Acetyltransferase p300 Is a Putative Epidrug Target for Amelioration of Cellular Aging-Related Cardiovascular Disease

Cardiovascular disease is the leading cause of accelerated as well as chronological aging-related human morbidity and mortality worldwide. Genetic, immunologic, unhealthy lifestyles including daily consumption of high-carb/high-fat fast food, lack of exercise, drug addiction, cigarette smoke, alcoholism, and exposure to environmental pollutants like particulate matter (PM)-induced stresses contribute profoundly to accelerated and chronological cardiovascular aging and associated life threatening diseases. All these stressors alter gene expression epigenetically either through activation or repression of gene transcription via alteration of chromatin remodeling enzymes and chromatin landscape by DNA methylation or histone methylation or histone acetylation. Acetyltransferase p300, a major epigenetic writer of acetylation on histones and transcription factors, contributes significantly to modifications of chromatin landscape of genes involved in cellular aging and cardiovascular diseases. In this review, the key findings those implicate acetyltransferase p300 as a major contributor to cellular senescence or aging related cardiovascular pathologies including vascular dysfunction, cardiac hypertrophy, myocardial infarction, cardiac fibrosis, systolic/diastolic dysfunction, and aortic valve calcification are discussed. The efficacy of natural or synthetic small molecule inhibitor targeting acetyltransferase p300 in amelioration of stress-induced dysregulated gene expression, cellular aging, and cardiovascular disease in preclinical study is also discussed.

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Pentraxin 3: A Novel Biomarker for Inflammatory Cardiovascular Disease

International Journal of Vascular Medicine ◽

10.1155/2012/657025 ◽

2012 ◽

Vol 2012 ◽

pp. 1-6 ◽

Cited By ~ 18

Author(s):

Kenji Inoue ◽

Tatsuhiko Kodama ◽

Hiroyuki Daida

Keyword(s):

Gene Expression ◽

Cardiovascular Disease ◽

Pentraxin 3 ◽

Human Endothelial Cells ◽

C Reactive Protein ◽

Physiological Concentration ◽

Reactive Protein ◽

Atherosclerotic Lesions ◽

Human Genes

Numerous studies have recently examined the role of pentraxin 3 (PTX3) in clinical situations. The pentraxin family includes C-reactive protein (CRP); however, unlike CRP, PTX3 is expressed predominantly in atherosclerotic lesions that involve macrophages, neutrophils, dendritic cells, or smooth muscle cells. Interestingly, PTX3 gene expression in human endothelial cells is suppressed to a greater extent by pitavastatin than the expression of 6,000 other human genes that have been examined, suggesting that PTX3 may be a novel biomarker for inflammatory cardiovascular disease. The expression and involvement of PTX3 in cardiovascular diseases are discussed in this paper, along with the characteristics of PTX3 that make it a suitable biomarker; namely, that the physiological concentration is known and it is independent of other risk factors. The results discussed in this paper suggest that further investigations into the potential novel use of PTX3 as a biomarker for inflammatory cardiovascular disease should be undertaken.

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DNA methylation and gene expression integration in cardiovascular disease

Clinical Epigenetics ◽

10.1186/s13148-021-01064-y ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Guillermo Palou-Márquez ◽

Isaac Subirana ◽

Lara Nonell ◽

Alba Fernández-Sanlés ◽

Roberto Elosua

Keyword(s):

Gene Expression ◽

Cardiovascular Disease ◽

Dna Methylation ◽

Cardiovascular Diseases ◽

Disease Risk ◽

Cardiovascular Disease Risk ◽

Risk Function ◽

Predictive Biomarkers ◽

Independent Study ◽

Cell Type

Abstract Background The integration of different layers of omics information is an opportunity to tackle the complexity of cardiovascular diseases (CVD) and to identify new predictive biomarkers and potential therapeutic targets. Our aim was to integrate DNA methylation and gene expression data in an effort to identify biomarkers related to cardiovascular disease risk in a community-based population. We accessed data from the Framingham Offspring Study, a cohort study with data on DNA methylation (Infinium HumanMethylation450 BeadChip; Illumina) and gene expression (Human Exon 1.0 ST Array; Affymetrix). Using the MOFA2 R package, we integrated these data to identify biomarkers related to the risk of presenting a cardiovascular event. Results Four independent latent factors (9, 19, 21—only in women—and 27), driven by DNA methylation, were associated with cardiovascular disease independently of classical risk factors and cell-type counts. In a sensitivity analysis, we also identified factor 21 as associated with CVD in women. Factors 9, 21 and 27 were also associated with coronary heart disease risk. Moreover, in a replication effort in an independent study three of the genes included in factor 27 were also present in a factor identified to be associated with myocardial infarction (CDC42BPB, MAN2A2 and RPTOR). Factor 9 was related to age and cell-type proportions; factor 19 was related to age and B cells count; factor 21 pointed to human immunodeficiency virus infection-related pathways and inflammation; and factor 27 was related to lifestyle factors such as alcohol consumption, smoking and body mass index. Inclusion of factor 21 (only in women) improved the discriminative and reclassification capacity of the Framingham classical risk function and factor 27 improved its discrimination. Conclusions Unsupervised multi-omics data integration methods have the potential to provide insights into the pathogenesis of cardiovascular diseases. We identified four independent factors (one only in women) pointing to inflammation, endothelium homeostasis, visceral fat, cardiac remodeling and lifestyles as key players in the determination of cardiovascular risk. Moreover, two of these factors improved the predictive capacity of a classical risk function.

