Skip to main content

Advertisement

SpringerLink
Log in

Stem cells in the diabetic infarcted heart

  • Published:
Heart Failure Reviews Aims and scope Submit manuscript

Abstract

Diabetes mellitus is one of the leading causes of death, and the majority of these deaths are associated with cardiovascular diseases. Development and progression of myocardial infarction leading to heart failure is much more complex and multifactorial in diabetics compared with non-diabetics. Despite significant advances in pharmacological interventions and surgical techniques, the disease progression leading to diabetic end-stage heart failure remains very high. Recently, cell therapy has gained much attention as an alternative approach to treat various heart diseases. However, transplanted stem cell studies in diabetic animal models are very limited. In this review, we discuss the pathogenesis of the diabetic infarcted heart and the potential of stem cell therapy to repair and regenerate.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Aronson D, Rayfield EJ, Chesebro JH (1997) Mechanisms determining course and outcome of diabetic patients who have had acute myocardial infarction. Ann Intern Med 126:296–306

    CAS  PubMed  Google Scholar 

  2. Rahman S, Rahman T, Ismail AA, Rashid AR (2007) Diabetes-associated macrovasculopathy: pathophysiology and pathogenesis. Diabetes Obes Metab 9:767–780

    Article  CAS  PubMed  Google Scholar 

  3. Woodfield SL, Lundergan CF, Reiner JS, Greenhouse SW, Thompson MA, Rohrbeck SC, Deychak Y, Simoons ML, Califf RM, Topol EJ, Ross AM (1996) Angiographic findings and outcome in diabetic patients treated with thrombolytic therapy for acute myocardial infarction: the GUSTO-I experience. J Am Coll Cardiol 28:1661–1669

    Article  CAS  PubMed  Google Scholar 

  4. Singla DK, Hacker TA, Ma L, Douglas PS, Sullivan R, Lyons GE, Kamp TJ (2006) Transplantation of embryonic stem cells into the infarcted mouse heart: formation of multiple cell types. J Mol Cell Cardiol 40:195–200

    Article  CAS  PubMed  Google Scholar 

  5. Singla DK, Lyons GE, Kamp TJ (2007) Transplanted embryonic stem cells following mouse myocardial infarction inhibit apoptosis and cardiac remodeling. Am J Physiol Heart Circ Physiol 293:H1308–H1314

    Article  CAS  PubMed  Google Scholar 

  6. Min JY, Yang Y, Converso KL, Liu L, Huang Q, Morgan JP, Xiao YF (2002) Transplantation of embryonic stem cells improves cardiac function in postinfarcted rats. J Appl Physiol 92:288–296

    Article  PubMed  Google Scholar 

  7. Jing D, Parikh A, Canty JM Jr, Tzanakakis ES (2008) Stem cells for heart cell therapies Tissue Eng Part B Rev 14:393–406

    Google Scholar 

  8. Tenerz A, Lonnberg I, Berne C, Nilsson G, Leppert J (2001) Myocardial infarction and prevalence of diabetes mellitus. Is increased casual blood glucose at admission a reliable criterion for the diagnosis of diabetes? Eur Heart J 22:1102–1110

    Article  CAS  PubMed  Google Scholar 

  9. Roger VL, Weston SA, Gerber Y, Killian JM, Dunlay SM, Jaffe AS, Bell MR, Kors J, Yawn BP, Jacobsen SJ (2010) Trends in incidence, severity, and outcome of hospitalized myocardial infarction. Circulation 121:863–869

    Article  PubMed  Google Scholar 

  10. Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laakso M (1998) Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med 339:229–234

    Article  CAS  PubMed  Google Scholar 

  11. Hu G, Jousilahti P, Qiao Q, Peltonen M, Katoh S, Tuomilehto J (2005) The gender-specific impact of diabetes and myocardial infarction at baseline and during follow-up on mortality from all causes and coronary heart disease. J Am Coll Cardiol 45:1413–1418

    Article  PubMed  Google Scholar 

  12. Lundberg V, Stegmayr B, Asplund K, Eliasson M, Huhtasaari F (1997) Diabetes as a risk factor for myocardial infarction: population and gender perspectives. J Intern Med 241:485–492

