Advertisement

Ischemia/Reperfusion Damage in Diabetic Stroke

  • Poornima Venkat
  • Michael Chopp
  • Jieli Chen
Chapter
Part of the Springer Series in Translational Stroke Research book series (SSTSR)

Abstract

Stroke is a leading cause of death and long-term disability. Patients with diabetes mellitus suffer from an increased risk of cardiovascular and cerebrovascular diseases including ischemic stroke. Diabetic stroke patients sustain worse neurological deficits and battle high mortality rates. Diabetes triggers a detrimental pathophysiological cascade resulting in severe vascular dysfunction and I/R injury which result in poor outcome after stroke in this population. The various aspects of diabetic stroke induced vascular and reperfusion damage and the underlying mechanisms are discussed in this chapter.

Keywords

Stroke Diabetes mellitus Hyperglycemia Brain vascular injury Ischemia reperfusion injury 

Notes

Acknowledgements

None

Sources of funding This work was supported by National Institute of Neurological Disorders and Stroke R01 NS083078-01A1 (JC) and RO1 NS099030-01 (JC) and R01NS097747 (QJ/JC).

Disclosures None

References

  1. 1.
    Shaw JE, Sicree RA, Zimmet PZ. Global estimates of the prevalence of diabetes for 2010 and 2030. Diabetes Res Clin Pract. 2010;87:4–14.CrossRefPubMedGoogle Scholar
  2. 2.
    Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, et al. Heart disease and stroke statistics-2016 update: a report from the American heart association. Circulation. 2016;133:e38–360.CrossRefPubMedGoogle Scholar
  3. 3.
    Geiss LS, Wang J, Cheng YJ, et al. Prevalence and incidence trends for diagnosed diabetes among adults aged 20 to 79 years, united states, 1980-2012. JAMA. 2014;312:1218–26.CrossRefPubMedGoogle Scholar
  4. 4.
    Mast H, Thompson JL, Lee SH, Mohr JP, Sacco RL. Hypertension and diabetes mellitus as determinants of multiple lacunar infarcts. Stroke. 1995;26:30–3.CrossRefPubMedGoogle Scholar
  5. 5.
    Lindsberg PJ, Roine RO. Hyperglycemia in acute stroke. Stroke. 2004;35:363–4.CrossRefPubMedGoogle Scholar
  6. 6.
    Kissela BM, Khoury J, Kleindorfer D, Woo D, Schneider A, Alwell K, et al. Epidemiology of ischemic stroke in patients with diabetes: the greater Cincinnati/northern Kentucky stroke study. Diabetes Care. 2005;28:355–9.CrossRefPubMedGoogle Scholar
  7. 7.
    Yong M, Kaste M. Dynamic of hyperglycemia as a predictor of stroke outcome in the ECASS-II trial. Stroke. 2008;39:2749–55.CrossRefPubMedGoogle Scholar
  8. 8.
    Candelise L, Landi G, Orazio EN, Boccardi E. Prognostic significance of hyperglycemia in acute stroke. Arch Neurol. 1985;42:661–3.CrossRefPubMedGoogle Scholar
  9. 9.
    Megherbi SE, Milan C, Minier D, Couvreur G, Osseby GV, Tilling K, et al. Association between diabetes and stroke subtype on survival and functional outcome 3 months after stroke: data from the European biomed stroke project. Stroke. 2003;34:688–94.CrossRefPubMedGoogle Scholar
  10. 10.
    Ergul A, Hafez S, Fouda A, Fagan SC. Impact of comorbidities on acute injury and recovery in preclinical stroke research: focus on hypertension and diabetes. Transl Stroke Res. 2016;7:248–60.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    MEMBERS WG, Lloyd-Jones D, Adams RJ, Brown TM, Carnethon M, Dai S, et al. Heart disease and stroke statistics—2010 update: a report from the American heart association. Circulation. 2010;121:e46–e215.CrossRefGoogle Scholar
  12. 12.
    Callahan A, Amarenco P, Goldstein LB, Sillesen H, Messig M, Samsa GP, et al. Risk of stroke and cardiovascular events after ischemic stroke or transient ischemic attack in patients with type 2 diabetes or metabolic syndrome: secondary analysis of the stroke prevention by aggressive reduction in cholesterol levels (SPARCL) trial. Arch Neurol. 2011;68:1245–51.CrossRefPubMedGoogle Scholar
  13. 13.
    Li PA, Gisselsson L, Keuker J, Vogel J, Smith ML, Kuschinsky W, et al. Hyperglycemia-exaggerated ischemic brain damage following 30 min of middle cerebral artery occlusion is not due to capillary obstruction. Brain Res. 1998;804:36–44.CrossRefPubMedGoogle Scholar
  14. 14.
    Ye X, Chopp M, Liu X, Zacharek A, Cui X, Yan T, et al. Niaspan reduces high-mobility group box 1/receptor for advanced glycation endproducts after stroke in type-1 diabetic rats. Neuroscience. 2011;190:339–45.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Chen J, Cui X, Zacharek A, Cui Y, Roberts C, Chopp M. White matter damage and the effect of matrix metalloproteinases in type 2 diabetic mice after stroke. Stroke. 2011;42:445–52.CrossRefPubMedGoogle Scholar
  16. 16.