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Protective effects of a unique combination of nutritionally active ingredients on risk factors and gene expression associated with atherosclerosis in C57BL/6J mice fed a high fat diet

Food & Function ◽

10.1039/d0fo02867c ◽

2021 ◽

Author(s):

Joe W. E. Moss ◽

Jessica O Williams ◽

Wijdan Al-Ahmadi ◽

Victoria O'Morain ◽

Yee-Hung Chan ◽

...

Keyword(s):

Gene Expression ◽

Risk Factors ◽

Cardiovascular Disease ◽

High Fat Diet ◽

Inflammatory Disorder ◽

Protective Effects ◽

Unique Combination ◽

Omega 3 ◽

High Fat ◽

Food Ingredients

Atherosclerosis, an inflammatory disorder of the vasculature and the underlying cause of cardiovascular disease, is responsible for one in three global deaths. Consumption of active food ingredients such as omega-3...

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Variation in the SERPINA6/SERPINA1 locus alters morning plasma cortisol, hepatic corticosteroid binding globulin expression, gene expression in peripheral tissues, and risk of cardiovascular disease

Journal of Human Genetics ◽

10.1038/s10038-020-00895-6 ◽

2021 ◽

Author(s):

Andrew A. Crawford ◽

◽

Sean Bankier ◽

Elisabeth Altmaier ◽

Catriona L. K. Barnes ◽

...

Keyword(s):

Gene Expression ◽

Cardiovascular Disease ◽

Genetic Variants ◽

Plasma Cortisol ◽

Statistical Power ◽

Mendelian Randomisation ◽

Eqtl Analysis ◽

Causative Role ◽

Peripheral Tissues ◽

Corticosteroid Binding Globulin

AbstractThe stress hormone cortisol modulates fuel metabolism, cardiovascular homoeostasis, mood, inflammation and cognition. The CORtisol NETwork (CORNET) consortium previously identified a single locus associated with morning plasma cortisol. Identifying additional genetic variants that explain more of the variance in cortisol could provide new insights into cortisol biology and provide statistical power to test the causative role of cortisol in common diseases. The CORNET consortium extended its genome-wide association meta-analysis for morning plasma cortisol from 12,597 to 25,314 subjects and from ~2.2 M to ~7 M SNPs, in 17 population-based cohorts of European ancestries. We confirmed the genetic association with SERPINA6/SERPINA1. This locus contains genes encoding corticosteroid binding globulin (CBG) and α1-antitrypsin. Expression quantitative trait loci (eQTL) analyses undertaken in the STARNET cohort of 600 individuals showed that specific genetic variants within the SERPINA6/SERPINA1 locus influence expression of SERPINA6 rather than SERPINA1 in the liver. Moreover, trans-eQTL analysis demonstrated effects on adipose tissue gene expression, suggesting that variations in CBG levels have an effect on delivery of cortisol to peripheral tissues. Two-sample Mendelian randomisation analyses provided evidence that each genetically-determined standard deviation (SD) increase in morning plasma cortisol was associated with increased odds of chronic ischaemic heart disease (0.32, 95% CI 0.06–0.59) and myocardial infarction (0.21, 95% CI 0.00–0.43) in UK Biobank and similarly in CARDIoGRAMplusC4D. These findings reveal a causative pathway for CBG in determining cortisol action in peripheral tissues and thereby contributing to the aetiology of cardiovascular disease.

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The control of Ca2+ influx and NFATc3 signaling in arterial smooth muscle during hypertension

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.0808759105 ◽

2008 ◽

Vol 105 (40) ◽

pp. 15623-15628 ◽

Cited By ~ 65

Author(s):

Madeline Nieves-Cintrón ◽

Gregory C. Amberg ◽

Manuel F. Navedo ◽

Jeffery D. Molkentin ◽

Luis F. Santana

Keyword(s):

