Apelin a cardioprotective adipocytokine.

The epidemic of obesity has led to increased interest in its role in the pathogenesis of cardiometabolic disease. Adipose tissue, formerly regarded as purely an energy storage site, is now regarded as an important endocrine organ. It produces various peptide hormones, including the adipocytokines which are implicated in metabolic control and disease. Whilst some adipocytokines may contribute to the development of cardiovascular disease, others e.g. adiponectin, may protect against it. The recently identified ligand for the G protein coupled receptor APJ, apelin, is a unique vasoactive adipocytokine. Both apelin and APJ mRNA are highly expressed in the cardiovascular system. Apelin has been found to modulate cardiovascular function, fluid homeostasis and inflammation. To date, however, apelin has not been investigated in the context of ischemia-reperfusion and its benefits in this clinical setting are not yet established. APJ/apelin activates the cell survival cascades Akt/PKB and ERK-1/2 which are associated with the pro-survival Reperfusion Injury Salvage Kinase (RISK) pathway. Apelin also promotes mitogenesis, a feature commonly exhibited by cardioprotective agents. We, therefore, hypothesised that apelin may protect the heart via the RISK pathway in an ischemia/reperfusion (MR) model. We investigated if apelin has potential as a cardioprotective agent employing murine models of ischemia-reperfusion injury and rat cardiomyocytes, in which mitochondrial permeability transition pore (mPTP) opening was examined. Apelin- 13 was found to produce a concentration-dependent decrease in infarct size with a maximal effect being observed at 1000nM. The physiologically less active peptide, apelin-36, also reduced infarct size but to lesser extents than seen with the shorter isoform. LY294002 and U0126, inhibitors of the PI3K-Akt, p44/42, abolished the effects of apelin-13. Further evidence for the involvement of these pathways in the cardioprotective actions of apelin was obtained on Western blot analysis. Apelin-13 delayed mPTP opening which was blocked by LY294002 and MEK inhibitor 1, an alternative inhibitor of p44/42. This is the first study to demonstrate that apelin has a direct cardioprotective action involving the PI3K- Akt, and p44/42 signalling pathways