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Editorial Comment

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Tissue Inhibitor of Metalloproteinase-1: Actions beyond Matrix Metalloproteinase Inhibition

Lindsey M.L.a, b · Yabluchanskiy A.a · Ma Y.a

Author affiliations

aSan Antonio Cardiovascular Proteomics Center, Mississippi Center for Heart Research, Department of Physiology and Biophysics, University of Mississippi Medical Center, and bResearch Service, G.V. (Sonny) Montgomery Veterans Affairs Medical Center, Jackson, Miss., USA

Corresponding Author

Yonggang Ma, PhD

Department of Physiology and Biophysics

University of Mississippi Medical Center

2500 North State St., Jackson, MS 39216-4505 (USA)

E-Mail yma@umc.edu

Related Articles for ""

Cardiology 2015;132:147-150

Matrix metalloproteinases (MMPs) are a family of zinc-dependent enzymes that includes 25 current members. MMPs degrade the structural components of the extracellular matrix and process bioactive molecules including cytokines, chemokines and growth factors [1]. MMP activity is tightly controlled by the endogenous tissue inhibitors of metalloproteinases (TIMPs) comprising 4 homologous members (TIMP-1, TIMP-2, TIMP-3 and TIMP-4). The dynamic balance between MMPs and TIMPs controls extracellular matrix turnover and maintains tissue homeostasis. Alterations in the balance between MMPs and TIMPs are implicated in the pathogenesis of cardiovascular disease [2].

In this issue of Cardiology, Wang et al. [3] investigated whether plasma MMP-9 and TIMP-1 levels as well as the MMP-9/TIMP-1 ratio could be used as biomarkers to predict future cardiovascular events in Chinese patients with mild to moderate coronary artery stenosis. Immediately after diagnosis, plasma levels of MMP-9 and TIMP-1 were measured, and the patients were followed for a median of 64 months. Patients with median TIMP-1 levels >37.6 ng/ml had an increased incidence of major adverse cardiac events (MACEs) during the follow-up period, supported by the results of multivariate Cox proportional hazards analysis after adjustment of covariates. In contrast, no correlation was observed between MMP-9 or the MMP-9/TIMP-1 ratio and the incidence of MACEs. Therefore, TIMP-1 may serve as a promising biomarker to predict the outcomes of patients with mild to moderate coronary artery lesions.

TIMP-1, a 28-kDa glycoprotein, is produced by cardiac myocytes and fibroblasts in the normal heart [2]. TIMP-1 binds with active MMPs in a noncovalent 1:1 stoichiometric relation to inhibit MMP activity. Due to neutrophil infiltration, TIMP-1 mRNA levels increase by as early as 6 h after myocardial infarction (MI). TIMP-1 deficiency accelerates remodeling and dilation of the left ventricle (LV), and this effect could be rescued by MMP inhibition [4]. TIMP-1 overexpression reduces atherosclerotic lesions in apolipoprotein E-deficient mice, accompanied by a reduction in the MMP-2, MMP-3 and MMP-13 content [5]. Combined, these studies define that inhibiting MMP activity mediates TIMP-1-dependent favorable effects.

Independent of inhibiting MMP activity, TIMP-1 also modulates a broad range of biological processes, including cell growth, proliferation, apoptosis, migration and angiogenesis, by binding to unidentified receptors and inducing specific signaling cascades [6]. In vitro, TIMP-1 displays growth-promoting activity in a wide range of cells, mediated via the receptor tyrosine kinase/mitogen-activated protein kinase signaling pathway [7,8]. It is TIMP-1, and not an MMP inhibitor, that induces proliferation of aortic smooth muscle cells involving the phosphoinositide 3-kinase pathway [9]. TIMP-1 directly induces smooth-muscle actin expression and stimulates Smad-3 phosphorylation in cardiac fibroblasts as well as inhibiting apoptosis in myocytes [10]. Of note, TIMP-1 suppresses microvascular endothelial cell migration via both MMP-dependent and MMP-independent mechanisms [11]. The MMP-independent roles of TIMP-1 may, at least partially, explain why TIMP-1, but not MMP-9, independently predicted the risk of MACEs in the study by Wang et al. [3].

