Thyroid hormone and cardiac regeneration: from Prometheus myth to reality

Transcription

1 Thyroid hormone and cardiac regeneration: from Prometheus myth to reality C. Pantos Unit of Cardiac Regeneration and Cardiopreservation - University of Athens

2 Regeneration : an old concept

3 Amphibian metamorphosis : TH dependent nature s model of regeneration Slack JM, 2007

4 Early developmental stages : A window for regeneration Mourouzis et al, J Thyroid Res, 2011

5 Thyroid hormone : the same player in development and stress response TRα TRα Endocr. Rev. 2010

6 T3 TRα1 Development T3 TRα1 Stress T3 TRα1 Pantos et al, Heart Fail Rev, 2010

7 T3 and cell differentiation Linnane A et al, Ann N Y Ac Sci,2006

8 T3 induced tissue formation Pantos s laboratory data Chattergoon et al, FASEB J, 2011

9 Post-ischaemic remodeling and TH signaling: potential mechanisms and physiological consequences A. Normal Heart B. Untreated neonatal cardiomyocytes Compensated phase ERK( ), mtor ( ) TRα1 ( ) Post-infarcted heart scar TRα1 Phenylephrine treated neonatal cardiomyocytes ERK pathway PE mtor pathway α1-adrenergic receptor Pathological Growth Severe hypertrophy with α-mhc ( ) β-mhc( ) EF% ( ) LOW T3 TRα1 PE Decompensated phase ERK( ), mtor ( ) TRα1 ( ) scar TRα1 ERK pathway mtor pathway α1-adrenergic receptor Hypothyroid phenotype No further increase in hypertrophy with α- MHC ( ) β- MHC( ) EF% ( ) TRα1 Pantos et al, Heart Fail Rev, 2010

10 PE modulates TRα1 cytoplasmicnuclear shuttling CONT CLEN PE Pantos et al, J Physiol Pharmacol, 2008

11 TR α1: a molecular switch for the conversion of pathological to physiological growth Pantos et al, J Physiol Pharmacol, 2008

12 TH can rebuild the injured myocardium T3 TREATMENT Pantos et al, Heart Fail Rev, 2010

13 Submitted TH effect on postischaemic cardiac remodeling is a dose dependent process

14 Submitted TH effect on postischaemic cardiac remodeling is a dose dependent process

15 Submitted Akt : a molecular threshold for the TH beneficial/detrimental effect

16 T3 is a critical determinant of recovery of cardiac function after AMI Pantos et al, Eur J Endocrinol, 2007 Pantos et al, Eur J Endocrinol, 2011

17 IERVASI G et al Circulation 2010 A journey of one thousand miles begins with a single step The THiRST STUDY Acute and long term effects of Thyroid Hormone Replacement therapy in patients with ST-Elevation Myocardial Infarction (STEMI) and borderline/reduced triiodothyronine levels Eudract n

18 The analogy of heart failure and cancer

19 TR expression is altered in high grade glioma tumors Liappas A et al, J Thyroid Res, 2011

20 T3 re-differentiates cancer cells Liappas A et al, J Thyr Res, 2011

21 T3 suppresses cell proliferation Liappas A et al, J Thyr Res, 2011

22 The thyroid hormone paradox : TH protects against ischaemia Cell differentiation and response to stress share common signaling pathways Pantos et al, Heart Fail Rev, 2010

23 TRα1 : relevance to acute TH reparative effect DV Cokkinos, C Pantos, G Heusch, H Taegtmeyer (Eds), Myocardial ischemia : From mechanisms to therapeutic potentials, Springer, 2006

24 Studies in Isolated rat heart model of ischaemia /reperfusion Apoptosis/necrosis Function Increased apoptosis (red) Decreased apoptosis

25 T3 limits reperfusion injury by suppressing the activation of the pro-apoptotic p38mapk B. Non-treated T3-treated Sub-epicardium A. mid-myocardium T3 (40μg/L) Sub-endocardium 30 min Ischemia 60 min Reperfusio n Pantos et al, Basic Res Cardiol, 2008

26 T3 induced cardioprotection is TRα1 dependent Pantos et al, Mol Cell Biochem, 2011

27 Clinical analogy : T3 in CABG limits peri-operative injury CARDIAC INDEX C. Troponin release Ranasinghe et al, Circulation, 2006

28 Mourouzis et al, J Thyroid Res, 2011 Towards a new paradigm of stress response and tissue repair

29 Conclusions TH : the same player in organ development and response to stress Fetal phenotype is reactivated after stress and seems to be a window for regeneration- TH is involved in the reactivation of fetal phenotype after myocardial ischaemia TH can regenerate the ischaemic myocardium by reactivating developmental gene programming TH is a determinant of functional recovery after AMI in patients Clinical trials are underway to test the regenerative/reparative effect of TH in pts Thyroid analogs ( TRα1 agonists) may constitute new pharmacologic agents for regenerative treatments

30 C Pantos I Mourouzis V Malliopoulou C Xinaris E Karamanoli I Paizis S Tzeis P Moraitis D Kokkinos K Markakis A Dimopoulos T Saranteas K Mourouzis N Tsagoulis N Thempeyioti K Sfakianoudis A Kokkinos F Perimenis D Spanou G Galanopoulos DV Cokkinos

31 Thank you for your Attention

32 TH in GABG : a meta analysis Kaptein et al, J Clin Endocrin Metab, 2010

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