    Linfante I, Cipolla MJ. Improving reperfusion therapies in the era of mechanical thrombectomy. Transl Stroke Res. 2016;7:294–302.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    The national institute of neurological disorders and stroke rt-PA stroke study group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med. 1995;333:1581–7.CrossRefGoogle Scholar
  18. 18.
    Jauch EC, Saver JL, Adams HP Jr, Bruno A, Connors JJ, Demaerschalk BM, et al. Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American heart association/American stroke association. Stroke. 2013;44:870–947.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Ding D. Endovascular mechanical thrombectomy for acute ischemic stroke: a new standard of care. J Stroke. 2015;17:123–6.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Reeves MJ, Arora S, Broderick JP, Frankel M, Heinrich JP, Hickenbottom S, et al. Acute stroke care in the us: results from 4 pilot prototypes of the Paul Coverdell national acute stroke registry. Stroke. 2005;36:1232–40.CrossRefPubMedGoogle Scholar
  21. 21.
    Raychev R, Saver JL. Mechanical thrombectomy devices for treatment of stroke. Neurol Clin Pract. 2012;2:231–5.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Ergul A, Elgebaly MM, Middlemore M-L, Li W, Elewa H, Switzer JA, et al. Increased hemorrhagic transformation and altered infarct size and localization after experimental stroke in a rat model type 2 diabetes. BMC Neurol. 2007;7:33.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Ritter L, Davidson L, Henry M, Davis-Gorman G, Morrison H, Frye JB, et al. Exaggerated neutrophil-mediated reperfusion injury after ischemic stroke in a rodent model of type 2 diabetes. Microcirculation. 2011;18:552–61.CrossRefPubMedGoogle Scholar
  24. 24.
    Bas DF, Ozdemir AO, Colak E, Kebapci N. Higher insulin resistance level is associated with worse clinical response in acute ischemic stroke patients treated with intravenous thrombolysis. Transl Stroke Res. 2016;7:167–71.CrossRefPubMedGoogle Scholar
  25. 25.
    Poppe AY, Majumdar SR, Jeerakathil T, Ghali W, Buchan AM, Hill MD. Admission hyperglycemia predicts a worse outcome in stroke patients treated with intravenous thrombolysis. Diabetes Care. 2009;32:617–22.CrossRefPubMedGoogle Scholar
  26. 26.
    Pan J, Konstas A-A, Bateman B, Ortolano GA, Pile-Spellman J. Reperfusion injury following cerebral ischemia: pathophysiology, MR imaging, and potential therapies. Neuroradiology. 2007;49:93–102.CrossRefPubMedGoogle Scholar
  27. 27.
    de Courten-Myers GM, Kleinholz M, Holm P, DeVoe G, Schmitt G, Wagner KR, et al. Hemorrhagic infarct conversion in experimental stroke. Ann Emerg Med. 1992;21:120–6.CrossRefPubMedGoogle Scholar
  28. 28.
    Ahnstedt H, Sweet J, Cruden P, Bishop N, Cipolla MJ. Effects of early post-ischemic reperfusion and tPA on cerebrovascular function and nitrosative stress in female rats. Transl Stroke Res. 2016;7:228–38.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Caso V, Paciaroni M, Venti M, Palmerini F, Silvestrelli G, Milia P, et al. Determinants of outcome in patients eligible for thrombolysis for ischemic stroke. Vasc Health Risk Manag. 2007;3:749–54.PubMedPubMedCentralGoogle Scholar
  30. 30.
    Venkat P, Chopp M, Chen J. New insights into coupling and uncoupling of cerebral blood flow and metabolism in the brain. Croat Med J. 2016;57:223–8.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Abbott NJ, Patabendige AA, Dolman DE, Yusof SR, Begley DJ. Structure and function of the blood-brain barrier. Neurobiol Dis. 2010;37:13–25.CrossRefPubMedGoogle Scholar
  32. 32.
    Sandoval KE, Witt KA. Blood-brain barrier tight junction permeability and ischemic stroke. Neurobiol Dis. 2008;32:200–19.CrossRefPubMedGoogle Scholar
  33. 33.
    Shimizu F, Kanda T. disruption of the blood-brain barrier in inflammatory neurological diseases. Brain Nerve. 2013;65:165–76.PubMedPubMedCentralGoogle Scholar
  34. 34.
    Hall CN, Reynell C, Gesslein B, Hamilton NB, Mishra A, Sutherland BA, et al. Capillary pericytes regulate cerebral blood flow in health and disease. Nature. 2014;508:55–60.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Fernandez-Klett F, Potas JR, Hilpert D, Blazej K, Radke J, Huck J, et al. Early loss of pericytes and perivascular stromal cell-induced scar formation after stroke. J Cereb Blood Flow Metab. 2013;33:428–39.CrossRefPubMedGoogle Scholar
  36. 36.
    Belayev L, Busto R, Zhao W, Ginsberg MD. Quantitative evaluation of blood-brain barrier permeability following middle cerebral artery occlusion in rats. Brain Res. 1996;739:88–96.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Chen J, Ye X, Yan T, Zhang C, Yang XP, Cui X, et al. Adverse effects of bone marrow stromal cell treatment of stroke in diabetic rats. Stroke. 2011;42:3551–8.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Reeson P, Tennant KA, Gerrow K, Wang J, Weiser Novak S, Thompson K, et al. Delayed inhibition of VEGF signaling after stroke attenuates blood-brain barrier breakdown and improves functional recovery in a comorbidity-dependent manner. J Neurosci. 2015;35:5128–43.CrossRefPubMedGoogle Scholar
  39. 39.