The findings that TIMP-1 acts as an independent predictor of MACEs are supported in previous studies. The Framingham Heart Study revealed that plasma TIMP-1 levels are higher in men than women, and increase with age, body mass index and the total/high-density lipoprotein cholesterol ratio [12]. Subjects who smoke or have diabetes have higher plasma TIMP-1 levels. More importantly, after adjusting for age, sex and height, plasma TIMP-1 is positively correlated with LV mass, wall thickness, end-systolic diameter and the risk of having an increased LV end-diastolic diameter or wall thickness, but it is negatively associated with fractional shortening [12]. Lubos et al. [13 ]report that higher mean concentrations of TIMP-1 predispose patients with suspected coronary artery disease to a greater chance of MACEs independently of sex and age. Kelly et al. [14 ]have shown that plasma TIMP-1 levels are positively associated with the occurrence of MACEs in patients presenting with acute MI. TIMP-1 concentrations increase along with the quartiles of the GRACE (Global Registry of Acute Coronary Events) score, and a combination of TIMP-1 and GRACE score displays a greater area under the receiver operator characteristic curve [14]. This indicates that TIMP-1 offers information in addition to GRACE score for assessing prognosis.

MMP-9, one of the most studied MMPs, is involved in cardiac aging and multiple cardiovascular diseases such as MI, atherosclerosis and hypertension [1,15]. During cardiac aging, circulating and cardiac MMP-9 increase, and MMP-9 deletion abolishes age-induced diastolic dysfunction, which may be mediated by facilitating anti-inflammatory M2 macrophage polarization and inhibiting collagen deposition [15,16]. MMP-9 expression substantially increases after MI, and MMP-9 deletion attenuates cardiac dilation and dysfunction in both young (8-10 weeks) and old (11-36 months) mice, indicating a detrimental role for MMP-9 [17,18]. The potential mechanisms are strongly associated with promoting M2 macrophage polarization and suppressing inflammation [18]. However, transgenic overexpression of MMP-9 in macrophages also shows a beneficial impact on cardiac remodeling and function after MI, signifying the biphasic functions of MMP-9 [19]. Therefore, in the MI setting, MMP-9 may assert various roles, depending on its cellular source and spatiotemporal expression. In atherosclerosis, MMP-9 mainly derives from macrophage-derived foam cells, smooth-muscle cells and endothelial cells, and is positively correlated with increased plaque vulnerability and cardiovascular mortality [20]. MMP-9 activity is induced at a very early stage of hypertension development, promoting collagen breakdown and arterial destruction. Hypertensive patients have higher serum levels of MMP-9; this is positively associated with aortic stiffness [21].

Due to the critical roles MMP-9 plays in cardiovascular disease, evaluating MMP-9 as a biomarker has attracted much attention. Postmortem examination revealed that patients with infarct rupture after MI had higher cardiac MMP-9 activity and increased inflammatory cell numbers when compared to nonrupture patients [22]. This suggests that inflammatory cells generate MMP-9, which destroys collagen to impair infarct formation. In a clinical study of 1,127 patients with coronary artery disease, the median concentrations of plasma MMP-9 were significantly higher in the patients who subsequently experienced a fatal cardiovascular event than in those who did not [23]. Patients with the highest quartile of MMP-9 had the highest mortality rates during the follow-up period. After adjustment for clinical and therapeutic confounders, the MMP-9 levels were independently associated with a high rate of mortality. In another study, patients with acute coronary syndrome were found to have higher levels of MMP-9 in serum (median 4,000 pg/ml) than patients with stable angina pectoris (900 pg/ml) and healthy controls (87 pg/ml), and the patients presenting acute coronary syndrome with higher MMP-9 levels had poor outcomes (recurrent ischemic attacks, congestive heart failure or death) [24]. An MMP-9 cut-off value of 3,100 pg/ml has been proposed to distinguish MI from unstable angina, while the best prognostic utility has been set at 4,700 pg/ml, indicating good potential for MMP-9 as a marker for diagnosis and prognosis. Of interest, the study by Wang et al. [3 ]did not find a correlation between plasma MMP-9 concentrations and future cardiovascular events in the patient cohort. This discrepancy could be partially explained by the differences in inclusion criteria, the race of the patient and other confounding factors. For example, Blankenberg et al. [23] enrolled German patients with a stenosis of >30% for their study whereas Wang et al. [3] enrolled Chinese patients with a stenosis of 20-70% in a major coronary artery. Further investigation to determine why these different cohorts relied differently on MMP-9 could shed further mechanistic insight into its role in cardiovascular disease. A proteomics approach would be ideal for this investigation.

