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Anti-apoptotic Actions of PPAR-γ Against Ischemic Stroke

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Abstract

Stroke is a leading cause of adult disability and mortality. Diabetes is a major risk factor for stroke. Patients with diabetes have a higher incidence of stroke and a poorer prognosis after stroke. Peroxisome proliferator-activated receptor gamma (PPAR-γ) is a ligand-modulated transcriptional factor and a therapeutic target for treating type II diabetes. It is well-documented that activation of PPAR-γ can also attenuate postischemic inflammation and damage. In this review, we focus on the newly revealed anti-apoptotic actions of PPAR-γ against cerebral ischemia. PPAR-γ, by increasing superoxide dismutase/catalase and decreasing nicotinamide adenine dinucleotide phosphate oxidase levels, attenuated ischemia-induced reactive oxygen species and subsequently alleviated the postischemic degradation of Bcl-2, Bcl-xl, and Akt. The preserved Akt phosphorylated Bad. Meanwhile, PPAR-γ also promotes the transcription of 14-3-3ε. Elevated 14-3-3ε binds and sequesters p-Bad and prevents Bad translocation to neutralize the anti-apoptotic function of Bcl-2. This review further supports the notion that PPAR-γ may serve as a potential therapeutic target for treating ischemic stroke.

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References

  1. Nuclear Receptors Nomenclature Committee (1999) A unified nomenclature system for the nuclear receptor superfamily. Cell 97:161–163

    Article  Google Scholar 

  2. Issemann I, Green S (1990) Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators. Nature 347:645–650

    Article  CAS  PubMed  Google Scholar 

  3. Collino M, Patel NS, Thiemermann C (2008) PPARs as new therapeutic targets for the treatment of cerebral ischemia/reperfusion injury. Ther Adv Cardiovasc Dis 2:179–197

    Article  PubMed  Google Scholar 

  4. Dreyer C, Krey G, Keller H, Givel F, Helftenbein G, Wahli W (1992) Control of the peroxisomal beta-oxidation pathway by a novel family of nuclear hormone receptors. Cell 68:879–887

    Article  CAS  PubMed  Google Scholar 

  5. Hamblin M, Chang L, Fan Y, Zhang J, Chen YE (2009) PPARs and the cardiovascular system. Antioxid Redox Signal 11:1415–1452

    Article  CAS  PubMed  Google Scholar 

  6. Berger J, Moller DE (2002) The mechanisms of action of PPARs. Annu Rev Med 53:409–435

    Article  CAS  PubMed  Google Scholar 

  7. Chandra V, Huang P, Hamuro Y, Raghuram S, Wang Y, Burris TP, Rastinejad F (2008) Structure of the intact PPAR-γ-RXR-α nuclear receptor complex on DNA. Nature 456:350–356

    Article  PubMed  Google Scholar 

  8. Willson TM, Lambert MH, Kliewer SA (2001) Peroxisome proliferator-activated receptor gamma and metabolic disease. Annu Rev Biochem 70:341–367

    Article  CAS  PubMed  Google Scholar 

  9. Heneka MT, Landreth GE (2007) PPARs in the brain. Biochim Biophys Acta 1771:1031–1045

    CAS  PubMed  Google Scholar 

  10. Pialat JB, Cho TH, Beuf O, Joye E, Moucharrafie S, Langlois JB, Nemoz C, Janier M, Berthezene Y, Nighoghossian N, Desvergne B, Wiart M (2007) MRI monitoring of focal cerebral ischemia in peroxisome proliferator-activated receptor (PPAR)-deficient mice. NMR Biomed 20:335–342

    Article  CAS  PubMed  Google Scholar 

  11. Wu JS, Cheung WM, Tsai YS, Chen YT, Fong WH, Tsai HD, Chen YC, Liou JY, Shyue SK, Chen JJ, Chen YE, Maeda N, Wu KK, Lin TN (2009) Ligand-activated peroxisome proliferator-activated receptor-gamma protects against ischemic cerebral infarction and neuronal apoptosis by 14-3-3 epsilon upregulation. Circulation 119:1124–1134