    Borlongan CV, Glover LE, Sanberg PR, Hess DC. Permeating the blood brain barrier and abrogating the inflammation in stroke: implications for stroke therapy. Curr Pharm Des. 2012;18:3670–6.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Denes A, Ferenczi S, Kovacs KJ. Systemic inflammatory challenges compromise survival after experimental stroke via augmenting brain inflammation, blood- brain barrier damage and brain oedema independently of infarct size. J Neuroinflammation. 2011;8:164.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Hadi HAR, Suwaidi JA. Endothelial dysfunction in diabetes mellitus. Vasc Health Risk Manag. 2007;3:853–76.PubMedPubMedCentralGoogle Scholar
  42. 42.
    Chen R, Ovbiagele B, Feng W. Diabetes and stroke: epidemiology, pathophysiology, pharmaceuticals and outcomes. Am J Med Sci. 2016;351:380–6.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Aronson D, Rayfield EJ. How hyperglycemia promotes atherosclerosis: molecular mechanisms. Cardiovasc Diabetol. 2002;1:1.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Price TO, Eranki V, Banks WA, Ercal N, Shah GN. Topiramate treatment protects blood-brain barrier pericytes from hyperglycemia-induced oxidative damage in diabetic mice. Endocrinology. 2012;153:362–72.CrossRefPubMedGoogle Scholar
  45. 45.
    Haj-Yasein NN, Vindedal GF, Eilert-Olsen M, Gundersen GA, Skare O, Laake P, et al. Glial-conditional deletion of aquaporin-4 (aqp4) reduces blood-brain water uptake and confers barrier function on perivascular astrocyte endfeet. Proc Natl Acad Sci U S A. 2011;108:17815–20.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Li L, Lundkvist A, Andersson D, Wilhelmsson U, Nagai N, Pardo AC, et al. Protective role of reactive astrocytes in brain ischemia. J Cereb Blood Flow Metab. 2008;28:468–81.CrossRefPubMedGoogle Scholar
  47. 47.
    Li Y, Liu Z, Xin H, Chopp M. The role of astrocytes in mediating exogenous cell-based restorative therapy for stroke. Glia. 2014;62:1–16.CrossRefPubMedGoogle Scholar
  48. 48.
    Jing L, Mai L, Zhang J-Z, Wang J-G, Chang Y, Dong J-D, et al. Diabetes inhibits cerebral ischemia-induced astrocyte activation - an observation in the cingulate cortex. Int J Biol Sci. 2013;9:980–8.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Jing L, He Q, Zhang JZ, Li PA. Temporal profile of astrocytes and changes of oligodendrocyte-based myelin following middle cerebral artery occlusion in diabetic and non-diabetic rats. Int J Biol Sci. 2013;9:190–9.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Marlatt MW, Lucassen PJ, Perry G, Smith MA, Zhu X. Alzheimer’s disease: cerebrovascular dysfunction, oxidative stress, and advanced clinical therapies. J Alzheimers Dis. 2008;15:199–210.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Chen B, Friedman B, Cheng Q, Tsai P, Schim E, Kleinfeld D, et al. Severe blood–brain barrier disruption and surrounding tissue injury. Stroke. 2009;40:e666-e674.Google Scholar
  52. 52.
    Papadopoulos MC, Manley GT, Krishna S, Verkman AS. Aquaporin-4 facilitates reabsorption of excess fluid in vasogenic brain edema. FASEB J. 2004;18:1291–3.CrossRefPubMedGoogle Scholar
  53. 53.
    Rosenberg GA. Ischemic brain edema. Prog Cardiovasc Dis. 1999;42:209–16.CrossRefPubMedGoogle Scholar
  54. 54.
    Stokum JA, Gerzanich V, Simard JM. Molecular pathophysiology of cerebral edema. J Cereb Blood Flow Metab. 2016;36:513–38.CrossRefPubMedGoogle Scholar
  55. 55.
    Manley GT, Fujimura M, Ma T, Noshita N, Filiz F, Bollen AW, et al. Aquaporin-4 deletion in mice reduces brain edema after acute water intoxication and ischemic stroke. Nat Med. 2000;6:159–63.CrossRefPubMedGoogle Scholar
  56. 56.
    Ergul A, Kelly-Cobbs A, Abdalla M, Fagan SC. Cerebrovascular complications of diabetes: focus on stroke. Endocr Metab Immune Disord Drug Targets. 2012;12:148–58.CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Zhang L, Chopp M, Zhang Y, Xiong Y, Li C, Sadry N, et al. Diabetes mellitus impairs cognitive function in middle-aged rats and neurological recovery in middle-aged rats after stroke. Stroke. 2016;47:2112.CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Alvarez-Sabin J, Molina CA, Montaner J, Arenillas JF, Huertas R, Ribo M, et al. Effects of admission hyperglycemia on stroke outcome in reperfused tissue plasminogen activator--treated patients. Stroke. 2003;34:1235–41.CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Demchuk AM, Morgenstern LB, Krieger DW, Linda Chi T, Hu W, Wein TH, et al. Serum glucose level and diabetes predict tissue plasminogen activator–related intracerebral hemorrhage in acute ischemic stroke. Stroke. 1999;30:34–9.CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Fan X, Qiu J, Yu Z, Dai H, Singhal AB, Lo EH, et al. A rat model of studying tissue-type plasminogen activator thrombolysis in ischemic stroke with diabetes. Stroke. 2012;43:567–70.CrossRefPubMedGoogle Scholar
  61. 61.
