Physiological genomics最新文献

{"title":"Krüppel-like factor 4 in transcriptional control of the three unique isoforms of Agouti-related peptide in mice.","authors":"McKenzie L Ritter, Valerie A Wagner, Kirthikaa Balapattabi, Megan A Opichka, Ko-Ting Lu, Kelsey K Wackman, John J Reho, Henry L Keen, Anne E Kwitek, Lisa L Morselli, Aron M Geurts, Curt D Sigmund, Justin L Grobe","doi":"10.1152/physiolgenomics.00042.2023","DOIUrl":"10.1152/physiolgenomics.00042.2023","url":null,"abstract":"<p><p>Agouti-related peptide (AgRP/<i>Agrp</i>) within the hypothalamic arcuate nucleus (ARC) contributes to the control of energy balance, and dysregulated <i>Agrp</i> may contribute to metabolic adaptation during prolonged obesity. In mice, three isoforms of <i>Agrp</i> are encoded via distinct first exons. <i>Agrp-A</i> (ENSMUST00000005849.11) contributed 95% of total <i>Agrp</i> in mouse ARC, whereas <i>Agrp-B</i> (ENSMUST00000194654.2) dominated in placenta (73%). Conditional deletion of <i>Klf4</i> from <i>Agrp</i>-expressing cells (<i>Klf4^Agrp</i>^-KO mice) reduced <i>Agrp</i> mRNA and increased energy expenditure but had no effects on food intake or the relative abundance of <i>Agrp</i> isoforms in the ARC. Chronic high-fat diet feeding masked these effects of <i>Klf4</i> deletion, highlighting the context-dependent contribution of KLF4 to <i>Agrp</i> control. In the GT1-7 mouse hypothalamic cell culture model, which expresses all three isoforms of <i>Agrp</i> (including <i>Agrp-C</i>, ENSMUST00000194091.6), inhibition of extracellular signal-regulated kinase (ERK) simultaneously increased KLF4 binding to the <i>Agrp</i> promoter and stimulated <i>Agrp</i> expression. In addition, siRNA-mediated knockdown of <i>Klf4</i> reduced expression of <i>Agrp</i>. We conclude that the expression of individual isoforms of <i>Agrp</i> in the mouse is dependent upon cell type and that KLF4 directly promotes the transcription of <i>Agrp</i> via a mechanism that is superseded during obesity.<b>NEW & NOTEWORTHY</b> In mice, three distinct isoforms of Agouti-related peptide are encoded via distinct first exons. In the arcuate nucleus of the hypothalamus, Krüppel-like factor 4 stimulates transcription of the dominant isoform in lean mice, but this mechanism is altered during diet-induced obesity.</p>","PeriodicalId":20129,"journal":{"name":"Physiological genomics","volume":null,"pages":null},"PeriodicalIF":2.5,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10866620/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139032461","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"High-throughput methylome analysis reveals differential methylation for early and late onset preeclampsia for mothers and their children.","authors":"Cora E Layman, Samantha Ward, Brett A Davis, Kimberly A Nevonen, Mariam Okhovat, Monica Rincon, Amy Valent, Lucia Carbone, Kent L Thornburg","doi":"10.1152/physiolgenomics.00058.2023","DOIUrl":"10.1152/physiolgenomics.00058.2023","url":null,"abstract":"<p><p>Preeclampsia is a hypertensive disorder of pregnancy that affects ∼2%-5% of all pregnancies, contributes to 4 of the top 10 causes of pregnancy-related deaths, and remains a long-term risk factor for cardiometabolic diseases. Yet, little is still known about the molecular mechanisms that lead to this disease. There is evidence that some cases have a genetic cause. However, it is well appreciated that harmful factors in the environment, such as poor nutrition, stress, and toxins, may lead to epigenetics changes that can contribute to this disease. DNA methylation is one of the epigenetic modifications known to be fairly stable and impact gene expression. Using DNA from buccal swabs, we analyzed global DNA methylation among three groups of individuals: mothers who experienced <i>1</i>) early-stage preeclampsia (<32 wk), <i>2</i>) late-stage preeclampsia (>37 wk), or <i>3</i>) no complications during their pregnancies, as well as the children from these three groups. We found significant differentially methylated regions (DMRs) between mothers who experienced preeclampsia compared with those with no complications adjacent or within genes that are important for placentation, embryonic development, cell adhesion, and inflammation (e.g., the cadherin pathway). A significant portion of DMR genes showed expression in tissues relevant to preeclampsia (i.e., the brain, heart, kidney, uterus, ovaries, and placenta). As this study was performed on DNA extracted from cheek swabs, this opens the way to future studies in different tissues, aimed at identifying possible biomarkers of risk and early detection, developing targeted interventions, and reducing the progression of this life-threatening disease.