Abstract 12596: Manipulation of Gut Microbiota Influences Myocardial Mass in Mice

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Takehiro Kamo
Keyword(s):  
Gene Expression ◽  
Heart Failure ◽  
Body Weight ◽  
Gut Microbiota ◽  
Expression Profiles ◽  
Oral Treatment ◽  
Regulation Of Gene Expression ◽  
Heart Weight ◽  
Myocardial Mass ◽  
Antibiotic Cocktail

Introduction: Gut microbiota have developed a close relationship with human host during the co-evolutionary process for millions of years, and they play an essential role in the maintenance of host homeostasis. There is accumulating evidence that an imbalance in the gut microbial communities, referred to as dysbiosis, is associated with human pathologies including cardiovascular diseases. We and others have recently demonstrated that heart failure is associated with gut microbiota dysbiosis using 16S ribosomal RNA gene sequencing of fecal samples from patients with heart failure. This finding suggests a potential significance of gut microbiota in the pathophysiology of heart failure. However, the link between the gut microbiota and the heart remains largely unclear. Hypothesis: We hypothesized that manipulation of gut microbiota influences the structure of the heart. Methods: To determine the effects of gut microbiota depletion, cardiac structure and gene expression were evaluated in mice following treatment with orally administered broad-spectrum antibiotic cocktail. We subsequently explored the effects of administration of a single antibiotic agent on myocardial structure. Results: Antibiotic cocktail-treated mice showed a remarkable decrease in myocardial mass and cardiomyocyte size as compared with untreated mice (mean [±SD] ratio of heart weight to body weight, 3.87±0.25 mg/g in 44 antibiotic-treated mice vs. 4.38±0.21 mg/g in 45 untreated mice). The decrease in myocardial mass was associated with substantial changes in gene expression profiles in the heart, including the expression of genes encoding sarcomere proteins and extracellular matrix proteins. In addition, oral treatment with ampicillin alone led to a significant decrease in myocardial mass (mean [±SD] ratio of heart weight to body weight, 3.52±0.24 mg/g in 11 ampicillin-treated mice vs. 4.10±0.24 mg/g in 12 untreated mice). Conclusions: These results suggest that gut microbiota may modulate myocardial mass through the remote regulation of gene expression in the heart. Our study indicates an intimate relationship between the gut microbiota and the heart, and suggests the potential efficacy of manipulating gut microbiota in the prevention and treatment of heart failure.

scholarly journals Nourin-Associated miRNAs: Novel Inflammatory Monitoring Markers for Cyclocreatine Phosphate Therapy in Heart Failure

2021 ◽  
Vol 22 (7) ◽  
pp. 3575
Author(s):  
Salwa A. Elgebaly ◽  
Robert Todd ◽  
Donald L. Kreutzer ◽  
Robert Christenson ◽  
Nashwa El-Khazragy ◽  
...  
Keyword(s):  
Gene Expression ◽  
Heart Failure ◽  
Myocardial Injury ◽  
Cell Damage ◽  
Expression Profiles ◽  
Preventive Therapy ◽  
Heart Weight ◽  
Serum Samples ◽  
Expression Levels ◽  
Gene Expression Levels

