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

Date Published: June 13, 2019

Publisher: Public Library of Science

Author(s): Richard G. Bayles, Joanne Tran, Antoinette Olivas, William R. Woodward, Suzanne S. Fei, Lina Gao, Beth A. Habecker, Joohyung Lee.

http://doi.org/10.1371/journal.pone.0218133

Abstract

The stellate ganglia are the predominant source of sympathetic innervation to the heart. Remodeling of sympathetic nerves projecting to the heart has been observed in several cardiovascular diseases, and sympathetic dysfunction contributes to cardiac pathology. Wistar Kyoto rats are a common model for the study of cardiovascular diseases, but we lack a profile of the baseline transcriptomic and neurochemical characteristics of their cardiac sympathetic neurons. Most studies of cardiovascular disease have used male animals only, but in the future both male and female animals will be used for these types of studies; therefore, we sought to characterize the transcriptome of male and female stellate ganglia and to correlate that with catecholamine and acetylcholine content in the heart. We have generated a dataset of baseline RNA expression in male and female Wistar Kyoto rat stellate ganglia using RNA-seq, and have measured neurotransmitter levels in heart and stellate ganglia using HPLC and mass spectrometry. We identified numerous gene expression differences between male and female stellates, including genes encoding important developmental factors, receptors and neuropeptides. Female hearts had significantly higher neurotransmitter content than male hearts; however, no significant differences were detected in expression of the genes encoding neurotransmitter synthetic enzymes. Similarly, no statistically significant differences were identified between the sexes in cardiac tyrosine hydroxylase levels.

Partial Text

As researchers increasingly recognize the importance of studying both male and female animals in disease models, it becomes increasingly clear that a sound understanding of the baseline physiology needs to be established in both sexes, in line with ongoing efforts of the NIH [1]. Stellate ganglia contain the majority of sympathetic neurons projecting to the heart, and we previously generated a reference transcriptome from mouse stellate ganglia with associated tissue neurochemistry [2]. Significant differences were detected between the sexes both in terms of gene expression and atrial neurotransmitter levels, highlighting the need to identify this baseline information in both sexes.

To characterize baseline neurochemical characteristics of adult WKY rat hearts, norepinephrine (NE) and acetylcholine (ACh) were measured in atria, the right ventricle, and the base, mid-wall and apex of the left ventricle. A base to apex gradient in NE concentration is a well-established feature of cardiac physiology [27] and our data confirmed this gradient for WKY rats (region-specific differences p<0.0001) (Fig 1). In addition, a higher concentration of NE was observed across all regions of the heart in females compared to males. In right atria, a higher concentration of ACh was also observed in females compared to males, proportional to the increase in NE. Surprisingly, the NE metabolite DHPG was not detectable in any of the rat heart tissue samples, although the DHPG standards were readily detected. In the present study we generated a reference transcriptome of stellate ganglia in male and female adult WKY rats with associated tissue neurochemistry. Statistically significant differences were detected between the sexes both in terms of gene expression and cardiac neurotransmitter levels. The most abundant genes within all ganglia related to neurotransmission, and these genes were present at identical levels in male and female ganglia. Genes that were differentially expressed between the sexes in rat stellate ganglia were distinct from those that were differentially expressed in male and female mouse stellates. Most of the genes that were differentially expressed in stellates were expressed at similar levels in male and female SCG, suggesting sex differences that were specific to the stellate. Neurotransmitter levels were similar in male and female stellate ganglia, but NE levels were significantly higher across all regions of female hearts compared to male hearts. No physiological parameters were quantified in this study, which focused on transcriptomics and neurochemistry.   Source: http://doi.org/10.1371/journal.pone.0218133

 

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