    Article  CAS  PubMed  Google Scholar 

  13. Lee CD, Folsom AR, Pankow JS, Brancati FL (2004) Cardiovascular events in diabetic and nondiabetic adults with or without history of myocardial infarction. Circulation 109:855–860

    Article  PubMed  Google Scholar 

  14. Mak KH, Topol EJ (2000) Emerging concepts in the management of acute myocardial infarction in patients with diabetes mellitus. J Am Coll Cardiol 35:563–568

    Article  CAS  PubMed  Google Scholar 

  15. Lomuscio A, Castagnone M, Vergani D, Verzoni A, Beltrami A, Ravaglia R, Pozzoni L (1991) Clinical correlation between diabetic and non diabetic patients with myocardial infarction. Acta Cardiol 46:543–554

    CAS  PubMed  Google Scholar 

  16. Rees DA, Alcolado JC (2005) Animal models of diabetes mellitus. Diabet Med 22:359–370

    Article  CAS  PubMed  Google Scholar 

  17. Nishina PM, Lowe S, Wang J, Paigen B (1994) Characterization of plasma lipids in genetically obese mice: the mutants obese, diabetes, fat, tubby, and lethal yellow. Metabolism 43:549–553

    Article  CAS  PubMed  Google Scholar 

  18. McGaffin KR, Zou B, McTiernan CF, O’Donnell CP (2009) Leptin attenuates cardiac apoptosis after chronic ischaemic injury. Cardiovasc Res 83:313–324

    Article  CAS  PubMed  Google Scholar 

  19. Gundewar S, Calvert JW, Elrod JW, Lefer DJ (2007) Cytoprotective effects of N, N, N-trimethylsphingosine during ischemia- reperfusion injury are lost in the setting of obesity and diabetes. Am J Physiol Heart Circ Physiol 293:H2462–H2471

    Article  CAS  PubMed  Google Scholar 

  20. Srinivasan K, Ramarao P (2007) Animal models in type 2 diabetes research: an overview. Indian J Med Res 125:451–472

    CAS  PubMed  Google Scholar 

  21. Greer JJ, Ware DP, Lefer DJ (2006) Myocardial infarction and heart failure in the db/db diabetic mouse. Am J Physiol Heart Circ Physiol 290:146–153

    Article  Google Scholar 

  22. Iwatsuka H, Shino A, Suzuoki Z (1970) General survey of diabetic features of yellow KK mice. Endocrinol Jpn 17:23–35

    CAS  PubMed  Google Scholar 

  23. Chandler MP, Morgan EE, McElfresh TA, Kung TA, Rennison JH, Hoit BD, Young ME (2007) Heart failure progression is accelerated following myocardial infarction in type 2 diabetic rats. Am J Physiol Heart Circ Physiol 293:H1609–H1616

    Article  CAS  PubMed  Google Scholar 

  24. Cohen AM, Rosenmann E, Rosenthal T (1993) The Cohen diabetic (non-insulin-dependent) hypertensive rat model. Description of the model and pathologic findings. Am J Hypertens 6:989–995

    CAS  PubMed  Google Scholar 

  25. Weksler-Zangen S, Yagil C, Zangen DH, Ornoy A, Jacob HJ, Yagil Y (2001) The newly inbred cohen diabetic rat: a nonobese normolipidemic genetic model of diet-induced type 2 diabetes expressing sex differences. Diabetes 50:2521–2529

    Article  CAS  PubMed  Google Scholar 

  26. Matsushima S, Kinugawa S, Yokota T, Inoue N, Ohta Y, Hamaguchi S, Tsutsui H (2009) Increased myocardial NAD(P)H oxidase-derived superoxide causes the exacerbation of postinfarct heart failure in type 2 diabetes. Am J Physiol Heart Circ Physiol 297:H409–H416

    Article  CAS  PubMed  Google Scholar 

  27. Thakker GD, Frangogiannis NG, Bujak M, Zymek P, Gaubatz JW, Reddy AK, Taffet G, Michael LH, Entman ML, Ballantyne CM (2006) Effects of diet-induced obesity on inflammation and remodeling after myocardial infarction. Am J Physiol Heart Circ Physiol 291:H2504–H2514

