Abstract
Circulating progenitor cells of bone marrow origin have been implicated in transplant cardiac allograft vasculopathy (CAV) and cardiac fibrosis. HMG-CoA reductase inhibitors, called “statins,” have been shown to impair the progression of CAV and improve patient survival. We examined the in vitro effects of three HMG-CoA reductase inhibitors atorvastatin, simvastatin, and pravastatin on the viability of MSCs and expression of nuclear factor kappa B (NF-κB). Mesenchymal stem cells (MSCs) isolated from human patients were treated with atorvastatin, simvastatin, and pravastatin at 0.1, 1.0, or 10 μM ± mevalonate. Human MSC treatment with 1 and 10 μM simvastatin or atorvastatin resulted in progressively reduced cell viability, which was associated with a decline in NF-κB p65. Viability was rescued by co-incubation with mevalonate or by pretreatment with Inhibitor of nuclear factor kappa-B kinase subunit beta (Iκκ-β). Pravastatin did not affect MSC viability or NF-κB expression. Mevalonate depletion through HMG-CoA reductase inhibition impairs the viability of primary human MSC through down-regulating NF-κB.
Similar content being viewed by others
References
Mills, E. J., Wu, P., & Chong, G. (2011). Efficacy and safety of statin treatment for cardiovascular disease: A network meta-analysis of 170 255 patients from 76 randomized trials. Quarterly Journal of Medicine, 104, 109–124.
Liapis, C. D., Bell, P. R., Mikhailidis, D., et al. (2009). ESVS guidelines. Invasive treatment for carotid stenosis: indications, techniques. European Journal of Vascular and Endovascular Surgery, 37, 1–19.
Liapis, C. D., Bell, P. R., Mikhailidis, D., et al. (2010). ESVS guidelines: Section A—prevention in patients with carotid stenosis. Current Vascular Pharmacology, 8, 673–681.
Tahara, N., Kai, H., Ishibashi, M., Nakuara, H., Kaida, H., Baba, K., Hayabuchi, N., & Imaizumi, T. (2006). Simvastatin attenuates plaque inflammation: evaluation by fluorodeoxyglucose positron emission topography. Journal of the American College of Cardiology, 48, 1825–1831.
Sillesen, H. (2009). Statins and their use in preventing carotid disease. Current Atherosclerosis Reports, 11, 309–314.
Verzini, F., De, R. P., Parlani, G., Giordano, G., Caso, V., Cieri, E., Isernia, G., & Cao, P. (2011). Effects of statins on early and late results of coronary stenting. Journal of Vascular Surgery, 53, 71–79.
Kertai, M. D., Boersma, E., Westerhout, C. M., van Domburg, R., Klein, J., Bax, J. J., van Urk, H., & Poldermans, D. (2004). Association between long-term statin use and mortality after successful abdominal aortic aneurysm surgery. American Journal of Medicine, 116, 96–103.
Kalyanasundaram, A., Elmore, J. R., Manazer, J. R., Golden, A., Franklin, D. P., Galt, S. W., Zakhary, E. M., & Carey, D. J. (2006). Simvastatin suppresses experimental aortic aneurysm expansion. Journal of Vascular Surgery, 43, 117–124.
Schouten, O., van Laanen, J. H., Boersma, E., Vidakovic, R., Feringa, H. H., Dunkelgrün, M., Bax, J. J., Koning, J., van Urk, H., & Poldermans, D. (2006). Statins are associated with a reduced infrarenal abdominal aortic aneurysm growth. European Journal of Vascular and Endovascular Surgery, 32, 21–26.
Giri, J., McDermott, M. M., Greenland, P., Guralnik, J. M., Criqui, M. H., Liu, K., Ferrucci, L., Green, D., Schneider, J. R., & Tian, L. (2006). Statin use and functional decline in patients with and without peripheral artery disease. Journal of the American College of Cardiology, 47, 998–1004.
Heart Protection Study Group. (2007). Randomized trial of the effects of cholesterol-lowering with simvastatin on peripheral vascular and other major vascular outcomes in 20 536 people with peripheral arterial disease and other high-risk conditions. Journal of Vascular Surgery, 45, 645–654.
Kobashigawa, J. A., Katznelson, S., Laks, H., et al. (1995). Effect of pravastatin on outcomes after cardiac transplantation. New England Journal of Medicine, 333, 621–627.
Nissen, S. E., Nicholls, S. J., Sipahi, I., et al. (2006). Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial. JAMA, 295, 1556–1565.