Background: Cyclocreatine phosphate (CCrP) is a potent bioenergetic cardioprotective compound known to preserve high levels of cellular adenosine triphosphate during ischemia. Using the standard Isoproterenol (ISO) rat model of heart failure (HF), we recently demonstrated that the administration of CCrP prevented the development of HF by markedly reducing cardiac remodeling (fibrosis and collagen deposition) and maintaining normal ejection fraction and heart weight, as well as physical activity. The novel inflammatory mediator, Nourin is a 3-KDa formyl peptide rapidly released by ischemic myocardium and is associated with post-ischemic cardiac inflammation. We reported that the Nourin-associated miR-137 (marker of cell damage) and miR-106b-5p (marker of inflammation) are significantly upregulated in unstable angina patients and patients with acute myocardial infarction, but not in healthy subjects. Objectives: To test the hypothesis that Nourin-associated miR-137 and miR-106b-5p are upregulated in ISO-induced “HF rats” and that the administration of CCrP prevents myocardial injury (MI) and reduces Nourin gene expression in “non-HF rats”. Methods: 25 male Wistar rats (180–220 g) were used: ISO/saline (n = 6), ISO/CCrP (0.8 g/kg/day) (n = 5), control/saline (n = 5), and control/CCrP (0.8 g/kg/day) (n = 4). In a limited study, CCrP at a lower dose of 0.4 g/kg/day (n = 3) and a higher dose of 1.2 g/kg/day (n = 2) were also tested. The Rats were injected SC with ISO for two consecutive days at doses of 85 and 170 mg/kg/day, respectively, then allowed to survive for an additional two weeks. CCrP and saline were injected IP (1 mL) 24 h and 1 h before first ISO administration, then daily for two weeks. Serum CK-MB (U/L) was measured 24 h after the second ISO injection to confirm myocardial injury. After 14 days, gene expression levels of miR-137 and miR-106b-5p were measured in serum samples using quantitative real-time PCR (qPCR). Results: While high levels of CK-MB were detected after 24 h in the ISO/saline rats indicative of MI, the ISO/CCrP rats showed normal CK-MB levels, supporting prevention of MI by CCrP. After 14 days, gene expression profiles showed significant upregulation of miR-137 and miR-106b-5p by 8.6-fold and 8.7-fold increase, respectively, in the ISO/saline rats, “HF rats,” compared to the control/saline group. On the contrary, CCrP treatment at 0.8 g/kg/day markedly reduced gene expression of miR-137 by 75% and of miR-106b-5p by 44% in the ISO/CCrP rats, “non-HF rats,” compared to the ISO/Saline rats, “HF rats.” Additionally, healthy rats treated with CCrP for 14 days showed no toxicity in heart, liver, and renal function. Conclusions: Results suggest a role of Nourin-associated miR-137 and miR-106b-5p in the pathogenesis of HF and that CCrP treatment prevented ischemic injury in “non-HF rats” and significantly reduced Nourin gene expression levels in a dose–response manner. The Nourin gene-based mRNAs may, therefore, potentially be used as monitoring markers of drug therapy response in HF, and CCrP—as a novel preventive therapy of HF due to ischemia.

scholarly journals Genetic and epigenetic architecture of sex-biased expression in the jewel wasps Nasonia vitripennis and giraulti

2015 ◽  
Vol 112 (27) ◽  
pp. E3545-E3554 ◽  
Author(s):  
Xu Wang ◽  
John H. Werren ◽  
Andrew G. Clark
Keyword(s):  
Gene Expression ◽  
Expression Profiles ◽  
Regulation Of Gene Expression ◽  
Sequence Divergence ◽  
Adult Males ◽  
Rna Seq ◽  
Functional Categories ◽  
Nasonia Vitripennis ◽  
Constitutive Gene Expression ◽  
Genome Bisulfite Sequencing

There is extraordinary diversity in sexual dimorphism (SD) among animals, but little is known about its epigenetic basis. To study the epigenetic architecture of SD in a haplodiploid system, we performed RNA-seq and whole-genome bisulfite sequencing of adult females and males from two closely related parasitoid wasps, Nasonia vitripennis and Nasonia giraulti. More than 75% of expressed genes displayed significantly sex-biased expression. As a consequence, expression profiles are more similar between species within each sex than between sexes within each species. Furthermore, extremely male- and female-biased genes are enriched for totally different functional categories: male-biased genes for key enzymes in sex-pheromone synthesis and female-biased genes for genes involved in epigenetic regulation of gene expression. Remarkably, just 70 highly expressed, extremely male-biased genes account for 10% of all transcripts in adult males. Unlike expression profiles, DNA methylomes are highly similar between sexes within species, with no consistent sex differences in methylation found. Therefore, methylation changes cannot explain the extensive level of sex-biased gene expression observed. Female-biased genes have smaller sequence divergence between species, higher conservation to other hymenopterans, and a broader expression range across development. Overall, female-biased genes have been recruited from genes with more conserved and broadly expressing “house-keeping” functions, whereas male-biased genes are more recently evolved and are predominately testis specific. In summary, Nasonia accomplish a striking degree of sex-biased expression without sex chromosomes or epigenetic differences in methylation. We propose that methylation provides a general signal for constitutive gene expression, whereas other sex-specific signals cause sex-biased gene expression.

scholarly journals Food Bioactive HDAC Inhibitors in the Epigenetic Regulation of Heart Failure