    Article  CAS  PubMed  Google Scholar 

  28. Huang JP, Huang SS, Deng JY, Hung LM (2009) Impairment of insulin-stimulated Akt/GLUT4 signaling is associated with cardiac contractile dysfunction and aggravates I/R injury in STZ-diabetic rats. J Biomed Sci 16:77

    Article  CAS  PubMed  Google Scholar 

  29. Song GY, Wu YJ, Yang YJ, Li JJ, Zhang HL, Pei HJ, Zhao ZY, Zeng ZH, Hui RT (2009) The accelerated post-infarction progression of cardiac remodelling is associated with genetic changes in an untreated streptozotocin-induced diabetic rat model. Eur J Heart Fail 11:911–921

    Article  PubMed  Google Scholar 

  30. Miki T, Miura T, Hotta H, Tanno M, Yano T, Sato T, Terashima Y, Takada A, Ishikawa S, Shimamoto K (2009) Endoplasmic reticulum stress in diabetic hearts abolishes erythropoietin-induced myocardial protection by impairment of phospho-glycogen synthase kinase-3beta-mediated suppression of mitochondrial permeability transition. Diabetes 58:2863–2872

    Article  CAS  PubMed  Google Scholar 

  31. Dixon RA, Davidson SM, Wynne AM, Yellon DM, Smith CC (2009) The cardioprotective actions of leptin are lost in the Zucker obese (fa/fa) rat. J Cardiovasc Pharmacol 53:311–317

    Article  CAS  PubMed  Google Scholar 

  32. Kristiansen SB, Lofgren B, Stottrup NB, Khatir D, Nielsen-Kudsk JE, Nielsen TT, Botker HE, Flyvbjerg A (2004) Ischaemic preconditioning does not protect the heart in obese and lean animal models of type 2 diabetes. Diabetologia 47:1716–1721

    Article  CAS  PubMed  Google Scholar 

  33. Vahtola E, Louhelainen M, Forsten H, Merasto S, Raivio J, Kaheinen P, Kyto V, Tikkanen I, Levijoki J, Mervaala E (2010) Sirtuin1–p53, forkhead box O3a, p38 and post-infarct cardiac remodeling in the spontaneously diabetic Goto-Kakizaki rat. Cardiovasc Diabetol 9:5

    Article  PubMed  Google Scholar 

  34. Li TS, Takahashi M, Suzuki R, Kobayashi T, Ito H, Mikamo A, Hamano K (2006) Pravastatin improves remodeling and cardiac function after myocardial infarction by an antiinflammatory mechanism rather than by the induction of angiogenesis. Ann Thorac Surg 81:2217–2225

    Article  PubMed  Google Scholar 

  35. Bonora E (2006) The metabolic syndrome and cardiovascular disease. Ann Med 38:64–80

    Article  CAS  PubMed  Google Scholar 

  36. Durina J, Remkova A (2007) Prothrombotic state in metabolic syndrome. Bratisl Lek Listy 108:279–280

    CAS  PubMed  Google Scholar 

  37. Tschoepe D, Roesen P (1998) Heart disease in diabetes mellitus: a challenge for early diagnosis and intervention. Exp Clin Endocrinol Diabetes 106:16–24

    Article  CAS  PubMed  Google Scholar 

  38. Rizzo M, Berneis K (2007) Small dense low-density-lipoproteins and the metabolic syndrome. Diabetes Metab Res Rev 23:14–20

    Article  CAS  PubMed  Google Scholar 

  39. Anfossi G, Russo I, Doronzo G, Trovati M (2007) Relevance of the vascular effects of insulin in the rationale of its therapeutical use. Cardiovasc Hematol Disord Drug Targets 7:228–249

    Article  CAS  PubMed  Google Scholar 

  40. Cersosimo E, Defronzo RA (2006) Insulin resistance and endothelial dysfunction: the road map to cardiovascular diseases. Diabetes Metab Res Rev 22:423–436