    Ning R, Chopp M, Yan T, Zacharek A, Zhang C, Roberts C, et al. Tissue plasminogen activator treatment of stroke in type-1 diabetes rats. Neuroscience. 2012;222:326–32.CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Chen CH, Anatol M, Zhan Y, Liu WW, Ostrowki RP, Tang J, et al. Hydrogen gas reduced acute hyperglycemia-enhanced hemorrhagic transformation in a focal ischemia rat model. Neuroscience. 2010;169:402–14.CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Elgebaly MM, Prakash R, Li W, Ogbi S, Johnson MH, Mezzetti EM, et al. Vascular protection in diabetic stroke: role of matrix metalloprotease-dependent vascular remodeling. J Cereb Blood Flow Metab. 2010;30:1928–38.CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Quast MJ, Wei J, Huang NC, Brunder DG, Sell SL, Gonzalez JM, et al. Perfusion deficit parallels exacerbation of cerebral ischemia/reperfusion injury in hyperglycemic rats. J Cereb Blood Flow Metab. 1997;17:553–9.CrossRefPubMedGoogle Scholar
  65. 65.
    Prakash R, Li W, Qu Z, Johnson MA, Fagan SC, Ergul A. Vascularization pattern after ischemic stroke is different in control versus diabetic rats: relevance to stroke recovery. Stroke. 2013;44:2875–82.CrossRefPubMedGoogle Scholar
  66. 66.
    Arenillas JF, Sobrino T, Castillo J, Davalos A. The role of angiogenesis in damage and recovery from ischemic stroke. Curr Treat Options Cardiovasc Med. 2007;9:205–12.CrossRefPubMedGoogle Scholar
  67. 67.
    Navarro-Sobrino M, Rosell A, Hernandez-Guillamon M, Penalba A, Boada C, Domingues-Montanari S, et al. A large screening of angiogenesis biomarkers and their association with neurological outcome after ischemic stroke. Atherosclerosis. 2011;216:205–11.CrossRefPubMedGoogle Scholar
  68. 68.
    Wei L, Erinjeri JP, Rovainen CM, Woolsey TA. Collateral growth and angiogenesis around cortical stroke. Stroke. 2001;32:2179–84.CrossRefPubMedGoogle Scholar
  69. 69.
    Abdelsaid M, Prakash R, Li W, Coucha M, Hafez S, Johnson MH, et al. Metformin treatment in the period after stroke prevents nitrative stress and restores angiogenic signaling in the brain in diabetes. Diabetes. 2015;64:1804–17.CrossRefPubMedGoogle Scholar
  70. 70.
    Hoeben A, Landuyt B, Highley MS, Wildiers H, Van Oosterom AT, De Bruijn EA. Vascular endothelial growth factor and angiogenesis. Pharmacol Rev. 2004;56:549–80.CrossRefPubMedGoogle Scholar
  71. 71.
    Zechariah A, ElAli A, Doeppner TR, Jin FY, Hasan MR, Helfrich I, et al. Vascular endothelial growth factor promotes pericyte coverage of brain capillaries, improves cerebral blood flow during subsequent focal cerebral ischemia, and preserves the metabolic penumbra. Stroke. 2013;44:1690.CrossRefPubMedGoogle Scholar
  72. 72.
    Zhang ZG, Zhang L, Jiang Q, Zhang R, Davies K, Powers C, et al. VEGF enhances angiogenesis and promotes blood-brain barrier leakage in the ischemic brain. J Clin Investig. 2000;106:829–38.CrossRefPubMedGoogle Scholar
  73. 73.
    Kolluru GK, Bir SC, Kevil CG. Endothelial dysfunction and diabetes: effects on angiogenesis, vascular remodeling, and wound healing. Int J Vasc Med. 2012;2012:918267.PubMedPubMedCentralGoogle Scholar
  74. 74.
    Suri C, Jones PF, Patan S, Bartunkova S, Maisonpierre PC, Davis S, et al. Requisite role of angiopoietin-1, a ligand for the tie2 receptor, during embryonic angiogenesis. Cell. 1996;87:1171–80.CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Zacharek A, Chen J, Cui X, Li A, Li Y, Roberts C, et al. Angiopoietin1/tie2 and VEGF/Flk1 induced by MSC treatment amplifies angiogenesis and vascular stabilization after stroke. J Cereb Blood Flow Metab. 2007;27:1684–91.CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Gurnik S, Devraj K, Macas J, Yamaji M, Starke J, Scholz A, et al. Angiopoietin-2-induced blood-brain barrier compromise and increased stroke size are rescued by VE-PTP-dependent restoration of tie2 signaling. Acta Neuropathol. 2016;131:753–73.CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Lim HS, Lip GY, Blann AD. Angiopoietin-1 and angiopoietin-2 in diabetes mellitus: relationship to VEGF, glycaemic control, endothelial damage/dysfunction and atherosclerosis. Atherosclerosis. 2005;180:113–8.CrossRefPubMedGoogle Scholar
  78. 78.
