GTMB 7 - Gene Therapy & Molecular Biology

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Latchman: Protective effect of heat shock proteinsherbimycin as a tyrosine kinase inhibitor is likely to havesignificant effects on cellular growth and division.Similarly, none of these compounds has as yet beentested to see whether, unlike stressful procedures, they caninduce hsps in cells from aged animals or humans. This isof particular importance in the case of bimoclomol, whichappears to be non-toxic but which has recently been shownto act by targeting HSF-1 (Hargitai et al, 2003).Nonetheless, the identification of compounds able toinduce the hsps without inducing a full stress response ishighly promising and suggests that pharmacologicalinduction of hsp synthesis may be a viable therapy in thenot too distant future.B. Gene therapy proceduresClearly any potential side-effects of compoundswhich can induce hsps could be avoided if hsp genes couldbe efficiently delivered to the heart or the brain in vivo.Since transgenic procedures are evidently not applicable inhumans, this will require the development of proceduresable to safely and efficiently deliver hsp genes to the heartof individual patients.Encouragingly, it has been shown that the hsp70gene within a plasmid vector can be delivered to the heartvia intra-coronary infusion of liposome particlescontaining it. The elevated expression of hsp70 producedby this means confers effective protection againstsubsequent ischaemia-reperfusion (Suzuki et al, 1997) orendotoxin-induced cardiac damage (Meldrum et al, 1999).These experiments are of considerable importance sincethey demonstrate that hsp70 over-expression can have aprotective effect not only in a transgenic animal but also ina situation directly relevant to the human case where hspover-expression is produced in the adult heart byintroduction of the gene construct.As well as these experiments in the heart, similarsuccessful delivery of hsps to the intact nervous systemhas been reported. Indeed, Benn et al, (2002) have used anadenovirus vector over-expressing hsp27 to rescue sciaticmotor neurones in the intact animal from the cell deathwhich normally follows nerve transection. Similarly, usingour HSV vector over-expressing hsp27, we havedemonstrated a protective effect of inoculation of the brainwith this virus against kainate-induced cell death (Kalwyet al, 2003), reproducing the protective effect of hsp27 intransgenic animals.If these reports of the successful in vivo delivery andprotective effect of hsps can be followed up using viral ornon-viral vectors which combine sufficient efficiency withthe safety required for human use, then it may be possibleto contemplate gene therapy-type procedures with hsps.The results presented in this review however,indicate that it is necessary to develop such proceduresalways bearing in mind the fact that the protective effectof hsps can differ in different cell types and in differentsituations. Any attempt to use the hsps therapeuticallytherefore, has to be preceded by careful studies identifyingthe optimal hsp or combination of hsps to produce aprotective effect in a particular situation. This isillustrated, for example, by our experiments using aconstitutively active form of the heat shock transcriptionfactor, HSF1, which should induce a range of hsps. Whenan HSV vector expressing this HSF1 mutant was used toinfect neuronal cells, it induced accumulation of hsp70 butnot of hsp27 and therefore, did not result in protectionagainst apoptosis, although it was able to produceprotection against heat shock and ischaemia (Wagstaff etal, 1998).Nonetheless, the clear protective effect of the hsps inthe cardiac and nervous systems offers hope fortherapeutic procedures which enhance endogenous orexogenous hsp expression.ReferencesAkbar MT, Lundberg AM. C Liu K, Vidyadaran S, Wells, K. E,Dolatshad H, Wynn S, Wells DJ, Latchman DS and deBelleroche J, (2003) The neuroprotective effects of heatshock protein 27 overexpression in transgenic animalsagainst Kainate-induced seizures and hippocampal cell death.J Biol Chem 278, 19956-19965.Amin V, Cumming DVE and Latchman DS (1996) Overexpressionof heat shock protein 70 protects neuronal cellsagainst both thermal and ischaemic stress but with differentefficiencies. Neurosci Lett 206, 45-48.Amin V, Cumming DVE, Coffin RS and Latchman DS (1995)The degree of protection provided to neuronal cells by a preconditioningstress correlates with the amount of heat