    Article  CAS  PubMed  Google Scholar 

  41. Steinberg HO, Baron AD (2002) Vascular function insulin resistance and fatty acids. Diabetologia 45:623–634

    Article  CAS  PubMed  Google Scholar 

  42. Zinn A, Felson S, Fisher E, Schwartzbard A (2008) Reassessing the cardiovascular risks and benefits of thiazolidinediones. Clin Cardiol 31:397–403

    Article  PubMed  Google Scholar 

  43. Palumbo F, Bianchi C, Miccoli R, Del PS (2003) Hyperglycaemia and cardiovascular risk. Acta Diabetol 40(Suppl 2):S362–S369

    Article  PubMed  Google Scholar 

  44. Chyun DA, Young LH (2006) Diabetes mellitus and cardiovascular disease. Nurs Clin North Am 41:681–685

    Article  PubMed  Google Scholar 

  45. Bartnik M, Norhammar A, Ryden L (2007) Hyperglycaemia and cardiovascular disease. J Intern Med 262:145–156

    Article  CAS  PubMed  Google Scholar 

  46. Brownlee M (2001) Biochemistry and molecular cell biology of diabetic complications. Nature 414:813–820

    Article  CAS  PubMed  Google Scholar 

  47. Basta G, Schmidt AM, De CR (2004) Advanced glycation end products and vascular inflammation: implications for accelerated atherosclerosis in diabetes. Cardiovasc Res 63:582–592

    Article  CAS  PubMed  Google Scholar 

  48. Ramana KV, Chandra D, Srivastava S, Bhatnagar A, Srivastava SK (2003) Nitric oxide regulates the polyol pathway of glucose metabolism in vascular smooth muscle cells. FASEB J 17:417–425

    Article  CAS  PubMed  Google Scholar 

  49. Bonnefont-Rousselot D (2002) Glucose and reactive oxygen species. Curr Opin Clin Nutr Metab Care 5:561–568

    Article  CAS  PubMed  Google Scholar 

  50. Jay D, Hitomi H, Griendling KK (2006) Oxidative stress and diabetic cardiovascular complications. Free Radic Biol Med 40:183–192

    Article  CAS  PubMed  Google Scholar 

  51. Clark RJ, McDonough PM, Swanson E, Trost SU, Suzuki M, Fukuda M, Dillmann WH (2003) Diabetes and the accompanying hyperglycemia impairs cardiomyocyte calcium cycling through increased nuclear O-GlcNAcylation. J Biol Chem 278:44230–44237

    Article  CAS  PubMed  Google Scholar 

  52. Federici M, Menghini R, Mauriello A, Hribal ML, Ferrelli F, Lauro D, Sbraccia P, Spagnoli LG, Sesti G, Lauro R (2002) Insulin-dependent activation of endothelial nitric oxide synthase is impaired by O-linked glycosylation modification of signaling proteins in human coronary endothelial cells. Circulation 106:466–472

    Article  CAS  PubMed  Google Scholar 

  53. Watanabe K, Thandavarayan RA, Gurusamy N, Zhang S, Muslin AJ, Suzuki K, Tachikawa H, Kodama M, Aizawa Y (2009) Role of 14–3-3 protein and oxidative stress in diabetic cardiomyopathy. Acta Physiol Hung 96:277–287

    Article  CAS  PubMed  Google Scholar 

  54. Peppa M, Stavroulakis P, Raptis SA (2009) Advanced glycoxidation products and impaired diabetic wound healing. Wound Repair Regen 17:461–472

    Article  PubMed  Google Scholar 

  55. Zheng L, Kern TS (2009) Role of nitric oxide, superoxide, peroxynitrite and PARP in diabetic retinopathy. Front Biosci 14:3974–3987

    Article  CAS  PubMed  Google Scholar 

  56. Madsen-Bouterse SA, Kowluru RA (2008) Oxidative stress and diabetic retinopathy: pathophysiological mechanisms and treatment perspectives. Rev Endocr Metab Disord 9:315–327

    Article  CAS  PubMed  Google Scholar 

  57. Hamada Y, Fujii H, Fukagawa M (2009) Role of oxidative stress in diabetic bone disorder Bone 45(Suppl 1):S35–S38

    CAS  Google Scholar 

  58. Potenza MA, Gagliardi S, Nacci C, Carratu’ MR, Montagnani M (2009) Endothelial dysfunction in diabetes: from mechanisms to therapeutic targets. Curr Med Chem 16:94–112