Nutrients ◽  
2018 ◽  
Vol 10 (8) ◽  
pp. 1120 ◽  
Author(s):  
Levi Evans ◽  
Bradley Ferguson
Keyword(s):  
Gene Expression ◽  
Heart Failure ◽  
Signaling Pathways ◽  
Intracellular Signaling ◽  
Histone Deacetylases ◽  
Regulation Of Gene Expression ◽  
Hdac Inhibitors ◽  
Drug Efficacy ◽  
Histone Deacetylation ◽  
Epigenetic Modifiers

Approximately 5.7 million U.S. adults have been diagnosed with heart failure (HF). More concerning is that one in nine U.S. deaths included HF as a contributing cause. Current HF drugs (e.g., β-blockers, ACEi) target intracellular signaling cascades downstream of cell surface receptors to prevent cardiac pump dysfunction. However, these drugs fail to target other redundant intracellular signaling pathways and, therefore, limit drug efficacy. As such, it has been postulated that compounds designed to target shared downstream mediators of these signaling pathways would be more efficacious for the treatment of HF. Histone deacetylation has been linked as a key pathogenetic element for the development of HF. Lysine residues undergo diverse and reversible post-translational modifications that include acetylation and have historically been studied as epigenetic modifiers of histone tails within chromatin that provide an important mechanism for regulating gene expression. Of recent, bioactive compounds within our diet have been linked to the regulation of gene expression, in part, through regulation of the epi-genome. It has been reported that food bioactives regulate histone acetylation via direct regulation of writer (histone acetyl transferases, HATs) and eraser (histone deacetylases, HDACs) proteins. Therefore, bioactive food compounds offer unique therapeutic strategies as epigenetic modifiers of heart failure. This review will highlight food bio-actives as modifiers of histone deacetylase activity in the heart.

scholarly journals Spatial transcriptome profiling by MERFISH reveals subcellular RNA compartmentalization and cell cycle-dependent gene expression

2019 ◽  
Vol 116 (39) ◽  
pp. 19490-19499 ◽  
Author(s):  
Chenglong Xia ◽  
Jean Fan ◽  
George Emanuel ◽  
Junjie Hao ◽  
Xiaowei Zhuang
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Spatial Information ◽  
Detection Efficiency ◽  
Expression Profiles ◽  
Regulation Of Gene Expression ◽  
Rna Profiling ◽  
Spatially Resolved ◽  
Cycle Dependent

The expression profiles and spatial distributions of RNAs regulate many cellular functions. Image-based transcriptomic approaches provide powerful means to measure both expression and spatial information of RNAs in individual cells within their native environment. Among these approaches, multiplexed error-robust fluorescence in situ hybridization (MERFISH) has achieved spatially resolved RNA quantification at transcriptome scale by massively multiplexing single-molecule FISH measurements. Here, we increased the gene throughput of MERFISH and demonstrated simultaneous measurements of RNA transcripts from ∼10,000 genes in individual cells with ∼80% detection efficiency and ∼4% misidentification rate. We combined MERFISH with cellular structure imaging to determine subcellular compartmentalization of RNAs. We validated this approach by showing enrichment of secretome transcripts at the endoplasmic reticulum, and further revealed enrichment of long noncoding RNAs, RNAs with retained introns, and a subgroup of protein-coding mRNAs in the cell nucleus. Leveraging spatially resolved RNA profiling, we developed an approach to determine RNA velocity in situ using the balance of nuclear versus cytoplasmic RNA counts. We applied this approach to infer pseudotime ordering of cells and identified cells at different cell-cycle states, revealing ∼1,600 genes with putative cell cycle-dependent expression and a gradual transcription profile change as cells progress through cell-cycle stages. Our analysis further revealed cell cycle-dependent and cell cycle-independent spatial heterogeneity of transcriptionally distinct cells. We envision that the ability to perform spatially resolved, genome-wide RNA profiling with high detection efficiency and accuracy by MERFISH could help address a wide array of questions ranging from the regulation of gene expression in cells to the development of cell fate and organization in tissues.

