Role of Adenosine Receptor in Ischemic Preconditioning

Basic Knowledge

1.what is ischemic preconditioning (IPC)?A phenomenon by which a brief episodes of myocardial ischemia increases the ability of the heart to tolerate a subseqent prolonged period of ischemic injury.

2. Early phase (‘classical’conditioning ) and delayed phase (‘second window’of protection)

Early phase appears immediately; delayed phase appears at 24,48,72 hours following brief periods of preconditioning ischemia.

3.Triggers of ischemic preconditioning

1) Receptor dependent triggers

A. Adenosine receptors

B. Opioid receptors

2) Receptor independent triggers

A. Nitric oxide

B. Free radicals

Subtypes and Distributing of Adenosine receptors

•A1 adenosine receptor (A1AR)•A1AR is found in the myocytes and in the vascular smooth muscle.

•A2 adenosine receptor (A2AR)•A2AR including A2A and A2B,can be found in the endot

helium and the vascular smooth muscle .

•A3 adenosine receptor (A3AR)•Locate in the plasmatic membrane of the myocytes.

Structures of Adenosine Receptors

Fig.1.Sructures of adenosine receptor

Adenosine receptors are G-protein coupled receptors

Fig.2. Adenosine receptor subtypes and their coupled G-proteins.

A1 Adenosine Receptor Participates in Early Phase of

Ischemic Preconditioning

Fig.3.Values of left ventricular developed pressure (LVDP), in the control group,the group treated with adenosine, and the group where adenosine and DPCPX (A1 blocker) were administered.Note that adenosine attenuated the systolic alterations of post ischemic dysfunction. This effect was abolished with the administation of DPCPX.*P<0.05 vs. control.

Fig.4.Size of the infarct expressed as percentage of the area of the left ventricle in the control group, the group treated with adenosine,and the group where adenosine plus DDCPX(A1 blocker) was administered .*p<0.05 vs control.

A3 Adenosine Receptor Participates in early

preconditioning

Fig.5.The effect of 1microM MRS-1191 (adenosine A3 receptor antagonist ) upon

protection conferred by 2-Cl-IB-MECA at reperfusion.

Fig.6. Protective effect of activation of adenosine receptor A1 and A3.

Late Preconditioning Elicited by Activation of Adenosine A1

Receptor

Fig.7. Principal experimental evidence for participation of adenosine as a trigger of delayed preconditioning and for delayed myocardial protection induced by selective activation of adenosine receptor subtypes

Fig.8. Cellular protection against SI in A1AR- tgm compared with wt.(Wt:wild-type-mice;SMT, an iNOS inhibitor; Glb: a KATP channel blocker; 5-HD:a mitochondrial KATP channel blocker).

Late Preconditioning Elicited by Activation of Adenosine A3

Receptor

Fig.9.Effect of A3AR stimulation on attenuation in ischemia/reperfusion jury

Possible Pathways Mediated by Adenosine Receptors in Ischemic

Preconditioning

1.Molecules Invovled in Ischemic Preconditioning

•ATP-sensitive K channel

•PKC and tyrosine kinases

•p38 MAP kinase

•Heat shock protein (HSP27)

•Nuclear factor-κB and AP-1

•Superoxide dismutase

•Inducible nitric oxide symthase

Fig.12. Abrogation of protection provided by adenosine

1.Molecules Invovled in Ischemic Preconditioning

•ATP-sensitive K channel

•PKC and tyrosine kinases

•p38 MAP kinase

•Heat shock protein (HSP27)

•Nuclear factor-κB and AP-1

•Superoxide dismutase

•Inducible nitric oxide symthase

Fig.13. Effect of rottlerin (PKC-δ specific inhibitor) on infarct size confered by CCPA.

C

Fig.14. Western blot analysis of PKC-δ (A), PKC-ε (B) and iNOS (C).

1.Molecules Invovled in Ischemic Preconditioning

•ATP-sensitive K channel

•PKC and tyrosine kinases

•p38 MAP kinase

•Heat shock protein (HSP27)

•Nuclear factor-κB and AP-1

•Superoxide dismutase

•Inducible nitric oxide symthase

1.Molecules Invovled in Ischemic Preconditioning

•ATP-sensitive K channel

•PKC and tyrosine kinases

•p38 MAP kinase

•Heat shock protein (HSP27)

•Nuclear factor-κB and AP-1

•Superoxide dismutase

•Inducible nitric oxide symthase

1.Molecules Invovled in Ischemic Preconditioning

•ATP-sensitive K channel

•PKC and tyrosine kinases

•p38 MAP kinase

•Heat shock protein (HSP27)

•Nuclear factor-κB and AP-1

•Superoxide dismutase

•Inducible nitric oxide symthase

Fig.10. Nuclear Factor κB in A3AR- induced myocardial protection

Fig.15. Nuclear factor-κB expression after treatment with IB-MECA

1.Molecules Invovled in Ischemic Preconditioning

•ATP-sensitive K channel

•PKC and tyrosine kinases

•p38 MAP kinase

•Heat shock protein (HSP27)

•Nuclear factor-κB and AP-1

•Superoxide dismutase

•Inducible nitric oxide symthase

1.Molecules Invovled in Ischemic Preconditioning

•ATP-sensitive K channel

•PKC and tyrosine kinases

•p38 MAP kinase

•Heat shock protein (HSP27)

•Nuclear factor-κB and AP-1

•Superoxide dismutase

•Inducible nitric oxide symthase

Fig.11.Role of NO in A3AR-induced protection.

Fig.16. RT-PCR showing iNOS and β-actin transcription by IB-MECA.

2.Possible pathways

Fig.17. Primary and secondary pathways in early ischemic preconditioning

Fig.18.Outline of the principal stages leading to cellular adaptation in delayed preconditioning .Several diffusible mediators including adenosine,contribute critically to the trigger phase that initiates the adaptive response.

Fig.19. Hypothetical pathways by which adenosine receptor activation might lead to the delayed protection

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