Abstract
         
         Hyperthyroid hearts are shown to display a phenotype of cardioprotection against ischemic
            stress, but the underlying signaling mechanisms remain largely unknown. The present
            study investigated the possible relation of HSP70 to the thyroid hormone induced cardioprotection.
            HSP70 is a redox-regulated molecular chaperone, and enhances cell survival under stress.
            Thyroxin (25 µg/100 g body weight) was administered to Wistar male rats for four days
            (THYR-4d) and two weeks (THYR-14d), respectively, while untreated animals served as
            controls (CON-4d, CON-14d). Isolated hearts from control and thyroxin treated rats
            were subjected to 20 min zero-flow ischemia followed by 45 min of reperfusion (I/R).
            The amount of HSP70 in the myocardium for THYR-14d was 1.85 times the levels of CON-14d
            (p < 0.05). The levels of HSP70 expression were no different between THYR-4d and CON-4d,
            p > 0.05. This was only accompanied by an increase in MDA levels (used as an index
            of oxidative stress) in THYR-14d compared to untreated hearts. These changes corresponded
            to a differential response of the heart to I/R; post-ischemic recovery of function
            was significantly increased in THYR-14d compared to CON-14d, and was no different
            between the THYR-4d and CON-4d hearts. In conclusion, long-term thyroxin administration
            results in increased tolerance of the myocardium to I/R and enhances the expression
            of HSP70 which may, at least in part, account for this response.
         
         
         
            
Key words
         
         
            Thyroid hormone - heat shock proteins - heat stress - oxidative stress - ischemia
               reperfusion
          
      
    
   
      
         References
         
         
            - 1 
               Kahaly G J, Dillman W H. 
               Thyroid hormone action in the heart. 
               Endocrine reviews. 
               2005; 
               26 
               704-728 
               
 
            - 2 
               Pantos C, Malliopoulou V, Varonos D, Cokkinos D V. 
               Thyroid hormone and phenotypes of cardioprotection. 
               Basic Res Cardiol. 
               2004; 
               99 
               101-120 
               
 
            - 3 
               Buser P T, Wikman-Coffelt J, Wu S T, Derugin N, Parmley W W, Higgins C B. 
               Postischemic recovery of mechanical performance and energy metabolism in the presence
               of left ventricular hypertrophy. A 31P-NMR study. 
               Circ Res. 
               1990; 
               66(3) 
               735-746 
               
 
            - 4 
               Pantos C, Malliopoulou V, Mourouzis I, Karamanoli E, Paizis I, Steimberg N, Varonos D,
               Cokkinos D V. 
               Long-term Thyroxine Administration Protects the Heart in a Similar Pattern as Ischemic
               Preconditioning. 
               Thyroid. 
               2002; 
               12 
               325-329. Rapid communication  
               
 
            - 5 
               Pantos C, Malliopoulou V, Paizis I, Moraitis P, Mourouzis I, Tzeis S, Karamanoli E,
               Cokkinos D D, Carageorgiou H, Varonos D, Cokkinos D V. 
               Thyroid hormone and cardioprotection; study of p38 MAPK and JNKs during ischemia and
               at reperfusion in isolated rat heart. 
               Molecular and Cellular Biochemistry. 
               2003; 
               242 
               173-180 
               
 
            - 6 
               Pantos C, Malliopoulou V, Mourouzis I, Karamanoli E, Moraitis P, Tzeis S, Paizis I,
               Carageorgiou H, Varonos D, Cokkinos D V. 
               Thyroxine pretreatment increases basal myocardial HSP27 expression and accelerates
               translocation and phosphorylation of this protein upon ischemia. 
               Eur J Pharmacol. 
               2003; 
               478 
               53-60 
               
 
            - 7 
               Kuzman J A, Gerdes A M, Kobayashi S, Liang Q. 
               Thyroid hormone activates Akt and prevents serum starvation-induced cell death in
               neonatal rat cardiomyocytes. 
               J Mol Cell Cardiol. 
               2005; 
               39(5) 
               841-844 
               
 
            - 8 
               Zinman T, Shneyvays V, Tribulova N, Manoach M, Shainberg A. 
               Acute, nongenomic effect of thyroid hormones in preventing calcium overload in newborn
               rat cardiocytes. 
               J Cell Physiol. 
               2005; 
               (in press) 
               
 
            - 9 
               Ojamaa K, Kenessey A, Shenoy R, Klein I. 
               Thyroid hormone metabolism and cardiac gene expression after acute myocardial infarction
               in the rat. 
               Am J Physiol. 
               2000; 
               279(6) 
               E1319-1324 
               
 
            - 10 
               Dimitriadis G, Maratou E, Alevizaki M, Boutati E, Psara K, Papasteriades C, Raptis S A.
               