Expressed genome molecular signatures of heart failure

2005 ◽  
Vol 43 (5) ◽  
Author(s):  
Choong Chin Liew
Keyword(s):  
Gene Expression ◽  
Heart Failure ◽  
Blood Cells ◽  
Complex Disease ◽  
Expression Profiles ◽  
Single Gene ◽  
Molecular Signatures ◽  
Microarray Gene Expression ◽  
Genomic Technologies ◽  
Gene Expression Studies

AbstractTraditional gene expression studies typically focus on one or a few genes of interest. An important limitation of single-gene studies is that they present a portrait of disease that is essentially static. However, disease is a dynamic process, driven by a combination of genetic, epigenetic and environmental factors. Recently, genomic technologies have permitted better characterization of the dynamic aspect of disease progression. Genome-wide expression profiles of cardiovascular diseases, heart failure in particular, using microarrays have been published and are providing new insights into this complex disease. Tissue biopsies required for traditional microarray studies, however, are often invasive and not readily available. By contrast, blood samples are relatively non-invasive and are readily available. In a number of recent studies, blood cells appear to be a viable substitute for tissue biopsy. Blood cells have the ability to mirror the body's tissues and organs in health and disease; thus, we hypothesize that blood cells can indicate at the molecular level the presence of disease. Here we review microarray gene expression profiling of blood RNA for a number of different diseases. Sieving through gene expression molecular signatures has identified groups of genes characteristic of each and has identified biomarkers associated with specific diseases.

The influence of rosuvastatin on the gastrointestinal microbiota and host gene expression profiles

2017 ◽  
Vol 312 (5) ◽  
pp. G488-G497 ◽  
Author(s):  
J. A. Nolan ◽  
P. Skuse ◽  
K. Govindarajan ◽  
E. Patterson ◽  
N. Konstantinidou ◽  
...  
Keyword(s):  
Gene Expression ◽  
Community Structure ◽  
Bile Acid ◽  
Microbial Community ◽  
Gut Microbiota ◽  
Acid Metabolism ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Bile Acid Metabolism ◽  
Gastrointestinal Microbiota

Statins are the most widely prescribed medications worldwide for the treatment of hypercholesterolemia. They inhibit the activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-R), an enzyme involved in cholesterol synthesis in higher organisms and in isoprenoid biosynthesis in some bacteria. We hypothesized that statins may influence the microbial community in the gut through either direct inhibition or indirect mechanisms involving alterations to host responses. We therefore examined the impact of rosuvastatin (RSV) on the community structure of the murine gastrointestinal microbiota. RSV was orally administered to mice and the effects on the gut microbiota, host bile acid profiles, and markers of inflammation were analyzed. RSV significantly influenced the microbial community in both the cecum and feces, causing a significant decrease in α-diversity in the cecum and resulting in a reduction of several physiologically relevant bacterial groups. RSV treatment of mice significantly affected bile acid metabolism and impacted expression of inflammatory markers known to influence microbial community structure (including RegIIIγ and Camp) in the gut. This study suggests that a commonly used statin (RSV) leads to an altered gut microbial composition in normal mice with attendant impacts on local gene expression profiles, a finding that should prompt further studies to investigate the implications of statins for gut microbiota stability and health in humans. NEW & NOTEWORTHY This work demonstrates that rosuvastatin administration in mice affects the gastrointestinal microbiota, influences bile acid metabolism, and alters transcription of genes encoding factors involved in gut homeostasis and immunity in the gastrointestinal tract.

scholarly journals Effects of folic acid supplementation to basal diets of broilers on growth performance, slaughter performance, IGF2 gene expression and methylation

2021 ◽  
Author(s):  
Xiuling Li ◽  
Yujie Zhang ◽  
Wenqian Jing ◽  
Weiqi Tang ◽  
Jinyi Xing ◽  
...  
Keyword(s):  
Gene Expression ◽  
Folic Acid ◽  
Average Daily Gain ◽  
Regulation Of Gene Expression ◽  
Subcutaneous Fat ◽  
Water Soluble ◽  
Heart Weight ◽  
Control Group ◽  
Igf2 Gene ◽  
Positive Effects