    Article  CAS  PubMed  Google Scholar 

  12. Zhu Y, Qi C, Korenberg JR, Chen XN, Noya D, Rao MS, Reddy JK (1995) Structural organization of mouse peroxisome proliferator-activated receptor gamma (mPPAR gamma) gene: alternative promoter use and different splicing yield two mPPAR gamma isoforms. Proc Natl Acad Sci USA 92:7921–7925

    Article  CAS  PubMed  Google Scholar 

  13. Zhou J, Wilson KM, Medh JD (2002) Genetic analysis of four novel peroxisome proliferator activated receptor-gamma splice variants in monkey macrophages. Biochem Biophys Res Commun 293:274–283

    Article  CAS  PubMed  Google Scholar 

  14. Chen Y, Jimenez AR, Medh JD (2006) Identification and regulation of novel PPAR-gamma splice variants in human THP-1 macrophages. Biochim Biophys Acta 1759:32–43

    CAS  PubMed  Google Scholar 

  15. Villacorta L, Schopfer FJ, Zhang J, Freeman BA, Chen YE (2009) PPARgamma and its ligands: therapeutic implications in cardiovascular disease. Clin Sci (Lond) 116:205–218

    Article  CAS  Google Scholar 

  16. Bell-Parikh LC, Ide T, Lawson JA, McNamara P, Reilly M, FitzGerald GA (2003) Biosynthesis of 15-deoxy-delta12, 14-PGJ2 and the ligation of PPARgamma. J Clin Invest 112:945–955

    CAS  PubMed  Google Scholar 

  17. Schopfer FJ, Lin Y, Baker PR, Cui T, Garcia-Barrio M, Zhang J, Chen K, Chen YE, Freeman BA (2005) Nitrolinoleic acid: an endogenous peroxisome proliferator-activated receptor gamma ligand. Proc Natl Acad Sci USA 102:2340–2345

    Article  CAS  PubMed  Google Scholar 

  18. Bazan NG (1976) Free arachidonic acid and other lipids in the nervous system during early ischemia and after electroshock. Adv Exp Med Biol 72:317–335

    CAS  PubMed  Google Scholar 

  19. Chan PH, Fishman RA, Longar S, Chen S, Yu A (1985) Cellular and molecular effects of polyunsaturated fatty acids in brain ischemia and injury. Prog Brain Res 63:227–235

    Article  CAS  PubMed  Google Scholar 

  20. Hsu CY, Liu TH, Xu J, Hogan EL, Chao J, Sun G, Tai HH, Beckman JS, Freeman BA (1989) Arachidonic acid and its metabolites in cerebral ischemia. Ann NY Acad Sci 559:282–295

    Article  CAS  PubMed  Google Scholar 

  21. Sun GY, Horrocks LA (1968) The fatty acid and aldehyde composition of the major phospholipids of mouse brain. Lipids 3:79–83

    Article  CAS  PubMed  Google Scholar 

  22. Wu JS, Lin TN, Wu KK (2009) Rosiglitazone and PPAR-gamma overexpression protect mitochondrial membrane potential and prevent apoptosis by upregulating anti-apoptotic Bcl-2 family proteins. J Cell Physiol 220:58–71

    Article  CAS  PubMed  Google Scholar 

  23. Lehmann JM, Moore LB, Smith-Oliver TA, Wilkison WO, Willson TM, Kliewer SA (1995) An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma). J Biol Chem 270:12953–12956

    Article  CAS  PubMed  Google Scholar 

  24. Rubenstrunk A, Hanf R, Hum DW, Fruchart JC, Staels B (2007) Safety issues and prospects for future generations of PPAR modulators. Biochim Biophys Acta 1771:1065–1081

    CAS  PubMed  Google Scholar 

  25. Feinstein DL, Spagnolo A, Akar C, Weinberg G, Murphy P, Gavrilyuk V, Dello Russo C (2005) Receptor-independent actions of PPAR thiazolidinedione agonists: is mitochondrial function the key? Biochem Pharmacol 70:177–188

