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 , G Heusch, H Taegtmeyer (Eds), Myocardial ischemia : From mechanisms to therapeutic potentials, Springer , 2006

TH can modulate myocardial injury via non genomic action T3R LVDP (mmHg) T3 (40 μ g/L) 30 min Ischemia 60 min Reperfusion Pantos et al 2009, Basic Res Cardiol , 2009

TH limits apoptosis Pantos et al 2009, Basic Res Cardiol , 2009

Translational implications of non genomic action of TH

TH improves cardiac haemodynamics Ranasinghe et al, Circulation, 2006

TH limits the extent of myocardial injury Troponin release Ranasinghe et al, Circulation, 2006

TH- genomic action Pantos C ……. Cokkinos DV, Basic Res Cardiol, 2003

TH genomic action – TH nuclear receptors (TRs) Kv Κ + channels Heart rate HCN Κ + channels Heart rate TR α 1 α‐ MHC/ Contractility β‐ MHC Mol Endocrinol , 2005 TR β angiogenesis Makino A, Endocrinology, 2009

TH Membrane TR TR receptor receptor Nucleus Metabolism Ion homeostasis Geometry Contractile Growth function TH

Nature has already ‘used’ TH for tissue remodeling TH and bioengineering

Thyroid hormone is a regulator of stress response PE, α 1 adrenergic pro ‐ growth stimuli ERK P~ Nucleus +T3 P~ -T3 TR α 1 + - Positively Positively regulated regulated genes genes

Thyroid hormone is a regulator of stress response PE, α 1 adrenergic pro ‐ growth stimuli P~ ERK Nucleus P~ +T3 -T3 TR α 1 + - Positively Positively regulated genes regulated genes

Thyroid hormone is a regulator of stress response PE PE α 1 ‐ adrenergic receptor ERK Akt/mTOR pathway pathway ERK Akt/mTOR Membrane pathway pathway TR α 1 TR α 1 TR α 1 TR α 1 Nucleus - T3 + T3 Pathological Physiological Hypothyroid hypertrophy hypertrophy phenotype Actin β‐ MHC

Postischemic LV remodeling : The concept of fetal repogramming Viable hypertrophic Viable hypertrophic myocardium myocardium Scar tissue Scar tissue Ligation of coronary artery- acute MI in rats Overexpression of beta- myosin Left ventricle (LV) becomes spherical

TRs and remodeling

TH SWITCHES PATHOLOGICAL HYPERTROPHY TO PHYSIOLOGICAL HYPERTROPHY Normal Heart Ao S L THYROID HORMONE Post ‐ infarcted heart (non ‐ treated) scar Early phase Ao TR α 1( ↔ ) TR β 1( ↓ ) S L α‐ MHC ( ↓ ) β‐ MHC( ↑ ) EF% ( ↓ ) WTI ( ↑ ) SI ( ↓ ) scar Compensated phase Ao TR α 1 ( ↑ ) TR β 1( ↓↓ ) S L α‐ MHC ( ↓ ) β‐ MHC( ↑ ) EF% ( ↓ ) TH WTI ( ↔ ) SI ( ↓ ) treatment scar Decompensated phase scar Ao TR α 1 ( ↓↓ ) TR β 1 ( ↓↓ ) TR α 1 ( ↑ ) TR β 1( ↔ ) Ao S S α‐ MHC ( ↓↓ ) β‐ L L α‐ MHC ( ↑ ) β‐ MHC( ↓ ) MHC( ↑↑ ) EF% ( ↑ ) EF% ( ↓↓ ) WTI ( ↔ ) SI ( ↔ ) WTI ( ↑ ) SI ( ↓↓ )

TH AND CARDIAC GEOMETRY TH Membrane TR TR receptor receptor Nucleus Metabolism Ion homeostasis Geometry Contractile Growth function TH

CARDIAC GEOMETRY

CARDIAC GEOMETRY

CARDIAC GEOMETRY

Translational implications of TH actions T3 administration in pts with AMI 0.8 μ g/kg T3 bolus i.v. 0.113 μ g/kg/h T3 i.v. infusion for 6h 0 2days Discharge 6 months // // • Myocardial enzymes •SBP, DBP, HR • Myocardial enzymes • Myocardial enzymes •SBP, DBP, HR •SBP, DBP, HR • Echocardiography •SBP, DBP, HR • Echocardiography • Echocardiography • BNP • Echocardiography • BNP • BNP • T3, T4, TSH, FT3, FT4 • BNP • T3, T4, TSH, FT3, FT4 •T3, T4, TSH, FT3, FT4 • Ergospirometry • T3, T4, TSH, FT3, FT4

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

Cell models of pathological ( PE) and physiological (Clenbuterol ) growth Actin β‐ MHC Acti n CO CLEN NO INCREASE IN ERK 8 min CLEN 60 min CLEN 5 days CLEN Ph ‐ ERK CLE Total ERK PE INCREASE IN ERK 5 d PE PE

Cell models of pathological ( PE) and physiological (T3) growth Phenylephrine Thyroid (PE) hormone (T3) Pathological hypertrophy Physiological hypertrophy Actin β‐ MHC

T3 is superior to CLEN Marked decrease in β myosin less decrease in β myosin