<b>NEW & NOTEWORTHY</b> Preeclampsia is a life-threatening hypertensive disorder, affecting 2%-5% of pregnancies, that remains poorly understood. This study analyzed DNA methylation from buccal swabs from mothers who experienced early and late-stage preeclampsia and those with uncomplicated pregnancies, along with their children. Differentially methylated regions were found near and within genes crucial for placental function, embryonic development, and inflammation. Many of these genes are expressed in preeclampsia-related tissues, offering hope for future biomarker development for this condition.</p>","PeriodicalId":20129,"journal":{"name":"Physiological genomics","volume":null,"pages":null},"PeriodicalIF":2.5,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11283906/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139378182","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Limited WKY chromosomal regions confer increases in anxiety and fear memory in a F344 congenic rat strain","authors":"Michelle T Ji, Neha Pashankar, Aspen M Harter, Mariya Nemesh, Katherine J Przybyl, Megan K Mulligan, Hao Chen, Eva E. Redei","doi":"10.1152/physiolgenomics.00114.2023","DOIUrl":"https://doi.org/10.1152/physiolgenomics.00114.2023","url":null,"abstract":"Physiological Genomics, Ahead of Print. <br/>","PeriodicalId":20129,"journal":{"name":"Physiological genomics","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139688975","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrated miRNA-mRNA networks underlie attenuation of chronic β-adrenergic stimulation-induced cardiac remodeling by minocycline","authors":"Jacob J Russell, Srinivas Mummidi, Vincent G. Demarco, Laurel A. Grisanti, Chastidy A Bailey, Shawn B. Bender, Bysani Chandrasekar","doi":"10.1152/physiolgenomics.00140.2023","DOIUrl":"https://doi.org/10.1152/physiolgenomics.00140.2023","url":null,"abstract":"Physiological Genomics, Ahead of Print. <br/>","PeriodicalId":20129,"journal":{"name":"Physiological genomics","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139689158","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Complementary yet divergent effects of exercise and an exercise mimetic on microbiome in high-fat diet-induced obesity.","authors":"Josephine Yu, Neil A Youngson, D Ross Laybutt, Margaret J Morris, Sarah-Jane Leigh","doi":"10.1152/physiolgenomics.00066.2023","DOIUrl":"10.1152/physiolgenomics.00066.2023","url":null,"abstract":"<p><p>Exercise is beneficial for obesity, partially through increased mitochondrial activity and raised nicotinamide adenine dinucleotide (NAD), a coenzyme critical for mitochondrial function and metabolism. Recent work has shown that increasing the availability of NAD through pharmacological means improves metabolic health in rodent models of diet-induced obesity and that the effect of these supplements when administered orally may be modulated by the gut microbiome. The gut microbiome is altered by both diet and exercise and is thought to contribute to some aspects of high-fat diet-induced metabolic dysfunction. We examined the independent and combined effects of treadmill exercise and nicotinamide mononucleotide (NMN) supplementation on the gut microbiome of female C57Bl6/J mice chronically fed a high-fat diet. We showed that 8 wk of treadmill exercise, oral-administered NMN, or combined therapy exert unique effects on gut microbiome composition without changing bacterial species richness. Exercise and NMN exerted additive effects on microbiota composition, and NMN partially or fully restored predicted microbial functions, specifically carbohydrate and lipid metabolism, to control levels. Further research is warranted to better understand the mechanisms underpinning the interactions between exercise and oral NAD⁺ precursor supplementation on gut microbiome.<b>NEW & NOTEWORTHY</b> Exercise and NAD⁺ precursor supplementation exerted additive and independent effects on gut microbiota composition and inferred function in female mice with diet-induced obesity. Notably, combining exercise and oral nicotinamide mononucleotide supplementation restored inferred microbial functions to control levels, indicating that this combination may improve high-fat diet-induced alterations to microbial metabolism.