    Cui X, Chopp M, Zacharek A, Ye X, Roberts C, Chen J. Angiopoietin/tie2 pathway mediates type 2 diabetes induced vascular damage after cerebral stroke. Neurobiol Dis. 2011;43:285–92.CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    Wang YQ, Song JJ, Han X, Liu YY, Wang XH, Li ZM, et al. Effects of angiopoietin-1 on inflammatory injury in endothelial progenitor cells and blood vessels. Curr Gene Ther. 2014;14:128.CrossRefPubMedGoogle Scholar
  80. 80.
    Tarbell JM. Shear stress and the endothelial transport barrier. Cardiovasc Res. 2010;87:320–30.CrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    Cunningham KS, Gotlieb AI. The role of shear stress in the pathogenesis of atherosclerosis. Lab Invest. 2004;85:9–23.CrossRefGoogle Scholar
  82. 82.
    Gresele P, Guglielmini G, De Angelis M, Ciferri S, Ciofetta M, Falcinelli E, et al. Acute, short-term hyperglycemia enhances shear stress-induced platelet activation in patients with type ii diabetes mellitus. J Am Coll Cardiol. 2003;41:1013–20.CrossRefPubMedGoogle Scholar
  83. 83.
    Kernan WN, Inzucchi SE, Viscoli CM, Brass LM, Bravata DM, Horwitz RI. Insulin resistance and risk for stroke. Neurology. 2002;59:809–15.CrossRefPubMedGoogle Scholar
  84. 84.
    Cheng C, Daskalakis C. Association of adipokines with insulin resistance, microvascular dysfunction, and endothelial dysfunction in healthy young adults. Mediators Inflamm. 2015;2015:594039.PubMedPubMedCentralGoogle Scholar
  85. 85.
    Kaji H. Adipose tissue-derived plasminogen activator inhibitor-1 function and regulation. Compr Physiol. 2016;6:1873–96.CrossRefPubMedGoogle Scholar
  86. 86.
    Rizk NN, Rafols JA, Dunbar JC. Cerebral ischemia-induced apoptosis and necrosis in normal and diabetic rats: effects of insulin and c-peptide. Brain Res. 2006;1096:204–12.CrossRefPubMedGoogle Scholar
  87. 87.
    Liu H, Ou S, Xiao X, Zhu Y, Zhou S. Diabetes worsens ischemia-reperfusion brain injury in rats through gsk-3β. Am J Med Sci. 2015;350:204–11.CrossRefPubMedPubMedCentralGoogle Scholar
  88. 88.
    Chapin JC, Hajjar KA. Fibrinolysis and the control of blood coagulation. Blood Rev. 2015;29:17–24.CrossRefPubMedGoogle Scholar
  89. 89.
    Trost S, Pratley RE, Sobel BE. Impaired fibrinolysis and risk for cardiovascular disease in the metabolic syndrome and type 2 diabetes. Curr Diab Rep. 2006;6:47–54.CrossRefPubMedGoogle Scholar
  90. 90.
    Lijnen HR, Ds C. Impaired fibrinolysis and the risk for coronary heart disease. Circulation. 1996;94:2052–4.CrossRefPubMedGoogle Scholar
  91. 91.
    Jotic A, Milicic T, Covickovic Sternic N, Kostic VS, Lalic K, Jeremic V, et al. Decreased insulin sensitivity and impaired fibrinolytic activity in type 2 diabetes patients and nondiabetics with ischemic stroke. Int J Endocrinol. 2015;2015:934791.CrossRefPubMedPubMedCentralGoogle Scholar
  92. 92.
    Wyseure T, Rubio M, Denorme F, Martinez de Lizarrondo S, Peeters M, Gils A, et al. Innovative thrombolytic strategy using a heterodimer diabody against TAFI and PAI-1 in mouse models of thrombosis and stroke. Blood. 2015;125:1325–32.CrossRefPubMedGoogle Scholar
  93. 93.
    Dokken BB. The pathophysiology of cardiovascular disease and diabetes: beyond blood pressure and lipids. Diabetes Spectr. 2008;21:160–5.CrossRefGoogle Scholar
  94. 94.
    Poulsen RC, Knowles HJ, Carr AJ, Hulley PA. Cell differentiation versus cell death: extracellular glucose is a key determinant of cell fate following oxidative stress exposure. Cell Death Dis. 2014;5:e1074.CrossRefPubMedPubMedCentralGoogle Scholar
  95. 95.
    Sims NR, Muyderman H. Mitochondria, oxidative metabolism and cell death in stroke. Biochim Biophys Acta. 2010;1802:80–91.CrossRefPubMedGoogle Scholar
  96. 96.
    Doyle KP, Simon RP, Stenzel-Poore MP. Mechanisms of ischemic brain damage. Neuropharmacology. 2008;55:310–8.CrossRefPubMedPubMedCentralGoogle Scholar
  97. 97.
    Mishiro K, Imai T, Sugitani S, Kitashoji A, Suzuki Y, Takagi T, et al. Diabetes mellitus aggravates hemorrhagic transformation after ischemic stroke via mitochondrial defects leading to endothelial apoptosis. PLoS One. 2014;9:e103818.CrossRefPubMedPubMedCentralGoogle Scholar
  98. 98.
    Tang J, Li YJ, Li Q, Mu J, Yang DY, Xie P. Endogenous tissue plasminogen activator increases hemorrhagic transformation induced by heparin after ischemia reperfusion in rat brains. Neurol Res. 2010;32:541–6.CrossRefPubMedGoogle Scholar
  99. 99.
