J. Youn, J.W. Lee, S.G. Ahn, S.H. Lee, H. Choi, C.W. Yu, et al., Multicenter randomized trial of 3-month cilostazol use in addition to dual antiplatelet therapy after biolimus-eluting stent implantation for long or multivessel coronary artery disease, Am. Heart J. 167 (2014) 241–248. [9] J. Mehilli, R.A. Byrne, A. Wieczorek, R. Iijima, S. Schulz, O. Bruskina, et al., Randomized trial of three rapamycin-eluting stents with different coating strategies for the reduction of coronary restenosis, Eur. Heart J. 29 (2008) 1975–1982. [10] Q. Zhang, L. Lu, L. Pu, R. Zhang, J. Shen, Z. Zhu, et al., Neointimal hyperplasia persists at six months after sirolimus-eluting stent implantation in diabetic porcine, Cardiovasc. Diabetol. 6 (2007) 16. [11] K.S. Lim, M.H. Jeong, I.H. Bae, J.K. Park, D.S. Park, J.M. Kim, et al., Effect of atorvastatin-eluting stents in a rabbit iliac artery restenosis model, Chonnam Med. J. 49 (2013) 118–124. [12] W. Martinet, H. De Loof, G.R. De Meyer, mTOR inhibition: a promising strategy for stabilization of atherosclerotic plaques, Atherosclerosis 233 (2014) 601–607. [13] S.P. Parihar, R. Guler, R. Khutlang, D.M. Lang, R. Hurdayal, M.M. Mhlanga, et al., Statin therapy reduces the mycobacterium tuberculosis burden in human macrophages and in mice by enhancing autophagy and phagosome maturation, J. Infect. Dis. 209 (2014) 754–763.
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Letter to the Editor
Blockade of mTOR pathway inhibition in the neointimal hyperplasia and promoting macrophage autophagy — Effect of statin-eluting stents to reduce in-stent restenosis Heng-Jing Hu, Sheng-Hua Zhou, Qi-Ming Liu ⁎ Department of Cardiology/Cardiac Catheterisation Lab, Second Xiangya Hospital, Central South University, Changsha City, Hunan Province 410011, China
a r t i c l e
i n f o
Article history: Received 5 January 2015 Accepted 7 March 2015 Available online 20 March 2015 Keywords: Statins-eluting stents In-stent restenosis Mammalian target of rapamycin
To the editor, Nowadays stent surgery, which can save a great number of patients by choosing percutaneous coronary intervention (PCI) treatment in the endarterium of the arteria coronaria by delivery of stent implantation, is emerging as a new, effective and safe approach to achieve sustained dilatation stenosis or occlusion of arteria coronaria reduction in patients with unstable angina pectoris. Unfortunately, in-stent restenosis (ISR) has occurred frequently at a ratio as high as 20–30% 6 months after the surgery, which has become a major problem in stent implantation practice [1]. ISR has been characterized by a process called neointimal hyperplasia, a sequential event of inflammation, granulation, extracellular matrix remodeling, and vascular smooth muscle cell (VSMC) proliferation and migration. The drug-eluting stents (DES) indeed improve the performance of conventional bare-metal stents (BMS) to reduce ISR. However, ISR caused by DES has also been reported, and it has been attributed partially to the impairment of the arterial healing process characterized by neointimal hyperplasia and macrophage infiltration [2]. To achieve an effective inhibition of macrophage infiltration and neointimal hyperplasia that reduce of ISR form, a novel metallic material for stent applications has been developed extensively. ⁎ Corresponding author at: Department of Cardiology/Cardiac Catheterisation Lab, Second Xiangya Hospital, Central South University, 139 W Middle Renmin Road Changsha, 410011 Hunan, China. E-mail address: [email protected] (Q.-M. Liu).
http://dx.doi.org/10.1016/j.ijcard.2015.03.286 0167-5273/© 2015 Elsevier Ireland Ltd. All rights reserved.
