Optimising cardioprotection during myocardial ischaemia: targeting potential intracellular pathways with glucagon-like peptide-1

Abstract

Coronary heart disease and type-2 diabetes are both major global health burdens associated with an increased risk of myocardial infarction (MI). Following MI, ischaemia-reperfusion injury (IRI) remains a significant contributor to myocardial injury at the cellular level. Research has focussed on identifying a strategy or intervention to minimise IRI to optimise reperfusion therapy, with the aim of delivering a superior clinical outcome. The incretin hormone glucagon-like peptide-1, already an established basis for the treatment of type-2 diabetes, also has the potential to protect against IRI. We explain the physiology and cellular processes involved in IRI, and the intracellular pathways activated by GLP-1, which could intercept IRI and deliver cardioprotection. The review also examines the current preclinical and clinical evidence for GLP-1 in cardioprotection and future directions for research as we look for an effective adjunctive treatment to minimise IRI.

Figure 1

Possible mechanisms of protection against IRI by GLP-1. (a) Cellular mechanism of lethal ischaemic injury. (b) The links between the known intracellular pathways involved in IRI and the two distinct cardioprotective pathways capable of interrupting this: The pro-survival kinase pathway, and the metabolic pathway. MPTP is the intersection between the two pathways. The possible second GLP-1 receptor remains a hypothesis. Also shown are known modulators of the pathways and clinical measures of cardioprotection [9,23,24,47].

Figure 2

Illustrating the different therapeutic approaches targeting the GLP-1 axis and mechanistic considerations for each[46-48]. The possibilities of GLP-1 receptor independent effects and GLP-1 (28–36) and (32–36) mediated effects need validation.