</p>","PeriodicalId":20129,"journal":{"name":"Physiological genomics","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138441122","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lung proinflammatory microRNA and cytokine expression in a mouse model of allergic inflammation: role of sex chromosome complement and gonadal hormones.","authors":"Sarah Commodore, Carolyn Damilola Ekpruke, Dustin Rousselle, Rachel Alford, Maksat Babayev, Shikha Sharma, Aaron Buechlein, Douglas B Rusch, Patricia Silveyra","doi":"10.1152/physiolgenomics.00049.2023","DOIUrl":"10.1152/physiolgenomics.00049.2023","url":null,"abstract":"<p><p>Epigenetic alterations such as dysregulation of miRNAs have been reported to play important roles in interactions between genetic and environmental factors. In this study, we tested the hypothesis that induction of lung inflammation by inhaled allergens triggers a sex-specific miRNA regulation that is dependent on chromosome complement and hormonal milieu. We challenged the four core genotypes (FCGs) model through intranasal sensitization with a house dust mite (HDM) solution (or PBS as a control) for 5 wk. The FCG model allows four combinations of gonads and sex chromosomes: <i>1</i>) XX mice with ovaries (XXF), <i>2</i>) XY mice with testes (XYM), <i>3</i>) XX mice with testes (XXM), and <i>4</i>) XY mice with ovaries (XYF). Following the challenge (<i>n</i> = 5-7/group), we assessed the expression of 84 inflammatory miRNAs in lung tissue using a PCR array and cytokine levels in bronchoalveolar lavage fluid (BAL) by a multiplex protein assay (<i>n</i> = 4-7 animals/group). Our results showed higher levels of the chemokine KC (an Il-8 homolog) and IL-7 in BAL from XYF mice challenged with HDM. In addition, IL-17A was significantly higher in BAL from both XXF and XYF mice. A three-way interaction among treatment, gonads, and sex chromosome revealed 60 of 64 miRNAs that differed in expression depending on genotype; XXF, XXM, XYF, and XYM mice had 45, 32, 4, and 52 differentially expressed miRNAs, respectively. Regulatory networks of miRNAs identified in this study were implicated in pathways associated with asthma. Female gonadal hormonal effects may alter miRNA expression and contribute to the higher susceptibility of females to asthma.<b>NEW & NOTEWORTHY</b> miRNAs play important roles in regulating gene and environmental interactions. However, their role in mediating sex differences in allergic responses and lung diseases has not been elucidated. Our study used a targeted omics approach to characterize the contributions of gonadal hormones and chromosomal components to lung responses to an allergen challenge. Our results point to the influence of sex hormones in miRNA expression and proinflammatory markers in allergic airway inflammation.</p>","PeriodicalId":20129,"journal":{"name":"Physiological genomics","volume":null,"pages":null},"PeriodicalIF":2.5,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11281810/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138478426","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transcriptomics and proteomics revealed sex differences in human pulmonary microvascular endothelial cells.","authors":"Daria S Kostyunina, Nikolai V Pakhomov, Amina Jouida, Eugene Dillon, John A Baugh, Paul McLoughlin","doi":"10.1152/physiolgenomics.00051.2023","DOIUrl":"10.1152/physiolgenomics.00051.2023","url":null,"abstract":"<p><p>Marked sexual dimorphism is displayed in the onset and progression of pulmonary hypertension (PH). Females more commonly develop pulmonary arterial hypertension, yet females with pulmonary arterial hypertension and other types of PH have better survival than males. Pulmonary microvascular endothelial cells play a crucial role in pulmonary vascular remodeling and increased pulmonary vascular resistance in PH. Given this background, we hypothesized that there are sex differences in the pulmonary microvascular endothelium basally and in response to hypoxia that are independent of the sex hormone environment. Human pulmonary microvascular endothelial cells (HPMECs) from healthy male and female donors, cultured under physiological shear stress, were analyzed using RNA sequencing and label-free quantitative proteomics. Gene set enrichment analysis identified a number of sex-different pathways in both normoxia and hypoxia, including pathways that regulate cell proliferation. In vitro, the rate of proliferation in female HPMECs was lower than in male HPMECs, a finding that supports the omics results. Interestingly, thrombospondin-1, an inhibitor of proliferation, was more highly expressed in female cells than in male cells. These results demonstrate, for the first time, important differences between female and male HPMECs that persist in the absence of sex hormone differences and identify novel pathways for further investigation that may contribute to sexual dimorphism in pulmonary hypertensive diseases.