scholarly journals Transcriptome Analysis of Hypertrophic Heart Tissues from Murine Transverse Aortic Constriction and Human Aortic Stenosis Reveals Key Genes and Transcription Factors Involved in Cardiac Remodeling Induced by Mechanical Stress

2019 ◽  
Vol 2019 ◽  
pp. 1-10
Author(s):  
Peng Yu ◽  
Baoli Zhang ◽  
Ming Liu ◽  
Ying Yu ◽  
Ji Zhao ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Aortic Stenosis ◽  
Mechanical Stress ◽  
Cardiac Remodeling ◽  
Interaction Network ◽  
Cytokine Signaling ◽  
Transverse Aortic Constriction ◽  
Aortic Constriction ◽  
Genomic Changes

Background. Mechanical stress-induced cardiac remodeling that results in heart failure is characterized by transcriptional reprogramming of gene expression. However, a systematic study of genomic changes involved in this process has not been performed to date. To investigate the genomic changes and underlying mechanism of cardiac remodeling, we collected and analyzed DNA microarray data for murine transverse aortic constriction (TAC) and human aortic stenosis (AS) from the Gene Expression Omnibus database and the European Bioinformatics Institute. Methods and Results. The differential expression genes (DEGs) across the datasets were merged. The Venn diagrams showed that the number of intersections for early and late cardiac remodeling was 74 and 16, respectively. Gene ontology and protein–protein interaction network analysis showed that metabolic changes, cell differentiation and growth, cell cycling, and collagen fibril organization accounted for a great portion of the DEGs in the TAC model, while in AS patients’ immune system signaling and cytokine signaling displayed the most significant changes. The intersections between the TAC model and AS patients were few. Nevertheless, the DEGs of the two species shared some common regulatory transcription factors (TFs), including SP1, CEBPB, PPARG, and NFKB1, when the heart was challenged by applied mechanical stress. Conclusions. This study unravels the complex transcriptome profiles of the heart tissues and highlighting the candidate genes involved in cardiac remodeling induced by mechanical stress may usher in a new era of precision diagnostics and treatment in patients with cardiac remodeling.

scholarly journals Mineralocorticoid Receptor in Smooth Muscle Contributes to Pressure Overload–Induced Heart Failure

2021 ◽  
Vol 14 (2) ◽  
Author(s):  
Seung Kyum Kim ◽  
Lauren A. Biwer ◽  
M. Elizabeth Moss ◽  
Joshua J. Man ◽  
Mark J. Aronovitz ◽  
...  
Keyword(s):  
Gene Expression ◽  
Heart Failure ◽  
Smooth Muscle ◽  
Cardiac Remodeling ◽  
Mineralocorticoid Receptor ◽  
Pressure Overload ◽  
Transverse Aortic Constriction ◽  
Aortic Constriction ◽  
Flow Reserve ◽  
Intracardiac Pressure

Background: Mineralocorticoid receptor (MR) antagonists decrease heart failure (HF) hospitalization and mortality, but the mechanisms are unknown. Preclinical studies reveal that the benefits on cardiac remodeling and dysfunction are not completely explained by inhibition of MR in cardiomyocytes, fibroblasts, or endothelial cells. The role of MR in smooth muscle cells (SMCs) in HF has never been explored. Methods: Male mice with inducible deletion of MR from SMCs (SMC-MR-knockout) and their MR-intact littermates were exposed to HF induced by 27-gauge transverse aortic constriction versus sham surgery. HF phenotypes and mechanisms were measured 4 weeks later using cardiac ultrasound, intracardiac pressure measurements, exercise testing, histology, cardiac gene expression, and leukocyte flow cytometry. Results: Deletion of MR from SMC attenuated transverse aortic constriction-induced HF with statistically significant improvements in ejection fraction, cardiac stiffness, chamber dimensions, intracardiac pressure, pulmonary edema, and exercise capacity. Mechanistically, SMC-MR-knockout protected from adverse cardiac remodeling as evidenced by decreased cardiomyocyte hypertrophy and fetal gene expression, interstitial and perivascular fibrosis, and inflammatory and fibrotic gene expression. Exposure to pressure overload resulted in a statistically significant decline in cardiac capillary density and coronary flow reserve in MR-intact mice. These vascular parameters were improved in SMC-MR-knockout mice compared with MR-intact littermates exposed to transverse aortic constriction. Conclusions: These results provide a novel paradigm by which MR inhibition may be beneficial in HF by blocking MR in SMC, thereby improving cardiac blood supply in the setting of pressure overload–induced hypertrophy, which in turn mitigates the adverse cardiac remodeling that contributes to HF progression and symptoms.