    Article  CAS  PubMed  Google Scholar 

  59. Ha H, Hwang IA, Park JH, Lee HB (2008) Role of reactive oxygen species in the pathogenesis of diabetic nephropathy. Diabetes Res Clin Pract 82(Suppl 1):S42–S45

    Article  CAS  PubMed  Google Scholar 

  60. Figueroa-Romero C, Sadidi M, Feldman EL (2008) Mechanisms of disease: the oxidative stress theory of diabetic neuropathy. Rev Endocr Metab Disord 9:301–314

    Article  CAS  PubMed  Google Scholar 

  61. Di FC, Cuzzocrea S, Rossi F, Marfella R, D’Amico M (2006) Oxidative stress as the leading cause of acute myocardial infarction in diabetics. Cardiovasc Drug Rev 24:77–87

    Article  Google Scholar 

  62. Misra MK, Sarwat M, Bhakuni P, Tuteja R, Tuteja N (2009) Oxidative stress and ischemic myocardial syndromes. Med Sci Monit 15:RA209–RA219

    CAS  PubMed  Google Scholar 

  63. Hori M, Nishida K (2009) Oxidative stress and left ventricular remodelling after myocardial infarction. Cardiovasc Res 81:457–464

    Article  CAS  PubMed  Google Scholar 

  64. Lopez FA, Casado S (2001) Heart failure, redox alterations and endothelial dysfunction. Hypertension 38:1400–1405

    Article  Google Scholar 

  65. Kumar D, Jugdutt BI (2003) Apoptosis and oxidants in the heart. J Lab Clin Med 142:288–297

    Article  CAS  PubMed  Google Scholar 

  66. Kumar D, Lou H, Singal PK (2002) Oxidative stress and apoptosis in heart dysfunction. Herz 27:662–668

    Article  PubMed  Google Scholar 

  67. Backlund T, Palojoki E, Saraste A, Eriksson A, Finckenberg P, Kyto V, Lakkisto P, Mervaala E, Voipio-Pulkki LM, Laine M, Tikkanen I (2004) Sustained cardiomyocyte apoptosis and left ventricular remodelling after myocardial infarction in experimental diabetes. Diabetologia 47:325–330

    Article  CAS  PubMed  Google Scholar 

  68. Melo LG, Pachori AS, Kong D, Gnecchi M, Wang K, Pratt RE, Dzau VJ (2004) Molecular and cell-based therapies for protection, rescue and repair of ischemic myocardium: reasons for cautious optimism. Circulation 109:2386–2393

    Article  PubMed  Google Scholar 

  69. Cai L, Li W, Wang G, Guo L, Jiang Y, Kang YJ (2002) Hyperglycemia-induced apoptosis in mouse myocardium: mitochondrial cytochrome C-mediated caspase-3 activation pathway. Diabetes 51:1938–1948

    Article  CAS  PubMed  Google Scholar 

  70. Kumar D, Robertson S, Burns KD (2004) Evidence of apoptosis in human diabetic kidney. Mol Cell Biochem 259:67–70

    Article  CAS  PubMed  Google Scholar 

  71. Ejaz S, Chekarova I, Ejaz A, Sohail A, Lim CW (2008) Importance of pericytes and mechanisms of pericyte loss during diabetes retinopathy. Diabetes Obes Metab 10:53–63

    CAS  PubMed  Google Scholar 

  72. Kamboj SS, Vasishta RK, Sandhir R (2010) N-acetylcysteine inhibits hyperglycemia-induced oxidative stress and apoptosis markers in diabetic neuropathy. J Neurochem 112:77–91

    Article  CAS  PubMed  Google Scholar 

  73. Tuo QH, Zeng H, Stinnett A, Yu H, Aschner JL, Liao DF, Chen JX (2008) Critical role of angiopoietins/Tie-2 in hyperglycemic exacerbation of myocardial infarction and impaired angiogenesis. Am J Physiol Heart Circ Physiol 294:H2547–H2557