               Thyroid hormone excess increases basal and insulin-stimulated recruitment of GLUT3
               glucose transporters on cell surface. 
               Horm Metab Res.. 
               2005; 
               37(1) 
               15-20 
               
 
            - 11 
               Gray C C, Amrani M, Yacoub M H. 
               Heat stress proteins and myocardial protection: experimental model or potential clinical
               tool?. 
               The International J Biochem Cell Biol. 
               1999; 
               31 
               559-573 
               
 
            - 12 
               Papp E, Nardai G, Soti C, Csermely P. 
               Molecular chaperones, stress proteins and redox homeostasis. 
               Biofactors. 
               2003; 
               17 
               249-257 
               
 
            - 13 
               Kukreja R C, Kontos M C, Loesser K E, Batra S K, Qian Y Z, Gbur C J jr, Naseem S A,
               Jesse R L, Hess M L. 
               Oxidant stress increases heat shock protein 70 mRNA in isolated perfused rat heart. 
               Am J Physiol. 
               1994; 
               267(6 Pt 2) 
               H2213-2219 
               
 
            - 14 
               Marber M S, Walker J M, Latchman D S, Yellon D M. 
               Myocardial protection following whole body heat stress in the rabbit is dependent
               on metabolic substrate and is related to the amount of the inducible 70 kb Dalton
               heat shock protein. 
               J Clin Invest. 
               1994; 
               93 
               1087-1094 
               
 
            - 15 
               Mestril R, Chi S H, Sayen R, O R eilly, Dillmann W H. 
               Expression of inducible stress protein 70 in heart myogenic cells confers protection
               against simulated iscahemia-induced injury. 
               J Clin Invest. 
               1994; 
               93 
               759-767 
               
 
            - 16 
               Chen Y, Arrigo A-P, Currie R W. 
               Heat shock treatment suppresses angiotensin II-induced activation of NF-kB pathway
               and heart inflammation: a role for Ikk depletion by heat shock?. 
               Am J Physiol. 
               2004; 
               287 
               H1104-H1114 
               
 
            - 17 
               Pantos C, Mourouzis I, Saranteas T, Paizis I, Xinaris C, Malliopoulou V, Cokkinos D V.
               
               Thyroid hormone receptors alpha1 and beta1 are downregulated in the post-infarcted
               rat heart: consequences on the response to ischemia-reperfusion. 
               Basic Res Cardiol.. 
               2005; 
               100(5) 
               422-432 
               
 
            - 18 
               Morkin E, Ladenson P, Goldman S, Adamson C. 
               Thyroid hormone analogs for treatment of hypercholesterolemia and heart failure: past,
               present and future prospects. 
               J Mol Cell Cardiol. 
               2004; 
               37 
               1137-1146 
               
 
            - 19 
               Pantos C, Paizis I, Mourouzis I, Moraitis P, Tzeis S, Karamanoli E, Mourouzis C, Karageorgiou H,
               Cokkinos D V. 
               Blockade of angiotensin II type 1 receptor diminishes cardiac hypertrophy, but does
               not abolish thyroxin-induced preconditioning. 
               Horm Metab Res. 
               2005; 
               37(8) 
               500-504 
               
 
            - 20 
               Arrigo A P. 
               In search of the molecular mechanism by which small stress proteins counteract apoptosis
               during cellular differentiation. 
               J Cell Biochem. 
               2005; 
               94(2) 
               241-246. Review 
               