Mehra, M. R., Uber, P. A., Vivekananthan, K., Solis, S., Scott, R. L., Park, M. H., Milani, R. V., & Lavie, C. J. (2002). Comparative beneficial effects of simvastatin and pravastatin on cardiac allograft rejection and survival. Journal of the American College of Cardiology, 40, 1609–1614.
Kobashigawa, J. A., Moriguchi, J. D., Laks, H., Wener, L., Hage, A., Hamilton, M. A., Cogert, G., Marquez, A., Vassilakis, M. E., Patel, J., & Yeatman, L. (2005). Ten-year follow-up of a randomized trial of pravastatin in heart transplant patients. Journal of Heart and Lung Transplantation, 24, 1736–1740.
Schachter, M. (2005). Chemical, pharmacokinetic and pharmacodynamic properties of statins: An update. Fundamental and Clinical Pharmacology, 19, 117–125.
Bullano, M. F., Wertz, D. A., Yang, G. W., Kamat, S., Borok, G. M., Gandhi, S., McDonough, K. L., & Willey, V. J. (2006). Effect of rosuvastatin compared with other statins on lipid levels and national cholesterol education program goal attainment for low-density lipoprotein cholesterol in a usual care setting. Pharmacotherapy, 26, 469–478.
Lennernas, H., & Fager, G. (1997). Pharmacodynamis and pharmacokinetics of the HMG-CoA reductase inhibitors: Similarities and differences. Clinical Pharmacokinetics, 32, 403–425.
Singhvi, S. M., Pan, H. W., Morrison, R. A., & Willard, D. A. (1990). Disposition of pravastatin sodium, a tissue-selective HMG-CoA reductase inhibitor, in healthy subjects. British Journal of Clinical Pharmacology, 20, 239–243.
Zhou, Z., Rahme, E., & Pilote, L. (2006). Are statins created equal? Evidence from randomized trials of pravastatin, simvastatin, and atorvastatin for cardiovascular disease prevention. American Heart Journal, 151, 273–281.
Sopel, M. J., Rosin, N. L., Lee, T. D., & Legare, J. F. (2011). Myocardial fibrosis in response to angiotensin II is preceded by the recruitment of mesenchymal progenitor cells. Laboratory Investigation, 91, 565–578.
van Amerognen, M. J., Bou-Gharios, G., Popa, E., van Ark, J., Petersen, A. H., van Dam, G. M., van Luyn, M. J., & Harmsen, M. C. (2008). Bone marrow-derived myofibroblasts contribute functionally to scar formation after myocardial infarction. Journal of Pathology, 214, 377–386.
Möllmann, H., Nef, H. M., Kostin, S., Von, K. C., Pilz, I., Weber, M., Schaper, J., Hamm, C. W., & Elsässer, A. (2006). Bone marrow-derived cells contribute to infarct remodelling. Cardiovascular Research, 71, 661–671.
Salama, M., Andrukhova, O., Roedler, S., Zuckermann, A., Laufer, G., & Aharinejad, S. (2011). Association of CD14+ monocyte-derived progenitor cells with cardiac allograft vasculopathy. Journal of Thoracic and Cardiovascular Surgery, 142, 1246–1253.
Carlson, S., Trial, J., Soeller, C., & Entman, M. L. (2011). Cardiac mesenchymal stem cells contribute to scar formation after myocardial infarction. Cardiovascular Research, 91, 99–107.
van den Borne, S. W., Diez, J., Blankesteijn, W. M., Verjans, J., Hofstra, L., & Narula, J. (2010). Myocardial remodeling after infarction: The role of myofibroblasts. Nature Reviews Cardiology, 7, 30–37.
Hombach-Klonisch, S., Panigrahi, S., Rashedi, I., Seifert, A., Alberti, E., Pocar, P., Kurpisz, M., Schulze-Osthof, K., Mackiewicz, A., & Los, M. (2008). Adult stem cells and their trans-differentiation potential—Perspectives and therapeutic applications. Journal of Molecular Medicine, 86, 1301–1314.
Chamberlain, G., Fox, J., Ashton, B., & Middleton, J. (2007). Concise review: Mesenchymal stem cells: their phenotype, differentiation capacity, immunological features, and potential for homing. Stem Cells, 25, 2739–2749.
Orlic, D., Kajstura, J., Chimenti, S., Bodine, D. M., Leri, A., & Anversa, P. (2001). Transplanted adult bone marrow cells repair myocardial infarcts in mice. Annals of the New York Academy of Sciences, 938, 221–229.