scholarly journals Identification of the Potential Biomarkers Involved in the Human Oral Mucosal Wound Healing: A Bioinformatic Study

2021 ◽  
Vol 2021 ◽  
pp. 1-16
Author(s):  
Wanchen Ning ◽  
Xiao Jiang ◽  
Zhengyang Sun ◽  
Anthony Chukwunonso Ogbuehi ◽  
Wenli Gu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Wound Healing ◽  
Transcription Factors ◽  
Signaling Pathways ◽  
Oral Mucosa ◽  
Mirna Target ◽  
Interaction Network ◽  
Epigenetic Mechanisms ◽  
Ppi Network ◽  
Mucosal Wound

Objective. To identify the key genetic and epigenetic mechanisms involved in the wound healing process after injury of the oral mucosa. Materials and Methods. Gene expression profiling datasets pertaining to rapid wound healing of oral mucosa were identified using the Gene Expression Omnibus (GEO) database. Differential gene expression analysis was performed to identify differentially expressed genes (DEGs) during oral mucosal wound healing. Next, functional enrichment analysis was performed to identify the biological processes (BPs) and signaling pathways relevant to these DEGs. A protein-protein interaction (PPI) network was constructed to identify hub DEGs. Interaction networks were constructed for both miRNA-target DEGs and DEGs-transcription factors. A DEGs-chemical compound interaction network and a miRNA-small molecular interaction network were also constructed. Results. DEGs were found significantly enriched in several signaling pathways including arachidonic acid metabolism, cell cycle, p53, and ECM-receptor interaction. Hub genes, GABARAPL1, GABARAPL2, HDAC5, MAP1LC3A, AURKA, and PLK1, were identified via PPI network analysis. Two miRNAs, miR-34a-5p and miR-335-5p, were identified as pivotal players in the miRNA-target DEGs network. Four transcription factors FOS, PLAU, BCL6, and RORA were found to play key roles in the TFs-DEGs interaction network. Several chemical compounds including Valproic acid, Doxorubicin, Nickel, and tretinoin and small molecular drugs including atorvastatin, 17β-estradiol, curcumin, and vitamin D3 were noted to influence oral mucosa regeneration by regulating the expression of healing-associated DEGs/miRNAs. Conclusion. Genetic and epigenetic mechanisms and specific drugs were identified as significant molecular mechanisms and entities relevant to oral mucosal healing. These may be valuable potential targets for experimental research.

scholarly journals Hub Targets Analysis of miRNA-mRNA-TF Network in Diabetic Cardiomyopathy

2021 ◽  
Author(s):  
Bincheng Ren ◽  
Kaini He ◽  
Miao Yuan ◽  
Yu Wang ◽  
Yuanyuan Tie ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Diabetic Cardiomyopathy ◽  
Bioinformatics Analysis ◽  
Interaction Network ◽  
Gene Expression Omnibus ◽  
Vital Role ◽  
Data Sets ◽  
Go Enrichment ◽  
Geo Database

Abstract Background: The pathogenic mechanism and development of the diabetic cardiomyopathy(DCM) has been generally explained, and it is clear that the microRNAs(miRNAs), mRNAs and transcription factors(TFs) participate in the process of the DCM disease. Yet, the hub targets of the disease progression are not clear.Methods: To figure out the problem, we downloaded data sets from the Gene Expression Omnibus(GEO) database (GSE44179 and GSE4745). The targeted mRNAs of miRNAs were downloaded from TargetScan, miRBD and microT-CDS database. Gene Ontology (GO) enrichment of miRNAs and mRNAs were analysed in DAVID.R studio software was used to visualize the results of screened targets and GO enrichment. Cytoscape software was used to visualize the miRNA-mRNA-TF interaction network and calculate the hub targets. Results: We filtered eight miRNAs, nine mRNAs and ten transcription factors(TFs) by bioinformatics analysis, and constructed a miRNA-mRNA-TF network. The top ten degrees of nodes in the network are rno-miR-7a, Hnf4a, rno-miR-17, rno-miR-21, rno-miR-122, rno-miR-200c, Med1, Mlxipl, SP1 and rno-miR-34a, which were closely related to the process of DCM. Conclusion: This study revealed that rno-miR-7a, Hnf4a, rno-miR-17and rno-miR-21 may play vital role in the progress of diabetic cardiomyopathy.