    Won SJ, Tang XN, Suh SW, Yenari MA, Swanson RA. Hyperglycemia promotes tissue plasminogen activator-induced hemorrhage by increasing superoxide production. Ann Neurol. 2011;70:583–90.CrossRefPubMedPubMedCentralGoogle Scholar
  100. 100.
    Kim JY, Kawabori M, Yenari MA. Innate inflammatory responses in stroke: mechanisms and potential therapeutic targets. Curr Med Chem. 2014;21:2076–97.CrossRefPubMedPubMedCentralGoogle Scholar
  101. 101.
    Whitney NP, Eidem TM, Peng H, Huang Y, Zheng JC. Inflammation mediates varying effects in neurogenesis: relevance to the pathogenesis of brain injury and neurodegenerative disorders. J Neurochem. 2009;108:1343–59.CrossRefPubMedPubMedCentralGoogle Scholar
  102. 102.
    Wang C, Jiang J, Zhang X, Song L, Sun K, Xu R. Inhibiting hmgb1 reduces cerebral ischemia reperfusion injury in diabetic mice. Inflammation. 2016;39:1862–70.CrossRefPubMedPubMedCentralGoogle Scholar
  103. 103.
    di Penta A, Moreno B, Reix S, Fernandez-Diez B, Villanueva M, Errea O, et al. Oxidative stress and proinflammatory cytokines contribute to demyelination and axonal damage in a cerebellar culture model of neuroinflammation. PLoS One. 2013;8:e54722.CrossRefPubMedPubMedCentralGoogle Scholar
  104. 104.
    Pickup JC. Inflammation and activated innate immunity in the pathogenesis of type 2 diabetes. Diabetes Care. 2004;27:813–23.CrossRefPubMedGoogle Scholar
  105. 105.
    Kim JB, Sig Choi J, Yu YM, Nam K, Piao CS, Kim SW, et al. Hmgb1, a novel cytokine-like mediator linking acute neuronal death and delayed neuroinflammation in the postischemic brain. J Neurosci. 2006;26:6413–21.CrossRefPubMedGoogle Scholar
  106. 106.
    Qiu J, Nishimura M, Wang Y, Sims JR, Qiu S, Savitz SI, et al. Early release of hmgb-1 from neurons after the onset of brain ischemia. J Cereb Blood Flow Metab. 2008;28:927–38.CrossRefPubMedGoogle Scholar
  107. 107.
    Yang Q-W, Lu F-L, Zhou Y, Wang L, Zhong Q, Lin S, et al. Hmbg1 mediates ischemia–reperfusion injury by TRIF-adaptor independent toll-like receptor 4 signaling. J Cereb Blood Flow Metab. 2011;31:593–605.CrossRefPubMedGoogle Scholar
  108. 108.
    Qiu J, Xu J, Zheng Y, Wei Y, Zhu X, Lo EH, et al. High-mobility group box 1 promotes metalloproteinase-9 upregulation through toll-like receptor 4 after cerebral ischemia. Stroke. 2010;41:2077–82.CrossRefPubMedPubMedCentralGoogle Scholar
  109. 109.
    Maillard-Lefebvre H, Boulanger E, Daroux M, Gaxatte C, Hudson BI, Lambert M. Soluble receptor for advanced glycation end products: a new biomarker in diagnosis and prognosis of chronic inflammatory diseases. Rheumatology. 2009;48:1190–6.CrossRefPubMedGoogle Scholar
  110. 110.
    Bright R, Mochly-Rosen D. The role of protein kinase c in cerebral ischemic and reperfusion injury. Stroke. 2005;36:2781–90.CrossRefPubMedGoogle Scholar
  111. 111.
    Chen J, Venkat P, Zacharek A, Chopp M. Neurorestorative therapy for stroke. Front Hum Neurosci. 2014;8:382.PubMedPubMedCentralGoogle Scholar
  112. 112.
    Puddu P, Puddu GM, Cravero E, Muscari S, Muscari A. The involvement of circulating microparticles in inflammation, coagulation and cardiovascular diseases. Can J Cardiol. 2010;26:e140–5.CrossRefPubMedCentralGoogle Scholar
  113. 113.
    Colombo M, Raposo G, Thery C. Biogenesis, secretion, and intercellular interactions of exosomes and other extracellular vesicles. Annu Rev Cell Dev Biol. 2014;30:255–89.CrossRefPubMedGoogle Scholar
  114. 114.
    Kalani A, Tyagi A, Tyagi N. Exosomes: mediators of neurodegeneration, neuroprotection and therapeutics. Mol Neurobiol. 2014;49:590–600.CrossRefPubMedGoogle Scholar
  115. 115.
    Mesri M, Altieri DC. Leukocyte microparticles stimulate endothelial cell cytokine release and tissue factor induction in a jnk1 signaling pathway. J Biol Chem. 1999;274:23111–8.CrossRefPubMedGoogle Scholar
  116. 116.
    Tramontano AF, Lyubarova R, Tsiakos J, Palaia T, DeLeon JR, Ragolia L. Circulating endothelial microparticles in diabetes mellitus. Mediators Inflamm. 2010;2010:250476.CrossRefPubMedPubMedCentralGoogle Scholar
  117. 117.