 
            - 21 
               Manalo D J, Lin Z, Liu A Y. 
               Redox-dependent regulation of the conformation and function of human heat shock factor
               1. 
               Biochemistry. 
               2002; 
               41(8) 
               2580-2588 
               
 
            - 22 
               Barrett M J, Alones V, Wang K X, Phan L, Swerdlow R H. 
               Mitochondria-derived oxidative stress induces a heat shock protein response. 
               J Neurosci Res. 
               2004; 
               78(3) 
               420-429 
               
 
            - 23 
               McDuffee A T, Senisterra G, Huntley S, Lepock J R, Sekhar K R, Meredith M J, Borrelli M J,
               Morrow J D, Freeman M L. 
               Proteins containing disulfide bonds generated by oxidative stress can act as signals
               for the induction of the heat shock response. 
               J Cell Physiol. 
               1997; 
               171 
               143-151 
               
 
            - 24 
               Jacquier-Sarlin M R, Polla B S. 
               Dual regulation of heat-shock transcription factor (HSF) activation and DNA-binding
               activity by H2O2: role of thioredoxin. 
               Biochem J. 
               1996; 
               318 ( Pt 1) 
               187-193 
               
 
            - 25 
               Venditti P, De Rosa R, Di Meo S. 
               Effect of thyroid state on susceptibility to oxidants and swelling of mitochondria
               from rat tissues. 
               Free Radic Biol Med. 
               2003; 
               35(5) 
               485-494 
               
 
            - 26 
               Yehuda-Shnaidman E, Kalderon B, Bar-Tana J. 
               Modulation of mitochondrial transition pore components by thyroid hormone. 
               Endocrinology. 
               2005; 
               146(5) 
               2462-2472 
               
 
            - 27 
               Duntas L H. 
               Oxidants, antioxidants in physical exercise and relation to thyroid function. 
               Horm Metab Res.. 
               2005; 
               37(9) 
               572-576. Review  
               
 
            - 28 
               Pantos C, Malliopoulou V, Mourouzis I, Moraitis P, Tzeis S, Thempeyioti A, Paizis I,
               Cokkinos A D, Carageorgiou H, Varonos D, Cokkinos D V. 
               Involvement of p38 MAPK and JNK in the heat stress induced cardioprotection. 
               Basic Res Cardiol. 
               2003; 
               98 
               158-164 
               
 
            - 29 
               Latchman D S. 
               Heat shock proteins and cardiac protection. 
               Cardiovasc Res. 
               2001; 
               51 
               637-646 
               
 
            - 30 
               Gabai V L, Yaglom J A. 
               Hsp 72 mediated suppression of c -Jun N terminal kinase is implicated in the development
               of tolerance to caspace-independent cell death. 
               Mol Cell Biol. 
               2000; 
               20 
               6826-6836 
               
 
            - 31 
               Gabai V L, Meriin A B, Yaglom J A, Wei J Y, Mosser D D, Sherman M Y. 
               Suppression of stress kinase JNK is involved in hsp72-mediated protection of myogenic
               cells from transient energy deprivation: HSP70 alleviates the stress induced inhibition
               of JNK dephosphorylation. 
               J Biol Chem. 
               2000; 
               275(48) 
               38 088-38 094 
               
 
            - 32 
               Baxter J D, Webb P, Grover G, Scanlan T S. 
               Selective action of thyroid hormone signaling pathways by GC-1: a new approach to
               controlling cholesterol and body weight. 
               Trends Endocrinol Metab. 
               2004; 
               15(4) 
               154-157 
               
 
            - 33 
               Pantos C, Mourouzis I, Malliopoulou V, Paizis I, Tzeis S, Moraitis P, Sfakianoudis K,
               Varonos D D, Cokkinos D V. 
               Dronedarone administration prevents body weight gain and increases tolerance of the
               heart to ischemic stress: a possible involvement of thyroid hormone receptor alpha1. 
               Thyroid. 
               2005; 
               15(1) 
               16-23 
               
 
         
         
         Constantinos Pantos
            Department of Pharmacology
            
            University of Athens · 75 Mikras Asias Ave. · 11527 Goudi · Athens · Greece
            
            Fax: +30 (21) 07 70 51 85
            
            Email: cpantos@cc.uoa.gr