Microarray analysis of gene expression after transverse aortic constriction in mice

2004 ◽  
Vol 19 (1) ◽  
pp. 93-105 ◽  
Author(s):  
Mingming Zhao ◽  
Amy Chow ◽  
Jennifer Powers ◽  
Giovanni Fajardo ◽  
Daniel Bernstein
Keyword(s):  
Gene Expression ◽  
Statistical Analysis ◽  
Cardiac Hypertrophy ◽  
Heart Function ◽  
Expression Profiles ◽  
Alternative Methods ◽  
Transverse Aortic Constriction ◽  
Aortic Constriction ◽  
Altered Expression ◽  
Qrt Pcr

Cardiac hypertrophy is a compensatory response initially beneficial to heart function but can ultimately lead to cardiac decompensation. It is an integrated process involving multiple cellular signaling pathways and their cross talk. Microarray GeneChip technology is a powerful new tool to identify gene expression profiles of cardiac hypertrophy. To identify well-characterized as well as novel adaptive mechanisms, we utilized a murine model of compensated pressure overload hypertrophy (transverse aortic constriction, TAC). At 48 h, 10 days, and 3 wk, hearts were harvested and total RNA hybridized to Affymetrix U74Av2 GeneChips, which contain a 12,488-gene/EST probe set. Verification of gene expression was performed by SYBR quantitative real-time RT-PCR (QRT-PCR) for selected genes. A rigorous evaluation of the adequacy of the control condition was also performed. For statistical analysis we generated a four-step filtering criteria. Our results show an upregulation of 38 genes (48 h), 269 genes (10 days), and 203 genes (3 wk) and downregulation of 15 genes (48 h), 160 genes (10 days), and 124 genes (3 wk). Transcripts differentially expressed after TAC were categorized into 12 functional groups and revealed the presence of several intriguing transcripts, e.g., cell proliferation-related Ki-67 and several apoptosis-related genes. Overall changes in QRT-PCR were in accordance with GeneChip data, with the highest correlation for genes with the largest up- or downregulation with TAC. Thus TAC results in altered expression of genes in several pathways regulating both cardiac structure and function. However, for in vivo gene microarray experiments, it is critical to define adequate controls, perform rigorous statistical analysis, and provide validation by alternative methods.

scholarly journals Effect of Transverse Aortic Constriction on Cardiac Structure, Function and Gene Expression in Pregnant Rats

PLoS ONE ◽  
2014 ◽  
Vol 9 (2) ◽  
pp. e89559 ◽  
Author(s):  
Nils Thomas Songstad ◽  
David Johansen ◽  
Ole-Jacob How ◽  
Per Ivar Kaaresen ◽  
Kirsti Ytrehus ◽  
...  
Keyword(s):  
Gene Expression ◽  
Structure Function ◽  
Cardiac Structure ◽  
Transverse Aortic Constriction ◽  
Aortic Constriction ◽  
Pregnant Rats

scholarly journals Innate Immune Nod1/RIP2 Signaling Is Essential for Cardiac Hypertrophy but Requires Mitochondrial Antiviral Signaling Protein for Signal Transductions and Energy Balance

Circulation ◽  
2020 ◽  
Vol 142 (23) ◽  
pp. 2240-2258 ◽  
Author(s):  
Han-Bin Lin ◽  
Kotaro Naito ◽  
Yena Oh ◽  
Gedaliah Farber ◽  
Georges Kanaan ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Cardiac Remodeling ◽  
Innate Immune ◽  
Transverse Aortic Constriction ◽  
Wild Type ◽  
Aortic Constriction ◽  
Antiviral Signaling ◽  
Mitochondrial Antiviral Signaling ◽  
Mitochondrial Antiviral Signaling Protein