    Article  CAS  PubMed  Google Scholar 

  26. Scher JU, Pillinger MH (2005) 15d-PGJ2: the anti-inflammatory prostaglandin? Clin Immunol 114:100–109

    Article  CAS  PubMed  Google Scholar 

  27. Shimizu M, Yamashita D, Yamaguchi T, Hirose F, Osumi T (2006) Aspects of the regulatory mechanisms of PPAR functions: analysis of a bidirectional response element and regulation by sumoylation. Mol Cell Biochem 286:33–42

    Article  CAS  PubMed  Google Scholar 

  28. Lin TN, Cheung WM, Wu JS, Chen JJ, Lin H, Chen JJ, Liou JY, Shyue SK, Wu KK (2006) 15d-Prostaglandin J2 protects brain from ischemia–reperfusion injury. Arterioscler Thromb Vasc Biol 26:481–487

    Article  CAS  PubMed  Google Scholar 

  29. Liu HR, Tao L, Gao E, Lopez BL, Christopher TA, Willette RN, Ohlstein EH, Yue TL, Ma XL (2004) Anti-apoptotic effects of rosiglitazone in hypercholesterolemic rabbits subjected to myocardial ischemia and reperfusion. Cardiovasc Res 62:135–144

    Article  CAS  PubMed  Google Scholar 

  30. Shimazu T, Inoue I, Araki N, Asano Y, Sawada M, Furuya D, Nagoya H, Greenberg JH (2005) A peroxisome proliferator-activated receptor-γ agonist reduces infarct size in transient but not in permanent ischemia. Stroke 36:353–359

    Article  CAS  PubMed  Google Scholar 

  31. Sundararajan S, Gamboa JL, Victor NA, Wanderi EW, Lust WD, Landreth GE (2005) Peroxisome proliferator-activated receptor-gamma ligands reduce inflammation and infarction size in transient focal ischemia. Neurosci 130:685–696

    Article  CAS  Google Scholar 

  32. Yue TL, Chen J, Bao W, Narayanan PK, Bril A, Jiang W, Lysko PG, Gu JL, Boyce R, Zimmerman DM, Hart TK, Buckingham RE, Ohlstein EH (2001) In vivo myocardial protection from ischemia/reperfusion injury by the peroxisome proliferator-activated receptor-γ agonist rosiglitazone. Circulation 104:2588–2594

    Article  CAS  Google Scholar 

  33. Chawla A, Barak Y, Nagy L, Liao D, Tontonoz P, Evans RM (2001) PPAR-γ dependent and independent effects on macrophage-gene expression in lipid metabolism and inflammation. Nature Med 7:48–52

    Article  CAS  PubMed  Google Scholar 

  34. Jiang C, Ting AT, Seed B (1998) PPAR-γ agonists inhibit production of monocyte inflammatory cytokines. Nature 391:82–86

    Article  CAS  PubMed  Google Scholar 

  35. Ricote M, Li AC, Willson TM, Kelly CJ, Glass CK (1998) The peroxisome proliferator-activated receptor-γ is a negative regulator of macrophage activation. Nature 391:79–82

    Article  CAS  PubMed  Google Scholar 

  36. Bordet R, Ouk T, Petrault O, Gelé P, Gautier S, Laprais M, Deplanque D, Duriez P, Staels B, Fruchart JC, Bastide M (2006) PPAR: a new pharmacological target for neuroprotection in stroke and neurodegenerative diseases. Biochem Soc Trans 34:1341–1346

    Article  CAS  PubMed  Google Scholar 

  37. Culman J, Zhao Y, Gohlke P, Herdegen T (2007) PPAR-gamma: therapeutic target for ischemic stroke. Trends Pharmacol Sci 28:244–249

    Article  CAS  PubMed  Google Scholar 

  38. Giaginis C, Tsourouflis G, Theocharis S (2008) Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) ligands: novel pharmacological agents in the treatment of ischemia reperfusion injury. Curr Mol Med 8:562–579

    Article  CAS  PubMed  Google Scholar 

  39. Kapadia R, Yi JH, Vemuganti R (2008) Mechanisms of anti-inflammatory and neuroprotective actions of PPAR-gamma agonists. Front Biosci 13:1813–1826