Orlic, D., Kajstura, J., Chimenti, S., Jakoniuk, I., Anderson, S. M., Li, B., Pickel, J., McKay, R., Nadal-Ginard, B., Bodine, D. M., Leri, A., & Anversa, P. (2001). Bone marrow cells regenerate infarcted myocardium. Nature, 410, 701–705.
Bittira, B., Kuang, J. Q., Al-Khaldi, A., Shum-Tim, D., & Chiu, R. C. (2002). In vitro preprogramming of marrow stromal cells for myocardial regeneration. Annals of Thoracic Surgery, 74, 1154–1159.
Chedrawy, E. G., Wang, J. S., Nguyen, D. M., Shum-Tim, D., & Chiu, R. C. (2002). Incorporation and integration of implanted myogenic and stem cells into native myocardial fibers: Anatomic basis for functional improvements. Journal of Thoracic and Cardiovascular Surgery, 124, 584–590.
Balsam, L. B., Wagers, A. J., Christensen, J. L., Kofidis, T., Weissman, I. L., & Robbins, R. C. (2004). Haematopoietic stem cells adopt mature haematopoietic fates in ischaemic myocardium. Nature, 428, 668–673.
Bellini, A., & Mattoli, S. (2007). The role of the fibrocyte, a bone marrow-derived mesenchymal progenitor, in reactive and reparative fibroses. Laboratory Investigation, 87, 858–870.
Keeley, E. C., Mehrad, B., Janardhanan, R., Salerno, M., Hunter, J. R., Burdick, M. M., Field, J. J., Strieter, R. M., & Kramer, C. M. (2012). Elevated circulating fibrocyte levels in patients with hypertensive heart disease. Journal of Hypertension, 30, 1856–1861.
Lei, P. P., Qu, Y. Q., Shuai, Q., Tao, S. M., Bao, Y. X., Wang, Y., Wang, S. W., & Wang, D. H. (2013). Fibrocytes are associated with the fibrosis of coronary heart disease. Pathology, Research and Practice, 209, 36–43.
Cox, N., Pilling, D., & Gomer, R. H. (2012). NaCl potentiates human fibrocyte differentiation. PLoS One, 7, e45674.
Buhaescu, I., & Izzedine, H. (2007). Mevalonate pathway: A review of clinical and therapeutical implications. Clinical Biochemistry, 40, 575–584.
Hilgendorff, A., Muth, H., Parviz, B., Staubitz, A., Haberbosch, W., Tillmanns, H., & Hölschermann, H. (2003). Statins differ in their ability to block NF-kappaB activation in human blood monocytes. International Journal of Clinical Pharmacology and Therapeutics, 41, 397–401.
Dhingra, R., Gang, H., Wang, Y., Biala, A. K., Aviv, Y., Margulets, V., Tee, A., & Kirshenbaum, L. A. (2013). Bidirectional regulation of nuclear factor- κB and mammalian target of rapamycin signaling functionally links Bnip3 gene repression and cell survival of ventricular myocytes. Circulation. Heart Failure, 6, 335–343.
Friedernstein, A. J., Gorskaja, J. F., & Kulagina, N. N. (1976). Fibroblast precursors in normal and irradiated mouse hematopoietic organs. Experimental Hematology, 4, 267–274.
Caplan, A. I. (1991). Mesenchyma stem cells. Journal of Orthopaedic Research, 9, 641–650.
Sciarretta, S., Hariharan, N., Monden, Y., Zablocki, D., & Sadoshima, J. (2011). Is autophagy in response to ischemia and reperfusion protective or detrimental for the heart? Pediatric Cardiology, 32, 275–281.
Wang, E. Y., Gang, H., Aviv, Y., Dhingra, R., Margulets, V., & Kirshenbaum, L. A. (2013). p53 mediates autophagy and cell death by a mechanism contingent on Bnip3. Hypertension, 62, 70–77.
Liu, Y., Wang, L., Kikuiri, T., Akiyama, K., Chen, C., Xu, X., Yang, R., Chen, W., Wang, S., & Shi, S. (2011). Mesenchymal stem cell-based tissue regeneration is governed by recipient T lymphocytes via IFN-γ and TNF-α. Nature Medicine, 17, 1594–1601.