    Zampetaki A, Kiechl S, Drozdov I, Willeit P, Mayr U, Prokopi M, et al. Plasma microrna profiling reveals loss of endothelial mir-126 and other micrornas in type 2 diabetes. Circ Res. 2010;107:810–7.CrossRefPubMedGoogle Scholar
  118. 118.
    Shantikumar S, Caporali A, Emanueli C. Role of micrornas in diabetes and its cardiovascular complications. Cardiovasc Res. 2012;93:583–93.CrossRefPubMedGoogle Scholar
  119. 119.
    Lim LP, Lau NC, Garrett-Engele P, Grimson A, Schelter JM, Castle J, et al. Microarray analysis shows that some micrornas downregulate large numbers of target mRNAs. Nature. 2005;433:769–73.CrossRefPubMedGoogle Scholar
  120. 120.
    Wang S, Aurora AB, Johnson BA, Qi X, McAnally J, Hill JA, et al. The endothelial-specific microrna mir-126 governs vascular integrity and angiogenesis. Dev Cell. 2008;15:261–71.CrossRefPubMedPubMedCentralGoogle Scholar
  121. 121.
    Zampetaki A, Willeit P, Drozdov I, Kiechl S, Mayr M. Profiling of circulating micrornas: from single biomarkers to re-wired networks. Cardiovasc Res. 2012;93:555–62.CrossRefPubMedGoogle Scholar
  122. 122.
    Long G, Wang F, Li H, Yin Z, Sandip C, Lou Y, et al. Circulating mir-30a, mir-126 and let-7b as biomarker for ischemic stroke in humans. BMC Neurol. 2013;13:1–10.CrossRefGoogle Scholar
  123. 123.
    Fish JE, Santoro MM, Morton SU, Yu S, Yeh RF, Wythe JD, et al. Mir-126 regulates angiogenic signaling and vascular integrity. Dev Cell. 2008;15:272–84.CrossRefPubMedPubMedCentralGoogle Scholar
  124. 124.
    Cui C, Ye X, Chopp M, Venkat P, Zacharek A, Yan T, et al. Mir-145 regulates diabetes-bone marrow stromal cell-induced neurorestorative effects in diabetes stroke rats. Stem Cells Transl Med. 2016;26:2015–0349.Google Scholar
  125. 125.
    Altintas O, Ozgen Altintas M, Kumas M, Asil T. Neuroprotective effect of ischemic preconditioning via modulating the expression of cerebral miRNAs against transient cerebral ischemia in diabetic rats. Neurol Res. 2016;38:1003–11.CrossRefPubMedGoogle Scholar
  126. 126.
    Zhao W, Zhao S-P, Zhao Y-H. Microrna-143/-145 in cardiovascular diseases. Biomed Res Int. 2015;2015:9.Google Scholar
  127. 127.
    Jordan SD, Kruger M, Willmes DM, Redemann N, Wunderlich FT, Bronneke HS, et al. Obesity-induced overexpression of mirna-143 inhibits insulin-stimulated Akt activation and impairs glucose metabolism. Nat Cell Biol. 2011;13:434–46.CrossRefPubMedGoogle Scholar
  128. 128.
    Jia L, Hao F, Wang W, Qu Y. Circulating mir-145 is associated with plasma high-sensitivity c-reactive protein in acute ischemic stroke patients. Cell Biochem Funct. 2015;33:314–9.CrossRefPubMedGoogle Scholar
  129. 129.
    Weiss JBW, Eisenhardt SU, Stark GB, Bode C, Moser M, Grundmann S. Micrornas in ischemia-reperfusion injury. Am J Cardiovasc Dis. 2012;2:237–47.PubMedPubMedCentralGoogle Scholar
  130. 130.
    Dharap A, Bowen K, Place R, Li LC, Vemuganti R. Transient focal ischemia induces extensive temporal changes in rat cerebral micrornaome. J Cereb Blood Flow Metab. 2009;29:675–87.CrossRefPubMedPubMedCentralGoogle Scholar
  131. 131.
    Climent M, Quintavalle M, Miragoli M, Chen J, Condorelli G, Elia L. Tgfbeta triggers mir-143/145 transfer from smooth muscle cells to endothelial cells, thereby modulating vessel stabilization. Circ Res. 2015;116:1753–64.CrossRefPubMedGoogle Scholar
  132. 132.
    Krupinski J, Kaluza J, Kumar P, Kumar S, Wang JM. Role of angiogenesis in patients with cerebral ischemic stroke. Stroke. 1994;25:1794–8.CrossRefPubMedGoogle Scholar
  133. 133.
    Zhu T, Song J, Hamblin MH, Chen YE, Yin K-J. Abstract 145: mir-15a/16-1 mediates blood-brain barrier dysfunction in ischemic stroke. Stroke. 2016;47:A145.Google Scholar
  134. 134.
    Yin K-J, Hamblin M, Zhang J, Zhu T, Chen YE. Abstract tp117: mir-15a/16-1 cluster inhibits angiogenesis in mouse after ischemic stroke. Stroke. 2013;44:ATP117.CrossRefGoogle Scholar
  135. 135.
    Willeit P, Zampetaki A, Dudek K, Kaudewitz D, King A, Kirkby NS, et al. Circulating micrornas as novel biomarkers for platelet activation. Circ Res. 2013;112:595–600.CrossRefPubMedGoogle Scholar
  136. 136.
