Role of cyclic AMP signalling mechanisms in heart protection against ischemia reperfusion injury

Role of Cyclic AMP Signalling Mechanisms in Heart Protection Against Ischemia - Reperfusion Injury Dr... Coronary Artery Occlusion and Heart Attack Heart Attack Risk Zone Reperfusion

Role of Cyclic AMP Signalling Mechanisms in Heart Protection Against Ischemia - Reperfusion

Injury

Dr Igor Khaliulin

Coronary Artery Occlusion and Heart Attack

Heart Attack

Risk Zone

Reperfusion

Reperfusion INJURY

Ischaemia-Myocardium

Atheroslcerosis

Thrombosis

TP Hearts Demonstrated the Highest Haemodynamic

Function Recovery

0 20 40 60 80 100

TP SHP

Brief Episodes of Hypothermic and Normothermic Perfusion

More Effective Cardioprotective

Intervention than Ischaemic

Preconditioning

Khaliulin I et al J Physiol 2007;581:1147-61

Study of the signalling

mechanisms of cardioprotective

effect of temperature

preconditioning have revealed that this intervention is mediated by

consecutive activation of PKA and

PKC as well as moderate production

of reactive oxygen species ( ROS )

Khaliulin I et al Cardiovasc Res 2010;88:324-33

Iso/Ade - Consecutive perfusion with

isoproterenol and adenosine

Consecutive Isoproterenol/Adenosine Treatment Drammatically Improves Haemodynamic Function Recovery During Reperfusion

0 20 40 60 80 100 120 140

Consecutive Isoproterenol/Adenosine treatment

(Iso/Ade) Significantly Reduces Infarct Size

% of the whole heart area

Consecutive treatment of hearts with a PKA activator ( isoproterenol ) and a PKC activator ( adenosine ) results in an

extraordinary cardioprotective effect

during normothermic (37°C) ischaemia and reperfusion

Khaliulin I et al Cardiovasc Res 2010;88:324-33

Ca 2+ -Induced Mitochondria Swelling Measured

After 30 min Global Ischemia

* P<0.05; ** P<0.01 vs Control

# P<0.05 vs Isoproterenol & Adenosine

Mitochondria Permeability Transition Pore

Isoproterenol Reduces Glycogen Content Before

Ischemia

0 2 4 6 8 10 12 14

Isoproterenol Promotes Hexokinase II Binding to the

Mitochondrial Membrane

0 1 2 3 4 5 6 7

Cyclic AMP -induced activation of PKA

(due to heart perfusion with

isoproterenol) depletes glycogen in

myocardium This promotes binding of

membrane and inhibition of mitochondria permeability transition pore (MPTP)

opening

Cyclic AMP -induced activation of PKA by (due to heart perfusion with

isoproterenol) depletes glycogen in

myocardium This promotes binding of

membrane and inhibition of mitochondria permeability transition pore (MPTP)

opening

Downstream Targets of Cyclic AMP

Cell-Permeable Cyclic AMP Analogue

(BioLog Life Science Institute, Bremen,

Germany)

8-Bromadenosine-3’,5’-cyclic monophosphate, acetoxymethyl ester

(8-Br-cAMP-AM)

Activates both PKA and Epac

0 10

haemodynamic function recovery

A B

Control 8-Br-cAMP-AM

Reduces Infarct Size

Cell-pemeable cyclic AMP analogue

against ishaemia/reperfusion injury

cardioprotective effect of cAMP

Doctor Andrew James

Doctor Mark Bond

Labs of Professor Saadeh Suleiman and

Professor Andrew Halestrap