Abstract 89: Differences in Orexin-related Gene Expression in the Brain in Early versus Late Stage Heart Failure in Male Rats

Abstract

Orexin is a neuropeptide produced exclusively by neurons in the lateral hypothalamus. Orexinergic neurons send projections throughout the brain and the system has been hypothesized to be critical for the coordination of “survival related-processes. Emerging evidence has identified that the orexin system is dysregulated in several forms of cardiovascular disease. In hypertension for example, upregulation of the orexin system contributes to elevated sympathetic drive. In heart failure, genomic changes in the orexin type 2 receptor have been linked to reduced cardiac function and pretreatment with an orexin type 2 receptor agonist prior to cardiac stress was identified to be cardio-protective. These data suggest changes in orexin system activation before or during cardiac stress may have therapeutic potential. The present study was undertaken to evaluate changes in the brain orexin system at 4 weeks following myocardial injury compared to the chronic changes previous documented at 16 weeks post infarction. Methods: Adult male rats underwent either sham operation (n=9) or ligation of the left main coronary artery (n=9) while under anesthesia and were allowed to recover either 4 weeks or 16 weeks. Results: The infarct size ranged from 21 to 39% of the left ventricle (28+/-6%, mean+/-STDEV). At 4 weeks of age hypothalamic orexin gene expression was upregulated 54% (P<0.07) when compared to sham operated animals. This was in contrast to a 78% reduction in gene expression at 16 weeks following myocardial infarction. No significant difference in orexin receptor expression (type 1 or type 2) within the hypothalamus was identified at either time point. These findings demonstrate that the orexin system undergoes dynamic changes following myocardial insult. Since orexin supplementation has been reported to be both neuroprotective and cardioprotective, it is possible that early orexin upregulation is an adaptive/protective response and sustained stimulation of the orexin system over a longer time period may improve health outcomes associated with heart failure.