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University of Athens C Pantos/ DV Cokkinos TH non genomic action - - PowerPoint PPT Presentation
University of Athens C Pantos/ DV Cokkinos TH non genomic action - - PowerPoint PPT Presentation
University of Athens C Pantos/ DV Cokkinos TH non genomic action TH can modulate myocardial injury via non genomic action Studies in Isolated rat heart preparations experimental model of ischaemia-reperfusion DV Cokkinos, C Pantos
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Studies in Isolated rat heart preparations – experimental model of ischaemia-reperfusion DV Cokkinos, C Pantos , G Heusch, H Taegtmeyer (Eds), Myocardial ischemia : From mechanisms to therapeutic potentials, Springer , 2006
TH can modulate myocardial injury via non genomic action
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T3R
LVDP (mmHg)
30 min Ischemia T3 (40μg/L) 60 min Reperfusion
Pantos et al 2009, Basic Res Cardiol , 2009
TH can modulate myocardial injury via non genomic action
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TH limits apoptosis
Pantos et al 2009, Basic Res Cardiol , 2009
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Translational implications of non genomic action of TH
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TH improves cardiac haemodynamics
Ranasinghe et al, Circulation, 2006
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TH limits the extent of myocardial injury
Ranasinghe et al, Circulation, 2006
Troponin release
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Pantos C ……. Cokkinos DV, Basic Res Cardiol, 2003
TH- genomic action
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TRα1
Heart rate Heart rate Contractility Kv Κ+ channels α‐MHC/ β‐MHC HCN Κ+ channels
TH genomic action – TH nuclear receptors (TRs)
Mol Endocrinol , 2005
TR β angiogenesis
Makino A, Endocrinology, 2009
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Membrane Nucleus
TR receptor TR receptor
TH
Growth Geometry Contractile function Metabolism Ion homeostasis
TH
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TH and bioengineering Nature has already ‘used’ TH for tissue remodeling
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Nucleus PE, α1 adrenergic pro‐growth stimuli ERK P~ TR α1 P~ +T3
- T3
+
- Positively
regulated genes Positively regulated genes
Thyroid hormone is a regulator of stress response
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Nucleus PE, α1 adrenergic pro‐growth stimuli ERK P~ TR α1 P~ +T3
- T3
+
- Positively
regulated genes Positively regulated genes
Thyroid hormone is a regulator of stress response
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α1‐adrenergic receptor PE Akt/mTOR pathway ERK pathway
TRα1 TRα1
PE
TRα1 TRα1
Physiological hypertrophy Pathological hypertrophy
- T3
+ T3 Akt/mTOR pathway ERK pathway Hypothyroid phenotype Nucleus Membrane
Actin β‐MHC
Thyroid hormone is a regulator of stress response
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Viable hypertrophic myocardium Scar tissue
Viable hypertrophic myocardium Scar tissue
Ligation of coronary artery- acute MI in rats Overexpression of beta- myosin
Postischemic LV remodeling : The concept of fetal repogramming Left ventricle (LV) becomes spherical
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TRs and remodeling
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Decompensated phase
TRα1 (↓↓) TRβ1 (↓↓) α‐MHC (↓↓) β‐ MHC(↑↑) EF% (↓↓) WTI (↑) SI (↓↓)
Ao
scar
L S
Ao
S L
Normal Heart Post‐infarcted heart (non‐treated)
Ao
scar
S L
Early phase Compensated phase
Ao
S L
scar
TRα1(↔) TRβ1(↓) α‐MHC (↓) β‐ MHC(↑) EF% (↓) WTI (↑) SI (↓) TRα1 (↑) TRβ1(↓↓) α‐MHC (↓) β‐ MHC(↑) EF% (↓) WTI (↔) SI (↓)
Ao
S L
scar
TRα1 (↑) TRβ1(↔) α‐MHC (↑) β‐MHC(↓) EF% (↑) WTI (↔) SI (↔)
TH treatment
TH SWITCHES PATHOLOGICAL HYPERTROPHY TO PHYSIOLOGICAL HYPERTROPHY THYROID HORMONE
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Membrane Nucleus
TR receptor TR receptor
TH
Growth Geometry Contractile function Metabolism Ion homeostasis
TH TH AND CARDIAC GEOMETRY
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CARDIAC GEOMETRY
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CARDIAC GEOMETRY
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CARDIAC GEOMETRY
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2days Discharge 6 months
- Myocardial enzymes
- SBP, DBP, HR
- Echocardiography
- BNP
- T3, T4, TSH, FT3, FT4
0.8 μg/kg T3 bolus i.v. 0.113 μg/kg/h T3 i.v. infusion for 6h
- Myocardial enzymes
- SBP, DBP, HR
- Echocardiography
- BNP
- T3, T4, TSH, FT3, FT4
- Myocardial enzymes
- SBP, DBP, HR
- Echocardiography
- BNP
- T3, T4, TSH, FT3, FT4
- SBP, DBP, HR
- Echocardiography
- BNP
- T3, T4, TSH, FT3, FT4
- Ergospirometry
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T3 administration in pts with AMI Translational implications of TH actions
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DV Cokkinos
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
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Acti n CO CLE PE
5 d PE
5 days CLEN 60 min CLEN 8 min CLEN
Ph‐ERK Total ERK
Cell models of pathological ( PE) and physiological (Clenbuterol ) growth
Actin β‐MHC
CLEN NO INCREASE IN ERK PE INCREASE IN ERK
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β‐MHC
Physiological hypertrophy Pathological hypertrophy
Actin
Phenylephrine (PE) Thyroid hormone (T3) Cell models of pathological ( PE) and physiological (T3) growth
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