This study has several minor limitations that should be taken into consideration. First, TIMP-1 and MMP-9 levels were measured at one time point only, i.e. right after diagnosis. Multiple time point measurements during the follow-up period would be better for understanding the correlation between TIMP-1 and MMP-9 with MACEs in patients at specific times along the pathology continuum. Second, large-scale, multicenter clinical trials are warranted to validate the findings in larger populations and to better understand if different populations use TIMP-1 and MMP-9 differently.

In conclusion, Wang et al. [3 ]demonstrated that TIMP-1, but not MMP-9, can serve as an independent biomarker to predict MACEs in Chinese patients with mild to moderate coronary artery stenosis.

Acknowledgements

We acknowledge the support of the American Heart Association 15SDG22930009 (Y.M.), the National Institutes of Health HHSN 268201000036C (N01-HV-00244), HL075360 and GM114833 (M.L.L.), P01HL051971 and P20GM104357 and the Biomedical Laboratory Research and Development Service of the Veterans Affairs Office of Research and Development Award 5I01BX000505 (M.L.L.).

Conflict of Interest

No conflicts of interest were declared.


References

  1. Yabluchanskiy A, Ma Y, Iyer RP, Hall ME, Lindsey ML: Matrix metalloproteinase-9: Many shades of function in cardiovascular disease. Physiology 2013;28:391-403.
  2. Ma Y, de Castro Bras LE, Toba H, Iyer RP, Hall ME, Winniford MD, Lange RA, Tyagi SC, Lindsey ML: Myofibroblasts and the extracellular matrix network in post-myocardial infarction cardiac remodeling. Pflugers Arch 2014;466:1113-1127.
  3. Wang W, Song X, Chen Y, Yuan F, Xu F, Zhang M, Tan K, Yang X, Yu X, Lv S: The long-term influence of tissue inhibitor of matrix metalloproteinase-1 in patients with mild to moderate coronary artery lesions in a Chinese population: a 7-year follow-up study. Cardiology 2015;132:151-158.
  4. Ikonomidis JS, Hendrick JW, Parkhurst AM, Herron AR, Escobar PG, Dowdy KB, Stroud RE, Hapke E, Zile MR, Spinale FG: Accelerated LV remodeling after myocardial infarction in TIMP-1-deficient mice: Effects of exogenous MMP inhibition. Am J Physiol Heart Circ Physiol 2005;288:H149-H158.
  5. Rouis M, Adamy C, Duverger N, Lesnik P, Horellou P, Moreau M, Emmanuel F, Caillaud JM, Laplaud PM, Dachet C, Chapman MJ: Adenovirus-mediated overexpression of tissue inhibitor of metalloproteinase-1 reduces atherosclerotic lesions in apolipoprotein E-deficient mice. Circulation 1999;100:533-540.
  6. Ries C: Cytokine functions of TIMP-1. Cell Mol Life Sci 2014;71:659-672.
  7. Hayakawa T, Yamashita K, Tanzawa K, Uchijima E, Iwata K: Growth-promoting activity of tissue inhibitor of metalloproteinases-1 (TIMP-1) for a wide range of cells. A possible new growth factor in serum. FEBS Lett 1992;298:29-32.
  8. Wang T, Yamashita K, Iwata K, Hayakawa T: Both tissue inhibitors of metalloproteinases-1 (TIMP-1) and TIMP-2 activate Ras but through different pathways. Biochem Biophys Res Commun 2002;296:201-205.
  9. Akahane T, Akahane M, Shah A, Thorgeirsson UP: TIMP-1 stimulates proliferation of human aortic smooth muscle cells and Ras effector pathways. Biochem Biophys Res Commun 2004;324:440-445.
  10. Uchinaka A, Kawaguchi N, Mori S, Hamada Y, Miyagawa S, Saito A, Sawa Y, Matsuura N: Tissue inhibitor of metalloproteinase-1 and -3 improves cardiac function in an ischemic cardiomyopathy model rat. Tissue Eng Part A 2014;20:3073-3084.