    Article  CAS  PubMed  Google Scholar 

  40. Barak Y, Nelson MC, Ong ES, Jones YZ, Ruiz-Lozano P, Chien KR, Koder A, Evans RM (1999) PPAR gamma is required for placental, cardiac, and adipose tissue development. Mol Cell 4:585–595

    Article  CAS  PubMed  Google Scholar 

  41. Tsai YS, Kim HJ, Takahashi N, Kim HS, Hagaman JR, Kim JK, Maeda N (2004) Hypertension and abnormal fat distribution but not insulin resistance in mice with P465L PPARgamma. J Clin Invest 114:240–249

    CAS  PubMed  Google Scholar 

  42. Zhao X, Strong R, Zhang J, Sun G, Tsien JZ, Cui Z, Grotta JC, Aronowski J (2009) Neuronal PPARgamma deficiency increases susceptibility to brain damage after cerebral ischemia. J Neurosci 29:6186–6195

    Article  CAS  PubMed  Google Scholar 

  43. Schock SC, Xu J, Duquette PM, Qin Z, Lewandowski AJ, Rai PS, Thompson CS, Seifert EL, Harper ME, Chen HH (2008) Rescue of neurons from ischemic injury by peroxisome proliferator-activated receptor-gamma requires a novel essential cofactor LMO4. J Neurosci 28:12433–12444

    Article  CAS  PubMed  Google Scholar 

  44. Hengartner MO (2000) The biochemistry of apoptosis. Nature 407:770–776

    Article  CAS  PubMed  Google Scholar 

  45. Kerr JF, Wyllie AH, Currie AR (1972) Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer 26:239–257

    CAS  PubMed  Google Scholar 

  46. Youle RJ, Strasser A (2008) The Bcl-2 protein family: opposing activities that mediate cell death. Nat Rev Mol Cell Biol 9:47–59

    Article  CAS  PubMed  Google Scholar 

  47. Mehta SL, Manhas N, Raghubir R (2007) Molecular targets in cerebral ischemia for developing novel therapeutics. Brain Res Rev 54:34–66

    Article  CAS  PubMed  Google Scholar 

  48. Fuenzalida K, Quintanilla R, Ramos P, Piderit D, Fuentealba RA, Martinez G, Inestrosa NC, Bronfman M (2007) Peroxisome proliferator-activated receptor gamma up-regulates the Bcl-2 anti-apoptotic protein in neurons and induces mitochondrial stabilization and protection against oxidative stress and apoptosis. J Biol Chem 282:37006–37015

    Article  CAS  PubMed  Google Scholar 

  49. Lin H, Lin TN, Cheung WM, Nian GM, Tseng PH, Chen SF, Chen JJ, Shyue SK, Liou JY, Wu CW, Wu KK (2002) Cyclooxygenase-1 and bicistronic cyclooxygenase-1/prostacyclin synthase gene transfer protect against ischemic cerebral infarction. Circulation 105:1962–1969

    Article  CAS  PubMed  Google Scholar 

  50. Wang YL, Frauwirth KA, Rangwala SM, Lazar MA, Thompson CB (2002) Thiazolidinedione activation of peroxisome proliferator-activated receptor gamma can enhance mitochondrial potential and promote cell survival. J Biol Chem 277:31781–31788

    Article  CAS  PubMed  Google Scholar 

  51. Lim S, Jin CJ, Kim M, Chung SS, Park HS, Lee IK, Lee CT, Cho YM, Lee HK, Park KS (2006) PPARgamma gene transfer sustains apoptosis, inhibits vascular smooth muscle cell proliferation, and reduces neointima formation after balloon injury in rats. Arterioscler Thromb Vasc Biol 26:808–813

    Article  CAS  PubMed  Google Scholar 

  52. Pérez-Ortiz JM, Tranque P, Vaquero CF, Domingo B, Molina F, Calvo S, Jordán J, Ceña V, Llopis J (2004) Glitazones differentially regulate primary astrocyte and glioma cell survival. Involvement of reactive oxygen species and peroxisome proliferator-activated receptor-gamma. J Biol Chem 279:8976–8985