Peng, C. F., Han, Y. L., Jie-Deng, Y. C. H., Jian-Kang, B.-L., & Jie-Li. (2011). Overexpression of cellular repressor of E1A-stimulated genes inhibits TNF-α-induced apoptosis via NFκB in mesenchymal stem cells. Biochemical and Biophysical Research Communications, 406, 601–607.
Kim, J. M., Cho, H. H., Lee, S. Y., Hong, C. P., Yang, J. W., Kim, Y. S., Suh, K. T., & Jung, J. S. (2012). Role of IRAK1 on TNF-induced proliferation and NFκB activation in human bone marrow mesenchymal stem cells. Cellular Physiology and Biochemistry, 30, 46–60.
Gauthaman, K., Fong, C. Y., & Bongso, A. (2009). Statins, stem cells, and cancer. Journal of Cellular Biochemistry, 106, 975–983.
Patel, S., Mason, R. M., Suzuki, J., Imaizumi, A., Kamimura, T., & Zhang, Z. (2006). Inhibitory effect of statins on renal epithelial-to-mesenchymal transition. American Journal of Nephrology, 26, 381–387.
Piotrowski, P. C., Kwintkiewicz, J., Rzepczynska, I. J., Seval, Y., Cakmak, H., Arici, A., & Duleba, A. J. (2006). Statins inhibit growth of human endometrial stromal cells independently of cholesterol availability. Biology of Reproduction, 75, 107–111.
Shao, H., Tan, Y., Eton, D., Yang, Z., Uberti, M. G., Li, S., Schulick, A., & Yu, H. (2008). Statin and stromal cell-derived factor-1 additively promote angiogenesis by enhancement of progenitor cells incorporation into new vessels. Stem Cells, 26, 1376–1384.
Assmus, B., Urbich, C., Aicher, A., Hofmann, W. K., Haendeler, J., Rössig, L., Spyridopoulos, I., Zeiher, A. M., & Dimmeler, S. (2003). HMG-CoA reductase inhibitors reduce senescence and increase proliferation of endothelial progenitor cells via regulation of cell cycle regulatory genes. Circulation Research, 92, 1049–1055.
Satoh, M., Minami, Y., Takahashi, Y., Tabuchi, T., Itoh, T., & Nakamura, M. (2009). Effect of intensive lipid-lowering therapy on telomere erosion in endothelial progenitor cells obtained from patients with coronary artery disease. Clinical Science (London), 116, 827–835.
Zhang, Y., Zhang, R., Li, Y., He, G., Zhang, D., & Zhang, F. (2012). Simvastatin augments the efficacy of therapeutic angiogenesis induced by bone-marrow-derived mesenchymal stem cells in a murine model of hindlimb ischemia. Molecular Biology Reports, 39, 285–293.
Xu, H., Yang, Y. J., Qian, H. Y., Tang, Y. D., Wang, H., & Zhang, Q. (2011). Rosuvastatin treatment activates JAK-STAT pathway and increases efficacy of allogenic mesenchymal stem cell transplantation in infracted hearts. Circulation Journal, 75, 1476–1485.
Zhang, Q., Yang, Y. J., Wang, H., Dong, Q. T., Wang, T. J., Qian, H. Y., & Xu, H. (2012). Autophagy activation: a novel mechanism of atrovastatin to protect mesenchymal stem cell from hypoxia and serum deprivation via AMP-activated protein kinase/mammalian target of rapamycin pathway. Stem Cells and Development, 21, 1321–1332.
Disclosures
Atorvastatin was provided by Pfizer. No other disclosures.
Informed Consent
This study utilized bone marrow obtained solely from informed patients who gave consent under ethics approved by the Bannatyne Campus Research Ethics Board of the University of Manitoba.
Animal Research
No animal studies were carried out by the authors for this article.
Sources of Funding
Funding was provided by the St. Boniface Hospital Foundation, Canadian Institutes of Health Research, and the University of Manitoba Department of Surgery. The experiments performed in this manuscript complied with the laws of Canada where the experiments were performed.
Author information
Authors and Affiliations
Corresponding author
Additional information
Editor-in-Chief Jennifer L. Hall oversaw the review of this article
Rights and permissions
About this article
Cite this article
Li, Y., Müller, A.L., Ngo, M.A. et al. Statins Impair Survival of Primary Human Mesenchymal Progenitor Cells via Mevalonate Depletion, NF-κB Signaling, and Bnip3. J. of Cardiovasc. Trans. Res. 8, 96–105 (2015). https://doi.org/10.1007/s12265-014-9603-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12265-014-9603-3