  11. Akahane T, Akahane M, Shah A, Connor CM, Thorgeirsson UP: TIMP-1 inhibits microvascular endothelial cell migration by MMP-dependent and MMP-independent mechanisms. Exp Cell Res 2004;301:158-167.
  12. Sundstrom J, Evans JC, Benjamin EJ, Levy D, Larson MG, Sawyer DB, Siwik DA, Colucci WS, Wilson PW, Vasan RS: Relations of plasma total TIMP-1 levels to cardiovascular risk factors and echocardiographic measures: The Framingham Heart Study. Eur Heart J 2004;25:1509-1516.
  13. Lubos E, Schnabel R, Rupprecht HJ, Bickel C, Messow CM, Prigge S, Cambien F, Tiret L, Munzel T, Blankenberg S: Prognostic value of tissue inhibitor of metalloproteinase-1 for cardiovascular death among patients with cardiovascular disease: results from the Atherogene Study. Eur Heart J 2006;27:150-156.
  14. Kelly D, Squire IB, Khan SQ, Dhillon O, Narayan H, Ng KH, Quinn P, Davies JE, Ng LL: Usefulness of plasma tissue inhibitors of metalloproteinases as markers of prognosis after acute myocardial infarction. Am J Cardiol 2010;106:477-482.
  15. Ma Y, Chiao YA, Clark R, Flynn ER, Yabluchanskiy A, Ghasemi O, Zouein F, Lindsey ML, Jin YF: Deriving a cardiac aging signature to reveal matrix metalloproteinase-9 dependent inflammatory signaling in senescence. Cardiovasc Res 2015;106:421-431.
  16. Chiao YA, Ramirez TA, Zamilpa R, Okoronkwo SM, Dai Q, Zhang J, Jin YF, Lindsey ML: Matrix metalloproteinase-9 deletion attenuates myocardial fibrosis and diastolic dysfunction in ageing mice. Cardiovasc Res 2012;96:444-455.
  17. Ducharme A, Frantz S, Aikawa M, Rabkin E, Lindsey M, Rohde LE, Schoen FJ, Kelly RA, Werb Z, Libby P, Lee RT: Targeted deletion of matrix metalloproteinase-9 attenuates left ventricular enlargement and collagen accumulation after experimental myocardial infarction. J Clin Invest 2000;106:55-62.
  18. Yabluchanskiy A, Ma Y, DeLeon-Pennell KY, Altara R, Halade GV, Voorhees AP, Nguyen NT, Jin YF, Winniford MD, Hall ME, Han HC, Lindsey ML: Myocardial infarction superimposed on aging: MMP-9 deletion promotes M2 macrophage polarization. J Gerontol A Biol Sci Med Sci 2015, Epub ahead of print.
  19. Zamilpa R, Ibarra J, de Castro Bras LE, Ramirez TA, Nguyen N, Halade GV, Zhang J, Dai Q, Dayah T, Chiao YA, Lowell W, Ahuja SS, D'Armiento J, Jin YF, Lindsey ML: Transgenic overexpression of matrix metalloproteinase-9 in macrophages attenuates the inflammatory response and improves left ventricular function post-myocardial infarction. J Mol Cell Cardiol 2012;53:599-608.
  20. Wagsater D, Zhu C, Bjorkegren J, Skogsberg J, Eriksson P: MMP-2 and MMP-9 are prominent matrix metalloproteinases during atherosclerosis development in the Ldlr (-/-)Apob(100/100) mouse. Int J Mol Med 2011;28:247-253.
  21. Tan J, Hua Q, Xing X, Wen J, Liu R, Yang Z: Impact of the metalloproteinase-9/tissue inhibitor of metalloproteinase-1 system on large arterial stiffness in patients with essential hypertension. Hypertens Res 2007;30:959-963.
  22. van den Borne SW, Cleutjens JP, Hanemaaijer R, Creemers EE, Smits JF, Daemen MJ, Blankesteijn WM: Increased matrix metalloproteinase-8 and -9 activity in patients with infarct rupture after myocardial infarction. Cardiovasc Pathol 2009;18:37-43.
  23. Blankenberg S, Rupprecht HJ, Poirier O, Bickel C, Smieja M, Hafner G, Meyer J, Cambien F, Tiret L, AtheroGene I: Plasma concentrations and genetic variation of matrix metalloproteinase 9 and prognosis of patients with cardiovascular disease. Circulation 2003;107:1579-1585.
  24. Hamed GM, Fattah MF: Clinical relevance of matrix metalloproteinase 9 in patients with acute coronary syndrome. Clin Appl Thromb Hemost 2015, Eub ahead of print.