shockprotein it induces and not with the similarity of thesubsequent stress. Neurosci Lett Neurosci Lett 200, 85-88.Amrani M, Latif N, Morrison K, Gray C, Jayakumar J, Corbett J,Goodwin AT, Dunn MJ and Yacoub MH, (1998) Relativeinduction of heat shock protein in coronary endothelial cellsand cardiomyocytes, implications for myocardial protection.J Thorac Cardiovasc Surg 115, 200-209.Barbe MF, Tytell M, Gower DJ and Welch, WJ, (1988)Hyperthermia protects against light damage in the rat retina.Science 241, 1817-1820Benn SC Perrelet, D, Kato AC Scholz J, Decosterd I, MannionRJ, Bakowska JC and Woolf C. J, (2002) Hsp27Upregulation and phosphorylation is required for injuredsensory and motor neuron survival. Neuron 36, 45-56Brar, BS, Stephanou A, Wagstaff MJD, Coffin RS, Marber MS,Engelman, G and Latchman DS (1999) Heat shock proteinsdelivered with a virus vector can protect cardiac cells againstapoptosis as well as against thermal or ischaemic stress. JMol Cell Cardiol 31, 135-146.Chopp, M Chen H, Ho, K-L, Dereski MO, Brown, E, Hetzel, F.W and Welch, K. M, (1989) Transient hyperthermia protectsagainst subsequent forebrain ischemic cell damage in the rat.Neurology 39, 1396-1398.Collins, P. and Hightower LE, (1982) Newcastle disease virusstimulates the cellular accumulation of stress (heat shock)mRNAs and proteins. J Virol 44, 703-707.Conde AG, Lau SS, Dillmann, H and Mestril R, (1997) Inductionof heat shock proteins by tyrosine kinase inhibitors in ratcardiomyocytes and myogenic cells confers protectionagainst simulated ischemia. J Mol Cell Cardiol 26, 1927-1938.Cumming DVE, Heads RJ Coffin RS, Yellon DM and LatchmanDS (1996a) Pharmacological preconditioning of primary ratcardiac myocytes by FK506. Basic Res Cardiol 91, 367-373.Cumming DVE, Heads RJ, Watson A, Latchman DS and YellonDM, (1996b) Differential protection of primary ratcardiocytes by transfection of specific heat stress proteins. JMol Cell Cardiol 28, 2343-2349.252
Gene Therapy and Molecular Biology Vol 7, page 253Currie RW, Karmazyn, M and KloC M, (1988) Heat-shockresponse is associated with enhanced postischemicventricular recovery. Circ Res 63, 543-549.Donnelly, T. J, Sievers RE, Vissern, F. L. J, Welch, W. J andWolfe C. L, (1992) Heat shock protein induction in rathearts. A role for improved myocardial salvage afterischemia and reperfusion? Circulation 85, 769-778.Ellis RJ (1990) Molecular Chaperones. Semin Cell Biol 1, 1-72.Fenton RA, Dickson EW, Meyer TE and Dobson JG, (2000)Ageing reduces the cardioprotective effect of ischemicpreconditioning in the rat heart. J Mol Cell Cardiol 32,1371-1375.Fink SL Chang LK, Ho DY and Sapolsky RM, (1997) Defectiveherpes simplex virus vectors expressing the rat brain stressinducibleheat shock protein 72 protect cultured neuronsfrom severe heat shock. J Neurochem 68, 961-969.Gowda A, Yang C Asimakis GK, Rastegar, S and Motamedi M,(1998a) Heat shock improves recovery and providesprotection against global ischemia after hypothermic storage.Ann Thorac Surg 66, 1991-1997.Gowda A, Yang C-j Asimakis GK, Ruef J, Rastegar S, RungeMS and Motamedi M, (1998b) Cardioprotection by localheating, improved myocardial salvage after ischemia andreperfusion. Ann Thorac Surg 65, 1241-1247.Hargitai J, Lewis H, Boros I, Racz T, Fiser A, Kurucz I,Benjamin I, Vigh L, Penzes, Z Csermely, P and LatchmanDS (2003) Bimoclomol a heat shock protein co-inducer Actsby the prolonged activation of heat shock factor-1. BiochemBiophys Res Commun 307, 689-695.Heads RJ, Latchman DS and Yellon DM, (1994) Stable highlevel expression of a transfected human HSP70 gene protectsa heart-derived muscle cell line against thermal stress. J MolCell Cardiol 26, 695-699.Heads RJ, Yellon DM and Latchman DS (1995) Differentialcytoprotection against heat stress or hypoxia followingexpression of specific stress protein genes in myogenic cells.J Mol Cell Cardiol 27, 1669-1678.Hutter MM, Sievers RE, Barbosa V and Wolfe C. Heat shockprotein induction in rat hearts. A direct correlation betweenthe amount of heat shock protein induced and the degree ofmyocardial protection. Circulation 1994, 89, 353-360.Kalwy S, Akbar MT Coffin S, de Belleroche J and Latchman DS(2003) Heat shock protein 27 delivered via a herpes simplexvirus vector can protect neurones of the hippocampus againstkainic acid-induced cell loss. Mol Brain Res 111, 91-103.Karmazyn M, Mailer, K and Currie RW, (1990) Acquisition anddecay of heat-shock enhanced postischemic ventricularrecovery. Am J Physiol 259, H421-H431.Kh and