RNA Sequencing Reveals Novel Transcripts from Sympathetic Stellate Ganglia During Cardiac Sympathetic Hyperactivity

Abstract

Cardiovascular disease is the most prevalent age-related illness worldwide, causing approximately 15 million deaths every year. Hypertension is central in determining cardiovascular risk and is a strong predictive indicator of morbidity and mortality; however, there remains an unmet clinical need for disease-modifying and prophylactic interventions. Enhanced sympathetic activity is a well-established contributor to the pathophysiology of hypertension, however the cellular and molecular changes that increase sympathetic neurotransmission are not known. The aim of this study was to identify key changes in the transcriptome in normotensive and spontaneously hypertensive rats. We validated 15 of our top-scoring genes using qRT-PCR, and network and enrichment analyses suggest that glutamatergic signalling plays a key role in modulating Ca2+ balance within these ganglia. Additionally, phosphodiesterase activity was found to be altered in stellates obtained from the hypertensive rat, suggesting that impaired cyclic nucleotide signalling may contribute to disturbed Ca2+ homeostasis and sympathetic hyperactivity in hypertension. We have also confirmed the presence of these transcripts in human donor stellate samples, suggesting that key genes coupled to neurotransmission are conserved. The data described here may provide novel targets for future interventions aimed at treating sympathetic hyperactivity associated with cardiovascular disease and other dysautonomias.

Sex differences in sympathetic gene expression and cardiac neurochemistry in Wistar Kyoto rats

“…Separation of the sexes was observed during multidimensional scaling (MDS) analysis to determine how the expression profiles of each sample compared to all others ( Fig 2 ). Genes associated with sympathetic neurotransmission were among the most highly expressed genes, consistent with our previous studies in mice[2] and with previous analyses of male rat stellates[8, 9]. Similar to mice, the top 100 most highly expressed genes were almost identical in males and females ( S1 Table ).…”

“…It will be interesting to see if the same genes are dysregulated in female SHR ganglia, and if cardiac NE is higher in the female heart. The most highly expressed stellate ganglion genes in the current study match the most abundant genes in the Bardsley study [8, 9] and our earlier mouse study[2] , providing confirmation of the core stellate ganglion transcriptome. Although we identified sex-specific differences in the expression of many genes, those associated with noradrenergic transmission were expressed at similar levels in male and female ganglia.…”

“…Our male-female comparison data in WKY rat ganglia complement other investigations of stellate transcriptomes. A recent study by Bardsley and colleagues compared the stellate ganglion transcriptome of male Wistar and SHR rats [8, 9]. That work identified increased expression of multiple genes in male SHR ganglia that might contribute to excess sympathetic transmission and hypertension [7, 10].…”

“…This is true for studies of a broad range of diseases including heart failure, arrhythmias, and hypertension that utilize a variety of different rat strains [3–7]. Recently, Bardsley and colleagues compared the stellate ganglion transcriptome of Wistar rats with spontaneously hypertensive rats (SHR)[8, 9]. Differences were observed in the expression of genes related to calcium handling and cyclic nucleotide signaling that were consistent with alterations in neuronal calcium handling and cyclic nucleotide metabolism identified in physiological experiments [7, 10].…”

Effects of ticagrelor pretreatment on electrophysiological properties of stellate ganglion neurons following myocardial infarction

“…The stellate ganglion (SG) in the autonomic nervous system plays a central role in the regulation of cardiac homeostasis 1 . Increased SG activity has been implicated in the pathogenesis of various cardiovascular diseases, 2 and interventions blocking SG activity may exert protective effects in these circumstances 3‐5 .…”