Author Contacts

Yonggang Ma, PhD

Department of Physiology and Biophysics

University of Mississippi Medical Center

2500 North State St., Jackson, MS 39216-4505 (USA)

E-Mail yma@umc.edu


Article / Publication Details

Received: May 19, 2015
Accepted: May 19, 2015
Published online: August 01, 2015
Issue release date: October 2015

Number of Print Pages: 4
Number of Figures: 0
Number of Tables: 0

ISSN: 0008-6312 (Print)
eISSN: 1421-9751 (Online)

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References

  1. Yabluchanskiy A, Ma Y, Iyer RP, Hall ME, Lindsey ML: Matrix metalloproteinase-9: Many shades of function in cardiovascular disease. Physiology 2013;28:391-403.
  2. Ma Y, de Castro Bras LE, Toba H, Iyer RP, Hall ME, Winniford MD, Lange RA, Tyagi SC, Lindsey ML: Myofibroblasts and the extracellular matrix network in post-myocardial infarction cardiac remodeling. Pflugers Arch 2014;466:1113-1127.
  3. Wang W, Song X, Chen Y, Yuan F, Xu F, Zhang M, Tan K, Yang X, Yu X, Lv S: The long-term influence of tissue inhibitor of matrix metalloproteinase-1 in patients with mild to moderate coronary artery lesions in a Chinese population: a 7-year follow-up study. Cardiology 2015;132:151-158.
  4. Ikonomidis JS, Hendrick JW, Parkhurst AM, Herron AR, Escobar PG, Dowdy KB, Stroud RE, Hapke E, Zile MR, Spinale FG: Accelerated LV remodeling after myocardial infarction in TIMP-1-deficient mice: Effects of exogenous MMP inhibition. Am J Physiol Heart Circ Physiol 2005;288:H149-H158.
  5. Rouis M, Adamy C, Duverger N, Lesnik P, Horellou P, Moreau M, Emmanuel F, Caillaud JM, Laplaud PM, Dachet C, Chapman MJ: Adenovirus-mediated overexpression of tissue inhibitor of metalloproteinase-1 reduces atherosclerotic lesions in apolipoprotein E-deficient mice. Circulation 1999;100:533-540.
  6. Ries C: Cytokine functions of TIMP-1. Cell Mol Life Sci 2014;71:659-672.
  7. Hayakawa T, Yamashita K, Tanzawa K, Uchijima E, Iwata K: Growth-promoting activity of tissue inhibitor of metalloproteinases-1 (TIMP-1) for a wide range of cells. A possible new growth factor in serum. FEBS Lett 1992;298:29-32.
  8. Wang T, Yamashita K, Iwata K, Hayakawa T: Both tissue inhibitors of metalloproteinases-1 (TIMP-1) and TIMP-2 activate Ras but through different pathways. Biochem Biophys Res Commun 2002;296:201-205.
  9. Akahane T, Akahane M, Shah A, Thorgeirsson UP: TIMP-1 stimulates proliferation of human aortic smooth muscle cells and Ras effector pathways. Biochem Biophys Res Commun 2004;324:440-445.
  10. Uchinaka A, Kawaguchi N, Mori S, Hamada Y, Miyagawa S, Saito A, Sawa Y, Matsuura N: Tissue inhibitor of metalloproteinase-1 and -3 improves cardiac function in an ischemic cardiomyopathy model rat. Tissue Eng Part A 2014;20:3073-3084.
  11. Akahane T, Akahane M, Shah A, Connor CM, Thorgeirsson UP: TIMP-1 inhibits microvascular endothelial cell migration by MMP-dependent and MMP-independent mechanisms. Exp Cell Res 2004;301:158-167.
  12. Sundstrom J, Evans JC, Benjamin EJ, Levy D, Larson MG, Sawyer DB, Siwik DA, Colucci WS, Wilson PW, Vasan RS: Relations of plasma total TIMP-1 levels to cardiovascular risk factors and echocardiographic measures: The Framingham Heart Study. Eur Heart J 2004;25:1509-1516.