    Article  PubMed  Google Scholar 

  53. Shiau CW, Yang CC, Kulp SK, Chen KF, Chen CS, Huang JW, Chen CS (2005) Thiazolidenediones mediate apoptosis in prostate cancer cells in part through inhibition of Bcl-xL/Bcl-2 functions independently of PPARgamma. Cancer Res 65:1561–1569

    Article  CAS  PubMed  Google Scholar 

  54. Calabrese EJ, Baldwin LA (2001) U-shaped dose-responses in biology, toxicology, and public health. Annu Rev Public Health 22:15–33

    Article  CAS  PubMed  Google Scholar 

  55. Calabrese EJ (2008) Drug therapies for stroke and traumatic brain injury often display U-shaped dose responses: occurrence, mechanisms, and clinical implications. Crit Rev Toxicol 38:557–577

    Article  CAS  PubMed  Google Scholar 

  56. Doonan F, Wallace DM, O'Driscoll C, Cotter TG (2009) Rosiglitazone acts as a neuroprotectant in retinal cells via up-regulation of sestrin-1 and SOD-2. J Neurochem 109:631–643

    Article  CAS  PubMed  Google Scholar 

  57. Girnun GD, Domann FE, Moore SA, Robbins ME (2002) Identification of a functional peroxisome proliferator-activated receptor response element in the rat catalase promoter. Mol Endocrinol 16:2793–2801

    Article  CAS  PubMed  Google Scholar 

  58. Hwang J, Kleinhenz DJ, Rupnow HL, Campbell AG, Thulé PM, Sutliff RL, Hart CM (2007) The PPARgamma ligand, rosiglitazone, reduces vascular oxidative stress and NADPH oxidase expression in diabetic mice. Vascul Pharmacol 46:456–462

    Article  CAS  PubMed  Google Scholar 

  59. Zhao X, Zhang Y, Strong R, Grotta JC, Aronowski J (2006) 15d-Prostaglandin J2 activates peroxisome proliferator-activated receptor-gamma, promotes expression of catalase, and reduces inflammation, behavioral dysfunction, and neuronal loss after intracerebral hemorrhage in rats. J Cereb Blood Flow Metab 26:811–820

    Article  CAS  PubMed  Google Scholar 

  60. Datta SR, Dudek H, Tao X, Masters S, Fu H, Gotoh Y, Greenberg ME (1997) Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell 91:231–241

    Article  CAS  PubMed  Google Scholar 

  61. Lin CY, Gurlo T, Haataja L, Hsueh WA, Butler PC (2005) Activation of peroxisome proliferator-activated receptor-gamma by rosiglitazone protects human islet cells against human islet amyloid polypeptide toxicity by a phosphatidylinositol 3′-kinase-dependent pathway. J Clin Endocrinol Metab 90:6678–6686

    Article  CAS  PubMed  Google Scholar 

  62. Zha J, Harada H, Yang E, Jockel J, Korsmeyer SJ (1996) Serine phosphorylation of death agonist BAD in response to survival factor results in binding to 14-3-3 not BCL-XL. Cell 87:619–628

    Article  CAS  PubMed  Google Scholar 

  63. Liou JY, Lee S, Ghelani D, Matijevic-Aleksic N, Wu KK (2006) Protection of endothelial survival by peroxisome proliferator-activated receptor-δ mediated 14-3-3ε upregulation. Arterioscler Thromb Vasc Biol 26:1481–1487

    Article  CAS  PubMed  Google Scholar 

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Acknowledgment

This work was supported by grants from National Science Council and Academia Sinica in Taiwan. We would like to thank Dr. Grace Sun of UM-Columbia for her critical reading of the manuscript.

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  1. Neuroscience Division, Institute of Biomedical Sciences, Academia Sinica, Rm 404, Taipei, Taiwan, Republic of China

    Wen-Hsuan Fong, Hsin-Da Tsai, Yu-Chang Chen, Jui-Sheng Wu & Teng-Nan Lin

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Fong, WH., Tsai, HD., Chen, YC. et al. Anti-apoptotic Actions of PPAR-γ Against Ischemic Stroke. Mol Neurobiol 41, 180–186 (2010). https://doi.org/10.1007/s12035-010-8103-y

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