<b>NEW & NOTEWORTHY</b> There is marked sexual dimorphism in the development and progression of pulmonary hypertension. We show differences in RNA and protein expression between female and male human pulmonary microvascular endothelial cells grown under conditions of physiological shear stress, which identify sex-different cellular pathways both in normoxia and hypoxia. Importantly, these differences were detected in the absence of sex hormone differences. The pathways identified may provide novel targets for the development of sex-specific therapies.</p>","PeriodicalId":20129,"journal":{"name":"Physiological genomics","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138478430","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Obesogenic diet disrupts tissue-specific mitochondrial gene signatures in the artery and capillary endothelium.","authors":"Luke S Dunaway, Melissa A Luse, Shruthi Nyshadham, Gamze Bulut, Gabriel F Alencar, Nicholas W Chavkin, Miriam Cortese-Krott, Karen K Hirschi, Brant E Isakson","doi":"10.1152/physiolgenomics.00109.2023","DOIUrl":"10.1152/physiolgenomics.00109.2023","url":null,"abstract":"<p><p>Endothelial cells (ECs) adapt to the unique needs of their resident tissue and metabolic perturbations, such as obesity. We sought to understand how obesity affects EC metabolic phenotypes, specifically mitochondrial gene expression. We investigated the mesenteric and adipose endothelium because these vascular beds have distinct roles in lipid homeostasis. Initially, we performed bulk RNA sequencing on ECs from mouse adipose and mesenteric vasculatures after a normal chow (NC) diet or high-fat diet (HFD) and found higher mitochondrial gene expression in adipose ECs compared with mesenteric ECs in both NC and HFD mice. Next, we performed single-cell RNA sequencing and categorized ECs as arterial, capillary, venous, or lymphatic. We found mitochondrial genes to be enriched in adipose compared with mesentery under NC conditions in artery and capillary ECs. After HFD, these genes were decreased in adipose ECs, becoming like mesenteric ECs. Transcription factor analysis revealed that peroxisome proliferator-activated receptor-γ (PPAR-γ) had high specificity in NC adipose artery and capillary ECs. These findings were recapitulated in single-nuclei RNA-sequencing data from human visceral adipose. The sum of these findings suggests that mesenteric and adipose arterial ECs metabolize lipids differently, and the transcriptional phenotype of the vascular beds converges in obesity due to downregulation of PPAR-γ in adipose artery and capillary ECs.<b>NEW & NOTEWORTHY</b> Using bulk and single-cell RNA sequencing on endothelial cells from adipose and mesentery, we found that an obesogenic diet induces a reduction in adipose endothelial oxidative phosphorylation gene expression, resulting in a phenotypic convergence of mesenteric and adipose endothelial cells. Furthermore, we found evidence that PPAR-γ drives this phenotypic shift. Mining of human data sets segregated based on body mass index supported these findings. These data point to novel mechanisms by which obesity induces endothelial dysfunction.</p>","PeriodicalId":20129,"journal":{"name":"Physiological genomics","volume":null,"pages":null},"PeriodicalIF":2.5,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11281809/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138047758","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Parental cardiorespiratory fitness influences early life energetics and metabolic health.","authors":"Daniel G Sadler, Lillie Treas, Taylor Ross, James D Sikes, Steven L Britton, Lauren G Koch, Brian D Piccolo, Elisabet Børsheim, Craig Porter","doi":"10.1152/physiolgenomics.00045.2023","DOIUrl":"10.1152/physiolgenomics.00045.2023","url":null,"abstract":"<p><p>High cardiorespiratory fitness (CRF) is associated with a reduced risk of metabolic disease and is linked to superior mitochondrial respiratory function. This study investigated how intrinsic CRF affects bioenergetics and metabolic health in adulthood and early life. Adult rats selectively bred for low and high running capacity [low capacity runners (LCR) and high capacity runners (HCR), respectively] underwent metabolic phenotyping before mating. Weanlings were evaluated at 4-6 wk of age, and whole body energetics and behavior were assessed using metabolic cages. Mitochondrial respiratory function was assessed in permeabilized tissues through high-resolution respirometry. Proteomic signatures of adult and weanling tissues were determined using mass spectrometry. The adult HCR group exhibited lower body mass, improved glucose tolerance, and greater physical activity compared with the LCR group. The adult HCR group demonstrated higher mitochondrial respiratory capacities in the soleus and heart compared with the adult LCR group, which coincided with