ijan, E. W. and Turler H, (1983) Simian virus 40 andpolyoma virus induce synthesis of heat shock proteins inpermissive cells. Mol Cell Biol 3, 1-8.Kitagawa K, Matsumoto M, Tagaya M, Hata R, Keda H NinobeM, Handa N, Fukunaga R, Kimura K, Mikshiba, K andKamada T, (1990) 'Ischaemic tolerance' phenomenon foundin the brain. Brain Res 528, 21-24.Kure S, Tuminaga T, Yoshimoto T, Tada, K and Narisawa K,(1991) Glutamate triggers internucleosomal DNA cleavagein neuronal cells. Biochem Biophys Res Commun 179, 39-45.La Thangue NB. and Latchman DS (1988) A cellular proteinrelated to heat shock protein 90 accumulates during herpessimplex virus infection and is over-expressed in transformedcells. Exp Cell Res 178, 169-179.Laios E, Rebeyka, IM and Prody CA, (1997) Characterization ofcold-induced heat shock protein expression in neonatal ratcardiomyocytes. Mol Cell Biochem 173, 153-159.Latchman DS (1998) Heat shock proteins, protective effect andpotential therapeutic use. Int J Mol Med 2, 375-381.Lau S, Patnaik N, Sayen MR and Mestril R, (1997) Simultaneousoverexpression of two stress proteins in rat cardiomyocytesand myogenic cells confers protection against ischemia.Circulation 96, 2287-2294.Lee JE, Yenari MA, Sun GH, Xu L, Emond MR Cheng, D,Steinberg GK and Giffard RG, (2001) Differentialneuroprotection from human heat shock protein 70 overexpressionin in vitro and in vivo models of ischaemia andischaemia-like conditions. Exp Neurol 170, 129-139.Leger JP, Smith, F. M and Currie RW, (2000) Confocalmicroscopic localisation of constitutive and heat shockinducedproteins HSP70 and HSP27 in the rat heart.Circulation 102, 1703-1709.Li GC. and Laszlo A, (1985) Amino acid analogues whileinducing heat shock protein sensitive cells to thermaldamage. J Cell Phys 122, 91-97.Lindquist S and Craig EA, (1988) The heat shock proteins. AnnuRev Genet 22, 631-677.Locke M and Tanguay RM, (1996) Diminished heat shockresponse in the aged myocardium. Cell Stress Chaperones1, 251-260.Lowenstein DH Chan, P. H and Miles MF, (1991) The stressprotein response in cultured neurons Characterization andevidence for a protective role in excitotoxicity. Neuron 7,1053-1060.Mailhos C, Howard MK and Latchman DS (1994) Heat shockproteins hsp90 and hsp70 protect neuronal cells from thermalstress but not from programmed cell death. J Neurochem 63,1787-1795.Mailhos C, Howard MK and Latchman DS (1993) Heat shockprotects neuronal cells from programmed cell death byapoptosis. Neuroscience 55, 621-627.Marber MS, Latchman DS, Walker JM and Yellon DM, (1993)Cardiac stress protein elevation 24 hours after briefischaemia or heat stress is associated with resistance tomyocardial infarction. Circulation Res 88, 1264-1272.Marber MS, Mestril R Chi SH and Sayen MR, (1995)Overexpression of the rat inducible 70kDa heat shock proteinin a transgenic mouse increases the resistance of the heart toischemic injury. J Clin Invest 95, 1446-1456.Marber MS, Walker JM, Latchman DS and Yellon DM, (1994)Myocardial protection following whole body heat stress inthe rabbit is dependent on metabolic substrate and is relatedto the amount of the inducible 70kb Dalton heat shockprotein. J Clin Invest 93, 1087-1094.Martin JL, Hickey, E, Weber LA, Dillmann WH and Mestril R,(1999) Influence of phosphorylation and oligomerization onthe protective role of the small heat shock protein 27 in ratadult cardiomyocytes. Gene Expr 7, 349-355.Martin JL, Mestril R, Hilal-Dandan R, Brunton LL and DilmannWH, (1997) Small heat shock proteins and protection againstischaemic injury in cardiac myocytes. Circulation 96, 4343-4348.Meldrum DR, Meng X, Shames BD, Pomerantz B, DonnahooKK, Banerjee A and Harken AH, (1999) Liposomal deliveryof heat-shock protein 72 into the heart prevents endotoxininducedmyocardial contractile dysfunction. Surgery 126,135-141.Meng, X, Brown JM Ao L, Banerjee A and Harken AH, (1996)Norepinephrine induces cardiac heat shock protein 70 anddelayed cardioprotection in the rat through α1 adrenoceptors.Cardiovasc Res, 32, 374-383.Mestril R Chi SH, Sayen R, O'Reilly, K and Dilmann WH,(1994) Expression of inducible stress protein 70 in heartmyogenic cells confers protection against simulatedischaemia-induced injury. J Clin Invest 93, 759-767.Morimoto RI, (1998) Regulation of the heat shock transcriptionalresponse Cross talk between a family of heat shock factors,253
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GTMB 7 - Gene Therapy & Molecular Biology

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