Background: Cardiac hypertrophy is a key biological response to injurious stresses such as pressure overload and, when excessive, can lead to heart failure. Innate immune activation by danger signals, through intracellular pattern recognition receptors such as nucleotide-binding oligomerization domain 1 (Nod1) and its adaptor receptor-interacting protein 2 (RIP2), might play a major role in cardiac remodeling and progression to heart failure. We hypothesize that Nod1/RIP2 are major contributors to cardiac hypertrophy, but may not be sufficient to fully express the phenotype alone. Methods: To elucidate the contribution of Nod1/RIP2 signaling to cardiac hypertrophy, we randomized Nod1 –/– , RIP2 –/– , or wild-type mice to transverse aortic constriction or sham operations. Cardiac hypertrophy, fibrosis, and cardiac function were examined in these mice. Results: Nod1 and RIP2 proteins were upregulated in the heart after transverse aortic constriction, and this was paralleled by increased expression of mitochondrial proteins, including mitochondrial antiviral signaling protein (MAVS). Nod1 –/– and RIP2 –/– mice subjected to transverse aortic constriction exhibited better survival, improved cardiac function, and decreased cardiac hypertrophy. Downstream signal transduction pathways that regulate inflammation and fibrosis, including NF (nuclear factor) κB and MAPK (mitogen-activated protein kinase)-GATA4/p300, were reduced in both Nod1 –/– and RIP2 –/– mice after transverse aortic constriction compared with wild-type mice. Coimmunoprecipitation of extracted cardiac proteins and confocal immunofluorescence microscopy showed that Nod1/RIP2 interaction was robust and that this complex also included MAVS as an essential component. Suppression of MAVS expression attenuated the complex formation, NF κB signaling, and myocyte hypertrophy. Interrogation of mitochondrial function compared in the presence or ablation of MAVS revealed that MAVS serves to suppress mitochondrial energy output and mediate fission/fusion related dynamic changes. The latter is possibly linked to mitophagy during cardiomyocytes stress, which may provide an intriguing link between innate immune activation and mitochondrial energy balance under stress or injury conditions. Conclusions: We have identified that innate immune Nod1/RIP2 signaling is a major contributor to cardiac remodeling after stress. This process is critically joined by and regulated through the mitochondrial danger signal adapter MAVS. This novel complex coordinates remodeling, inflammatory response, and mitochondrial energy metabolism in stressed cardiomyocytes. Thus, Nod1/RIP2/MAVS signaling complex may represent an attractive new therapeutic approach toward heart failure.

scholarly journals High Systolic Blood Pressure Induces Cerebral Microvascular Endothelial Dysfunction, Neurovascular Unit Damage, and Cognitive Decline in Mice

Hypertension ◽  
2019 ◽  
Vol 73 (1) ◽  
pp. 217-228 ◽  
Author(s):  
Olivia de Montgolfier ◽  
Anthony Pinçon ◽  
Philippe Pouliot ◽  
Marc-Antoine Gillis ◽  
Jonathan Bishop ◽  
...  
Keyword(s):  
Alzheimer Disease ◽  
Cognitive Decline ◽  
Vascular Dementia ◽  
Mechanical Stress ◽  
Neurovascular Unit ◽  
Brain Inflammation ◽  
Transverse Aortic Constriction ◽  
Wild Type ◽  
Aortic Constriction ◽  
Microvascular Endothelial

A chronic and gradual increase in pulse pressure (PP) is associated with cognitive decline and dementia in older individuals, but the mechanisms remain ill-defined. We hypothesized that a chronic elevation of PP would cause brain microvascular endothelial mechanical stress, damage the neurovascular unit, and ultimately induce cognitive impairment in mice, potentially contributing to the progression of vascular dementia and Alzheimer disease. To test our hypothesis, male control wild-type mice and Alzheimer disease model APP/PS1 (amyloid precursor protein/presenilin 1) mice were exposed to a transverse aortic constriction for 6 weeks, creating a PP overload in the right carotid (ipsilateral). We show that the transverse aortic constriction procedure associated with high PP induces a cascade of vascular damages in the ipsilateral parenchymal microcirculation: in wild-type mice, it impairs endothelial dilatory and blood brain barrier functions and causes microbleeds, a reduction in microvascular density, microvascular cell death by apoptosis, leading to severe hypoperfusion and parenchymal cell senescence. These damages were associated with brain inflammation and a significant reduction in learning and spatial memories. In APP/PS1 mice, that endogenously display severe cerebral vascular dysfunctions, microbleeds, parenchymal inflammation and cognitive dysfunction, transverse aortic constriction–induced high PP further aggravates cerebrovascular damage, Aβ (beta-amyloid) accumulation, and prevents learning. Our study, therefore, demonstrates that brain microvessels are vulnerable to a high PP and mechanical stress associated with transverse aortic constriction, promoting severe vascular dysfunction, disruption of the neurovascular unit, and cognitive decline. Hence, chronic elevated amplitude of the PP could contribute to the development and progression of vascular dementia including Alzheimer disease.

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