a greater abundance of proteins involved in lipid catabolism. HCR and LCR weanlings had similar body mass, but HCR weanlings displayed reduced adiposity. In addition, HCR weanlings exhibited better glucose tolerance and higher physical activity levels than LCR weanlings. Higher respiratory capacities were observed in the soleus, heart, and liver tissues of HCR weanlings compared with LCR weanlings, which were not owed to greater mitochondrial content. Proteomic analyses indicated a greater potential for lipid oxidation in the contractile muscles of HCR weanlings. In conclusion, offspring born to parents with high CRF possess an enhanced capacity for lipid catabolism and oxidative phosphorylation, thereby influencing metabolic health. These findings highlight that intrinsic CRF shapes the bioenergetic phenotype with implications for metabolic resilience in early life.<b>NEW & NOTEWORTHY</b> Inherited cardiorespiratory fitness (CRF) influences early life bioenergetics and metabolic health. Higher intrinsic CRF was associated with reduced adiposity and improved glucose tolerance in early life. This metabolic phenotype was accompanied by greater mitochondrial respiratory capacity in skeletal muscle, heart, and liver tissue. Proteomic profiling of these three tissues further revealed potential mechanisms linking inherited CRF to early life metabolism.</p>","PeriodicalId":20129,"journal":{"name":"Physiological genomics","volume":null,"pages":null},"PeriodicalIF":2.5,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11281807/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138441123","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transcriptional response of the heart to vagus nerve stimulation.","authors":"Daniel O Kellett, Qadeer Aziz, Jonathan D Humphries, Alla Korsak, Alice Braga, Ana Gutierrez Del Arroyo, Marilena Crescente, Andrew Tinker, Gareth L Ackland, Alexander V Gourine","doi":"10.1152/physiolgenomics.00095.2023","DOIUrl":"10.1152/physiolgenomics.00095.2023","url":null,"abstract":"<p><p>Heart failure is a major clinical problem, with treatments involving medication, devices, and emerging neuromodulation therapies such as vagus nerve stimulation (VNS). Considering the ongoing interest in using VNS to treat cardiovascular disease, it is important to understand the genetic and molecular changes developing in the heart in response to this form of autonomic neuromodulation. This experimental animal (rat) study investigated the immediate transcriptional response of the ventricular myocardium to selective stimulation of vagal efferent activity using an optogenetic approach. Vagal preganglionic neurons in the dorsal motor nucleus of the vagus nerve were genetically targeted to express light-sensitive chimeric channelrhodopsin variant ChIEF and stimulated using light. RNA sequencing of the left ventricular myocardium identified 294 differentially expressed genes (false discovery rate < 0.05). Qiagen Ingenuity Pathway Analysis (IPA) highlighted 118 canonical pathways that were significantly modulated by vagal activity, of which 14 had a <i>z</i> score of ≥2/≤-2, including EIF-2, IL-2, integrin, and NFAT-regulated cardiac hypertrophy. IPA revealed the effect of efferent vagus stimulation on protein synthesis, autophagy, fibrosis, autonomic signaling, inflammation, and hypertrophy. IPA further predicted that the identified differentially expressed genes were the targets of 50 upstream regulators, including transcription factors (e.g., MYC and NRF1) and microRNAs (e.g., miR-335-3p and miR-338-3p). These data demonstrate that the vagus nerve has a major impact on the myocardial expression of genes involved in the regulation of key biological pathways. The transcriptional response of the ventricular myocardium induced by stimulation of vagal efferents is consistent with the beneficial effect of maintained/increased vagal activity on the heart.<b>NEW & NOTEWORTHY</b> This experimental animal study investigated the immediate transcriptional response of the ventricular myocardium to selective stimulation of vagal efferent activity. Vagal stimulation induced significant transcriptional changes in the heart involving the pathways controlling autonomic signaling, inflammation, fibrosis, and hypertrophy. This study provides the first direct evidence that myocardial gene expression is modulated by the activity of the autonomic nervous system.</p>","PeriodicalId":20129,"journal":{"name":"Physiological genomics","volume":null,"pages":null},"PeriodicalIF":2.5,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7616044/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138478428","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}