Endocrine Abstracts (2005) 9 P29

Differential modulation of orexin receptors by hyperglycaemia in the mouse heart

E Karteris, J Chen, S Zervou, S Pelengaris, M Khan & HS Randeva

Department of Biological Sciences, University of Warwick, Coventry, UK.

Diabetes mellitus, characterised primarily by hyperglycaemia, is associated with a number of cellular stresses and changes that cause cardiomyocytes to adapt with those modifications that characterise the diabetic heart. Although orexins are cardiovascular regulators acting via the brain, little is known about their potentially critical roles in the heart. Orexins exert their actions by activating two distinct G protein coupled receptors, orexin-R1 (OXR1) amd orexin-R2 (OXR2). Recently, we have cloned and characterized two splice variants of the mouse OXR2, termed OX2R alpha and OX2R beta, with distinct signaling properties.

The aim of this study is to investigate the role of hyperglycaemia, as an independent risk factor, in the expression of orexin receptors in a unique transgenic 'diabetic-mouse'. We have employed the pIns-c-MycERTAM mouse model, which allows specific toxigenic ablation of beta cells in vivo. Consequently, the onset of hyperglycaemia can be reproducibly regulated. In 4-day hyperglycaemic male mice, the cardiac orexin receptor profile was assessed by real-time PCR.

We show that the mouse heart expresses both OX1R and OX2R at mRNA and protein level. Real- time PCR demonstrated that OX1R was significantly downregulated in the transgenic mouse when compared to wild type (45% compared to wt). Interestingly, OX2R beta but not OX2R alpha was significantly downregulated in the transgenic mouse model (by 85% compared to wt). This is of particular importance, since OX2R beta couples with higher affinity to the Gq/inositol triphosphate system.

In conclusion, the detected decrease of orexin receptors, known to couple to Gq proteins and influence calcium flux, may alter intracellular cardiomyocyte calcium dynamics, and therefore contribute to the increased morbidity of hyperglycaemia in acute coronary syndromes.

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