Autophagy (also referred to as macroautophagy) is an evolutionarily conserved controlled living cell catabolic process involving the delivery of cytoplasmic contents to the machinery for ultimate degradation and recycling [3]. This process removes damaged or redundant organelles such as dysfunction mitochondria and excess peroxisomes by degrading long-lived cytoplasmic macromolecules during periods of anaerobic glycolysis, and promotes cell survival. Macrophage autophagy promoted reduction of plaque area via lower lesional macrophage apoptosis, smaller oxidative stress index and alleviated inflammatory response [4]. Autophagy has effects on reduction of neointimal hyperplasia, however; the molecular basis and correlation between autophagy and neointimal hyperplasia remain unclear [5]. Mammalian target of rapamycin (mTOR) is an evolutionarily conserved protein kinase regulating autophagy, which is also critical in the regulation of embryonic cardiovascular development and in the control of vital cellular processes necessary for normal arteria coronaria growth and maintenance of cardiac function [6]. Recent reports have confirmed that mTOR can inhibit autophagy, and rapamycin or everolimus (both are specific inhibitors of the mTOR pathway) can selectively promote moderate autophagy of macrophage [7] and improve the performance of conventional BMS to reduce ISR [8,9]. However, rapamycin is effective in inhibiting neointimal hyperplasia , but neointimal hyperplasia still persisted after rapamycin-eluting stent implantation in the porcine aortic intima, which may be partly related to an exaggerated inflammatory response (for example TNF-α, IL-1β and IL-6) within the blood vessel wall [10]. Adverse effects correlated with rapamycin or everolimus such as dyslipidemia and hyperglycemia also have recently been identified. Developing novel metallic material for stent applications improve the impaired autophagy of macrophage and inhibit the neointimal hyperplasia after stenting has been extensively explored. Currently, statins as a novel metallic material for stent applications have been found [11]; they have pleiotropic effects, which include the inhibition of neointima hyperplasia [11], the inhibition of mTOR [12], and macrophage autophagy enhancement [13]. In additional, statins are potent cardiovascular protective agents that have been shown to reduce inflammatory response and oxidative stress, and inhibit platelet aggregation. Dyslipidemia is manageable via statins treatment; they also prevent hyperglycemia. Because statins has beneficial macrovascular effects, this drug in combination with an mTOR inhibitor might have significant promise to treat patients with unstable plaques. Moreover, statins are known to inhibit mTOR via AMPK activation so
32
H.-J. Hu et al. / International Journal of Cardiology 187 (2015) 31–32
that it would fully exploit the beneficial effects of mTOR inhibition in atherosclerosis (AS). Therefore, we can deduce that statin-eluting stents' selective inhibition of the mTOR signal transduction pathway can reduce neointima hyperplasia and reduce the AS plaque area by promoting macrophage autophagy, consequently improving the ISR in stent implantation without having adverse effects in both cholesterol and glucose metabolism by rapamycin or everolimus. In conclusion, we hypothesize that the mTOR mediates the neointimal hyperplasia efficacy and autophagy in ISR after stent implantation. Statin-eluting stents by regulating and controlling mTOR can reduce neointima hyperplasia and reduce the AS plaque area by promoting macrophage autophagy, consequently improving the ISR in stent implantation and reducing the occurrence of clinical events. Conflict of interest The authors report no relationships that could be construed as a conflict of interest. References [1] C. Bauters, J.L. Banos, E. Van Belle, E.P. Mc Fadden, J.M. Lablanche, M.E. Bertrand, Six-month angiographic outcome after successful repeat percutaneous intervention for in-stent restenosis, Circulation 97 (1998) 318–321. [2] S. Garg, P. Serruys, Benefits of and safety concerns associated with drug-eluting coronary stents, Expert. Rev. Cardiovasc. Ther. 8 (2010) 449–470.
[3] J.M. Vicencio, L. Galluzzi, N. Tajeddine, C. Ortiz, A. Criollo, E. Tasdemir, et al., Senescence, apoptosis or autophagy? When a damaged cell must decide its path — a mini-review, Gerontology 54 (2008) 92–99. [4] X. Liao, J.C. Sluimer, Y. Wang, M. Subramanian, K. Brown, J.S. Pattison, et al., Macrophage autophagy plays a protective role in advanced atherosclerosis, Cell Metab. 15 (2012) 545–553. [5] L. Li, S. Pan, X. Zhou, X. Meng, X. Han, Y. Ren, et al., Reduction of in-stent restenosis risk on nickel-free stainless steel by regulating cell apoptosis and cell cycle, PLoS One 8 (2013) e62193. [6] S. Sciarretta, M. Volpe, J. Sadoshima, Mammalian target of rapamycin signaling in cardiac physiology and disease, Circ. Res. 114 (2014) 549–564. [7] S. Verheye, W. Martinet, M.M. Kockx, M.W. Knaapen, K. Salu, J.P. Timmermans, et al., Selective clearance of macrophages in atherosclerotic plaques by autophagy, J. Am. Coll. Cardiol. 49 (2007) 706–715. [8] Y.J. Youn, J.W. Lee, S.G. Ahn, S.H. Lee, H. Choi, C.W. Yu, et al., Multicenter randomized trial of 3-month cilostazol use in addition to dual antiplatelet therapy after biolimus-eluting stent implantation for long or multivessel coronary artery disease, Am. Heart J. 167 (2014) 241–248. [9] J. Mehilli, R.A. Byrne, A. Wieczorek, R. Iijima, S. Schulz, O. Bruskina, et al., Randomized trial of three rapamycin-eluting stents with different coating strategies for the reduction of coronary restenosis, Eur. Heart J. 29 (2008) 1975–1982. [10] Q. Zhang, L. Lu, L. Pu, R. Zhang, J. Shen, Z. Zhu, et al., Neointimal hyperplasia persists at six months after sirolimus-eluting stent implantation in diabetic porcine, Cardiovasc. Diabetol. 6 (2007) 16. [11] K.S. Lim, M.H. Jeong, I.H. Bae, J.K. Park, D.S. Park, J.M. Kim, et al., Effect of atorvastatin-eluting stents in a rabbit iliac artery restenosis model, Chonnam Med. J. 49 (2013) 118–124. [12] W. Martinet, H. De Loof, G.R. De Meyer, mTOR inhibition: a promising strategy for stabilization of atherosclerotic plaques, Atherosclerosis 233 (2014) 601–607. [13] S.P. Parihar, R. Guler, R. Khutlang, D.M. Lang, R. Hurdayal, M.M. Mhlanga, et al., Statin therapy reduces the mycobacterium tuberculosis burden in human macrophages and in mice by enhancing autophagy and phagosome maturation, J. Infect. Dis. 209 (2014) 754–763.