    Article  CAS  PubMed  Google Scholar 

  74. Backlund T, Lakkisto P, Palojoki E, Gronholm T, Saraste A, Finckenberg P, Mervaala E, Tikkanen I, Laine M (2007) Activation of protective and damaging components of the cardiac renin-angiotensin system after myocardial infarction in experimental diabetes. J Renin Angiotensin Aldosterone Syst 8:66–73

    Article  CAS  PubMed  Google Scholar 

  75. Swynghedauw B (1999) Molecular mechanisms of myocardial remodeling. Physiol Rev 79:215–262

    CAS  PubMed  Google Scholar 

  76. Menasche P (2008) Skeletal myoblasts and cardiac repair. J Mol Cell Cardiol 45:545–553

    Article  CAS  PubMed  Google Scholar 

  77. Kim H, Kim SW, Nam D, Kim S, Yoon YS (2009) Cell therapy with bone marrow cells for myocardial regeneration. Antioxid Redox Signal 11:1897–1911

    Article  CAS  PubMed  Google Scholar 

  78. Nelson TJ, Martinez-Fernandez A, Yamada S, Perez-Terzic C, Ikeda Y, Terzic A (2009) Repair of acute myocardial infarction by human stemness factors induced pluripotent stem cells. Circulation 120:408–416

    Article  PubMed  Google Scholar 

  79. Cleland JG, Freemantle N, Coletta AP, Clark AL (2006) Clinical trials update from the American Heart Association: REPAIR-AMI, ASTAMI, JELIS, MEGA, REVIVE-II, SURVIVE and PROACTIVE. Eur J Heart Fail 8:105–110

    Article  CAS  PubMed  Google Scholar 

  80. Govaert JA, Swijnenburg RJ, Schrepfer S, Xie X, van der Bogt KE, Hoyt G, Stein W, Ransohoff KJ, Robbins RC, Wu JC (2009) Poor functional recovery after transplantation of diabetic bone marrow stem cells in ischemic myocardium. J Heart Lung Transplant 28:1158–1165

    Article  PubMed  Google Scholar 

  81. Bdel Aziz MT, El-Asmar MF, Haidara M, Atta HM, Roshdy NK, Rashed LA, Sabry D, Youssef MA, Bdel Aziz AT, Moustafa M (2008) Effect of bone marrow-derived mesenchymal stem cells on cardiovascular complications in diabetic rats. Med Sci Monit 14:BR249–BR255

    Google Scholar 

  82. Li JH, Zhang N, Wang JA (2008) Improved anti-apoptotic and anti-remodeling potency of bone marrow mesenchymal stem cells by anoxic pre-conditioning in diabetic cardiomyopathy. J Endocrinol Invest 31:103–110

    CAS  PubMed  Google Scholar 

  83. Zhang N, Li J, Luo R, Jiang J, Wang JA (2008) Bone marrow mesenchymal stem cells induce angiogenesis and attenuate the remodeling of diabetic cardiomyopathy. Exp Clin Endocrinol Diabetes 116:104–111

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgment

We acknowledge support provided by 1R21 HL085795-01A1 and 1R01HL090646-01 (to DKS). Dr. Singal is the holder of the Naranjan Dhalla Chair in Cardiovascular Research, supported by the St. Boniface Hospital & Research Foundation.

Author information

Authors and Affiliations

  1. Institute of Cardiovascular Sciences, St. Boniface General Hospital Research Centre, University of Manitoba, Winnipeg, MB, Canada

    Pawan K. Singal

  2. Biomolecular Science Center, Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, 4000 Central Florida BLVD, Room 224, Orlando, FL, 32816, USA

    Carley E. Glass & Dinender K. Singla

Authors
  1. Carley E. Glass
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Pawan K. Singal
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Dinender K. Singla
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Dinender K. Singla.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Glass, C.E., Singal, P.K. & Singla, D.K. Stem cells in the diabetic infarcted heart. Heart Fail Rev 15, 581–588 (2010). https://doi.org/10.1007/s10741-010-9172-8

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10741-010-9172-8

Keywords

Search

Navigation