  13. Lubos E, Schnabel R, Rupprecht HJ, Bickel C, Messow CM, Prigge S, Cambien F, Tiret L, Munzel T, Blankenberg S: Prognostic value of tissue inhibitor of metalloproteinase-1 for cardiovascular death among patients with cardiovascular disease: results from the Atherogene Study. Eur Heart J 2006;27:150-156.
  14. Kelly D, Squire IB, Khan SQ, Dhillon O, Narayan H, Ng KH, Quinn P, Davies JE, Ng LL: Usefulness of plasma tissue inhibitors of metalloproteinases as markers of prognosis after acute myocardial infarction. Am J Cardiol 2010;106:477-482.
  15. Ma Y, Chiao YA, Clark R, Flynn ER, Yabluchanskiy A, Ghasemi O, Zouein F, Lindsey ML, Jin YF: Deriving a cardiac aging signature to reveal matrix metalloproteinase-9 dependent inflammatory signaling in senescence. Cardiovasc Res 2015;106:421-431.
  16. Chiao YA, Ramirez TA, Zamilpa R, Okoronkwo SM, Dai Q, Zhang J, Jin YF, Lindsey ML: Matrix metalloproteinase-9 deletion attenuates myocardial fibrosis and diastolic dysfunction in ageing mice. Cardiovasc Res 2012;96:444-455.
  17. Ducharme A, Frantz S, Aikawa M, Rabkin E, Lindsey M, Rohde LE, Schoen FJ, Kelly RA, Werb Z, Libby P, Lee RT: Targeted deletion of matrix metalloproteinase-9 attenuates left ventricular enlargement and collagen accumulation after experimental myocardial infarction. J Clin Invest 2000;106:55-62.
  18. Yabluchanskiy A, Ma Y, DeLeon-Pennell KY, Altara R, Halade GV, Voorhees AP, Nguyen NT, Jin YF, Winniford MD, Hall ME, Han HC, Lindsey ML: Myocardial infarction superimposed on aging: MMP-9 deletion promotes M2 macrophage polarization. J Gerontol A Biol Sci Med Sci 2015, Epub ahead of print.
  19. Zamilpa R, Ibarra J, de Castro Bras LE, Ramirez TA, Nguyen N, Halade GV, Zhang J, Dai Q, Dayah T, Chiao YA, Lowell W, Ahuja SS, D'Armiento J, Jin YF, Lindsey ML: Transgenic overexpression of matrix metalloproteinase-9 in macrophages attenuates the inflammatory response and improves left ventricular function post-myocardial infarction. J Mol Cell Cardiol 2012;53:599-608.
  20. Wagsater D, Zhu C, Bjorkegren J, Skogsberg J, Eriksson P: MMP-2 and MMP-9 are prominent matrix metalloproteinases during atherosclerosis development in the Ldlr (-/-)Apob(100/100) mouse. Int J Mol Med 2011;28:247-253.
  21. Tan J, Hua Q, Xing X, Wen J, Liu R, Yang Z: Impact of the metalloproteinase-9/tissue inhibitor of metalloproteinase-1 system on large arterial stiffness in patients with essential hypertension. Hypertens Res 2007;30:959-963.
  22. van den Borne SW, Cleutjens JP, Hanemaaijer R, Creemers EE, Smits JF, Daemen MJ, Blankesteijn WM: Increased matrix metalloproteinase-8 and -9 activity in patients with infarct rupture after myocardial infarction. Cardiovasc Pathol 2009;18:37-43.
  23. Blankenberg S, Rupprecht HJ, Poirier O, Bickel C, Smieja M, Hafner G, Meyer J, Cambien F, Tiret L, AtheroGene I: Plasma concentrations and genetic variation of matrix metalloproteinase 9 and prognosis of patients with cardiovascular disease. Circulation 2003;107:1579-1585.
  24. Hamed GM, Fattah MF: Clinical relevance of matrix metalloproteinase 9 in patients with acute coronary syndrome. Clin Appl Thromb Hemost 2015, Eub ahead of print.
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