PTEN, the Achilles' heel of myocardial ischaemia/reperfusion injury?

Abstract

Myocardial ischaemia/reperfusion injury leading to myocardial infarction is one of the most frequent causes of debilitation and death in man. Considerable research has been undertaken to investigate the possibility of reducing myocardial infarction and increasing cell survival by activating certain endogenous prosurvival signaling pathways. Thus, it has been established that the activation of the PI3K (Phosphoinositide-3 kinase)/Akt (Protein kinase B, PKB) signaling pathway is essential for protection against ischaemia/reperfusion injury. This pathway has been shown to be activated by mechanical procedures (e.g. pre and post conditioning) as well as by a number of pharmacological agents. Although the activation of this prosurvival signaling pathway induces the phosphorylation of a large number of substrates implicated in increased cell survival, when activated over a prolonged period this pathway can have detrimental consequences by facilitating unwanted growth and malignancies. Importantly PTEN (phosphatase and tensin homolog deleted on chromosome ten), is the main phosphatase which negatively regulates the PI3K/Akt pathway. In this review we discuss: a) the significance and the limitations of inhibiting PTEN in myocardial ischaemia/reperfusion injury; b) PTEN and its relationship to ischaemic preconditioning, c) the role of PTEN in the development of tolerance to chronic administration of drugs known to limit infarction by activating PI3K/Akt pathway when given acutely, and d) the possible role of PTEN in the ischaemic/reperfused diabetic heart. The experimental evidence discussed in this review illustrates the importance of PTEN inhibition in the protection of the heart against ischaemia/reperfusion injury.

Figure 1

PTEN acts as a lipid phosphatase reversing the reaction catalyzed by the PI3K, that is dephosphorylating the second-messenger PtdIns(3,4,5)P3 (PIP3) to the precursor PtdIns(4,5)P2 (PIP2). The role of PIP3 is to recruit Akt and PDK1 at the membrane level. PDK1 phosphorylates Akt which thereafter acts upon numerous targets, activating the antiapoptotic substrates and inhibiting the proapoptotic substrates (sharp arrows, activation; blunt arrows, inhibition). R, membrane receptor.

Figure 2

PTEN regulation. PTEN is a constitutively active phosphatase. In summary, its activity can be unregulated by increased synthesis and downregulated by phosphorylation, oxidation and proteasomal degradation. The mechanisms through which its activity is regulated are complex and not yet elucidated completely.