    Fang Z, He Q-W, Li Q, Chen X-L, Baral S, Jin H-J, et al. Microrna-150 regulates blood–brain barrier permeability via tie-2 after permanent middle cerebral artery occlusion in rats. FASEB J. 2016;30:2097.CrossRefPubMedGoogle Scholar
  137. 137.
    Zhang R, Chopp M, Roberts C, Teng H, Wei M, Zhang L, et al. Abstract 49: deletion of miRNA 17-92 in cerebral endothelial cells induces disruption of bbb. Stroke. 2014;45:A49.CrossRefGoogle Scholar
  138. 138.
    T-y L, J-y L. Increased expression of mir-34a-5p and clinical association in acute ischemic stroke patients and in a rat model. Med Sci Monit. 2016;22:2950–5.CrossRefGoogle Scholar
  139. 139.
    Bukeirat M, Sarkar SN, Hu H, Quintana DD, Simpkins JW, Ren X. Mir-34a regulates blood–brain barrier permeability and mitochondrial function by targeting cytochrome c. J Cereb Blood Flow Metab. 2016;36:387–92.CrossRefPubMedGoogle Scholar
  140. 140.
    Nunez Lopez YO, Garufi G, Seyhan AA. Altered levels of circulating cytokines and micrornas in lean and obese individuals with prediabetes and type 2 diabetes. Mol Biosyst. 2016;13:106.CrossRefPubMedGoogle Scholar
  141. 141.
    Wang C, Wan S, Yang T, Niu D, Zhang A, Yang C, et al. Increased serum micrornas are closely associated with the presence of microvascular complications in type 2 diabetes mellitus. Sci Rep. 2016;6:20032.CrossRefPubMedPubMedCentralGoogle Scholar
  142. 142.
    Peng G, Yuan Y, Wu S, He F, Hu Y, Luo B. Microrna let-7e is a potential circulating biomarker of acute stage ischemic stroke. Transl Stroke Res. 2015;6:437–45.CrossRefPubMedGoogle Scholar
  143. 143.
    Sun J, Wang F, Ling Z, Yu X, Chen W, Li H, et al. Clostridium butyricum attenuates cerebral ischemia/reperfusion injury in diabetic mice via modulation of gut microbiota. Brain Res. 2016;1642:180–8.CrossRefPubMedGoogle Scholar
  144. 144.
    Bercik P, Collins SM, Verdu EF. Microbes and the gut-brain axis. Neurogastroenterol Motil. 2012;24:405–13.CrossRefPubMedGoogle Scholar
  145. 145.
    Benakis C, Brea D, Caballero S, Faraco G, Moore J, Murphy M, et al. Commensal microbiota affects ischemic stroke outcome by regulating intestinal γδt cells. Nat Med. 2016;22:516–23.CrossRefPubMedPubMedCentralGoogle Scholar
  146. 146.
    Singh V, Roth S, Llovera G, Sadler R, Garzetti D, Stecher B, et al. Microbiota dysbiosis controls the neuroinflammatory response after stroke. J Neurosci. 2016;36:7428–40.CrossRefPubMedGoogle Scholar
  147. 147.
    Yin J, Liao SX, He Y, Wang S, Xia GH, Liu FT, et al. Dysbiosis of gut microbiota with reduced trimethylamine-n-oxide level in patients with large-artery atherosclerotic stroke or transient ischemic attack. J Am Heart Assoc. 2015;4:pii: e002699.CrossRefGoogle Scholar
  148. 148.
    Karlsson FH, Tremaroli V, Nookaew I, Bergstrom G, Behre CJ, Fagerberg B, et al. Gut metagenome in European women with normal, impaired and diabetic glucose control. Nature. 2013;498:99–103.CrossRefPubMedGoogle Scholar
  149. 149.
    Yamashiro K, Tanaka R, Urabe T, Ueno Y, Yamashiro Y, Nomoto K, et al. Gut dysbiosis is associated with metabolism and systemic inflammation in patients with ischemic stroke. PLoS One. 2017;12:e0171521.CrossRefPubMedPubMedCentralGoogle Scholar
  150. 150.
    Le Chatelier E, Nielsen T, Qin J, Prifti E, Hildebrand F, Falony G, et al. Richness of human gut microbiome correlates with metabolic markers. Nature. 2013;500:541–6.CrossRefPubMedGoogle Scholar
  151. 151.
    Qin J, Li Y, Cai Z, Li S, Zhu J, Zhang F, et al. A metagenome-wide association study of gut microbiota in type 2 diabetes. Nature. 2012;490:55–60.CrossRefPubMedGoogle Scholar
  152. 152.
    Sato J, Kanazawa A, Ikeda F, Yoshihara T, Goto H, Abe H, et al. Gut dysbiosis and detection of “live gut bacteria” in blood of Japanese patients with type 2 diabetes. Diabetes Care. 2014;37:2343–50.CrossRefPubMedGoogle Scholar
  153. 153.
    Winek K, Engel O, Koduah P, Heimesaat MM, Fischer A, Bereswill S, et al. Depletion of cultivatable gut microbiota by broad-spectrum antibiotic pretreatment worsens outcome after murine stroke. Stroke. 2016;47:1354–63.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.NeurologyHenry Ford HospitalDetroitUSA
  2. 2.Department of PhysicsOakland UniversityRochesterUSA
  3. 3.Neurological & Gerontology InstituteTianjin Medical University General HospitalTianjinChina
  4. 4.Neurology ResearchHenry Ford HospitalDetroitUSA

Personalised recommendations