Folic acid (FA) is an important water-soluble vitamin and plays an important role as a cofactor and coenzyme in animal growth and development, and regulation of gene expression and methylation. A total of 270 female broiler chickens (1-day-old) were randomly allotted to three dietary treatments supplemented with 0 mg/kg (control group), 5 mg/kg, and 10 mg/kg FA in basal diets for 42 days, respectively. Each treatment had six replicate cages with 15 birds per cage. Dietary supplementation of 5 mg/kg FA significantly enhanced average body weight and average daily gain of 21-day-old broilers (P < 0.05), but significantly reduced subcutaneous fat thickness and widths of an intermuscular fat band of 42-day-old broilers by dietary FA treatments (P < 0.05). Also, a diet with 10 mg/kg FA supplementation significantly increased the relative heart weight of 42-day-old chickens (P < 0.05). Furthermore, dietary FA supplementation significantly improved the serum insulin-like growth factor 2 (IGF2) concentrations (P < 0.01) and IGF2 mRNA expression in the abdominal fat (P < 0.05), but no statistical differences were found in the methylation of IGF2 promoter (P > 0.05). The present study demonstrated that dietary FA supplementation may have positive effects on chicken growth through increased IGF2 gene expression.  

scholarly journals Oral Delivery of Bacillus subtilis Expressing Chicken NK-2 Peptide Protects Against Eimeria acervulina Infection in Broiler Chickens

2021 ◽  
Vol 8 ◽  
Author(s):  
Samiru S. Wickramasuriya ◽  
Inkyung Park ◽  
Youngsub Lee ◽  
Woo H. Kim ◽  
Chris Przybyszewski ◽  
...  
Keyword(s):  
Gene Expression ◽  
Body Weight ◽  
Bacillus Subtilis ◽  
Oral Delivery ◽  
Broiler Chickens ◽  
Oral Treatment ◽  
Body Weight Loss ◽  
Intestinal Damage ◽  
Gut Health ◽  
Gut Damage

Chicken NK-lysin peptide 2 (cNK-2) is a natural lytic peptide with direct cytotoxicity against many apicomplexan parasites including Eimeria. Developing an effective oral delivery strategy to express cNK-2 in the intestine, where Eimeria parasites interact with the host's gut epithelial cells, may effectively reduce the fecundity of parasites and minimize intestinal damage. Furthermore, cNK-2 modulates gut immune responses to decrease local inflammation elicited by Eimeria infection in the intestine. Therefore, we developed a stable strain of Bacillus subtilis (B. subtilis) that carries cNK-2 to the gut to determine its effectiveness in ameliorating the negative impacts of coccidiosis and to replace the use of antibiotics in controlling coccidiosis in commercial broiler chicken production. Chickens were randomly allocated into eight treatment groups: two control groups (NC: E. acervulina infected non-B. subtilis control; CON: non-infected control); three B. subtilis-empty vector (EV) groups (EV6: 106 cfu/day/bird; EV8: 108 cfu/day/bird; EV10: 1010 cfu/day/bird), and three B. subtilis-cNK-2 groups (NK6: 106 cfu/day/bird; NK8: 108 cfu/day/bird; NK10: 1010 cfu/day/bird). All chickens, except those in the CON group, were challenged with 5,000 freshly sporulated E. acervulina oocysts through oral gavage on day 15. Chickens were given an oral dose of B. subtilis on days 14, 15, and 16. Body weight, weight gains, and fecal oocyst shedding were measured. To investigate the efficacy of oral B. subtilis-cNK-2 against coccidiosis, gene expression of gut health-related biomarkers was measured using RT-PCR. Markers included SOD1, CAT, and HMOX1 for oxidative stress in the spleen and intestinal mucosa, OCLN, ZO-1, and JAM2 for tight junction proteins, and MUC2 for mucin gene expression in the gut. The results showed that oral treatment of young chickens with B. subtilis-cNK-2 improved growth performance, enhanced gut integrity, and reduced fecal oocyst shedding. Altogether, these results confirm B. subtilis-cNK-2 treatment as a promising and effective alternative strategy to replace antibiotics against coccidiosis based on its ability to reduce parasite survival, to reduce coccidiosis-induced body weight loss, and to decrease gut damage based on the enhanced expression of proteins associated with gut integrity and intestinal health.

Regulation of Gene Expression in the Failing Myocardium: Evidence for a Heart Failure Gene Program

1994 ◽  
pp. 7-16
Author(s):  
Arthur M. Feldman ◽  
Vinnette T. Edwards ◽  
Jennifer E. Lawrence ◽  
Randall E. Williams ◽  
Warren D. Rosenblum
Keyword(s):  
Gene Expression ◽  
Heart Failure ◽  
Regulation Of Gene Expression
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