Gene Expression ◽

Heart Failure ◽

Blood Pressure ◽

Smooth Muscle ◽

Vascular Dysfunction ◽

Signaling Cascade ◽

Myogenic Tone ◽

Excitable Cells ◽

Open Probability ◽

Induced Hypertension

Many excitable cells express L-type Ca2+ channels (LTCCs), which participate in physiological and pathophysiological processes ranging from memory, secretion, and contraction to epilepsy, heart failure, and hypertension. Clusters of LTCCs can operate in a PKCα-dependent, high open probability mode that generates sites of sustained Ca2+ influx called “persistent Ca2+ sparklets.” Although increased LTCC activity is necessary for the development of vascular dysfunction during hypertension, the mechanisms leading to increased LTCC function are unclear. Here, we tested the hypothesis that increased PKCα and persistent Ca2+ sparklet activity contributes to arterial dysfunction during hypertension. We found that PKCα and persistent Ca2+ sparklet activity is indeed increased in arterial myocytes during hypertension. Furthermore, in human arterial myocytes, PKCα-dependent persistent Ca2+ sparklets activated the prohypertensive calcineurin/NFATc3 signaling cascade. These events culminated in three hallmark signs of hypertension-associated vascular dysfunction: increased Ca2+ entry, elevated arterial [Ca2+]i, and enhanced myogenic tone. Consistent with these observations, we show that PKCα ablation is protective against the development of angiotensin II-induced hypertension. These data support a model in which persistent Ca2+ sparklets, PKCα, and calcineurin form a subcellular signaling triad controlling NFATc3-dependent gene expression, arterial function, and blood pressure. Because of the ubiquity of these proteins, this model may represent a general signaling pathway controlling gene expression and cellular function.

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Abstract 367: Lysyl Oxidase Expression by Cardiac Fibroblasts is Regulated by Integrin-mediated Signaling

Circulation Research ◽

10.1161/res.117.suppl_1.367 ◽

2015 ◽

Vol 117 (suppl_1) ◽

Author(s):

Albert Gao ◽

Lauren D Black

Keyword(s):

Gene Expression ◽

Cardiac Fibrosis ◽

Lysyl Oxidase ◽

Cardiac Fibroblasts ◽

Therapeutic Strategies ◽

Expression Of Genes ◽

Adverse Remodeling ◽

Novel Therapeutic Strategies ◽

Free Media ◽

Tgf Β1

Cardiac fibrosis following myocardial infarction (MI) leads to reduced cardiac function, and contributes to heart failure and mortality. Recent studies shown the extent of adverse remodeling may be mitigated by therapeutic strategies which regulate cardiac fibroblast mediated-remodeling. Since cross-linking by lysyl oxidase (LOX) increases following MI and alters the mechanical properties of the infarct, it is critical to characterize how its expression is regulated by CFs post-MI. While LOX expression is attributable to TGF-β1 signaling, we hypothesize that changes in the stiffness and composition of the ECM can also alter LOX expression via integrin-mediated signaling. To investigate this, we isolated CFs from healthy left ventricle (LV) and infarcted cardiac fibroblasts (ICFs) from 1 week post-MI LV and cultured them on tissue culture plastic (TCP) and collagen I-coated plates (COL) in serum-free media for 48 hours to assess the expression of genes associated with LOX signaling, fibrosis, and myofibroblast activation. Our results show an upregulation of LOX gene expression in both CFs and ICFs when cultured on COL and this is further emphasized with the presence of TGF-β1 (Fig. 1A). Gene expression of col1α1, integrin β1 subunit and αSMA (Fig. 1B-D) also exhibit similar upregulation. Ongoing studies will investigate how altered substrate stiffness and composition affect gene expression of LOX and other genes associated with fibrosis. By understanding the effect of the physical microenvironment on the expression of fibrotic genes including LOX, we aim to develop novel therapeutic strategies to attenuate cardiac fibrosis and thus improve cardiac recovery following MI.

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Evaluation of the Most Current and Effective Methods in the Analysis of Chlorinated Dioxins in Ground Beef

The Scientific World JOURNAL ◽

10.1100/tsw.2003.87 ◽

2003 ◽

Vol 3 ◽

pp. 913-921 ◽

Cited By ~ 2

Author(s):

Ebere C. Anyanwu ◽

Mohamed H. El-Saeid ◽

Akpan I. Akpan ◽

Mahmoud A. Saled

Keyword(s):

Food Chain ◽

Environmental Pollutants ◽

Ground Beef ◽

Extraction Methods ◽

Sample Introduction ◽

Animal Origin ◽

Clear Understanding ◽

Daily Consumption ◽

Contaminated Food ◽

Chlorinated Dioxins

Chlorinated dioxins are the group of environmental pollutants consisting of 210 chlorinated dibenzo-p-dioxins and dibenzofurans. They are highly toxic and persistent. They are lipophilic and can easily biomagnify in the food chain, hence posing a serious threat to human health. The daily consumption of low-level contaminated food, mainly of animal origin, leads to the accumulation of dioxins in the human body. The exposures of the general human population to dioxins and the specific issues of a risk assessment of dioxin pose serious concerns in public environmental and nutritional health. This paper reviews the analysis of chlorinated dioxins in ground beef. The sources of contamination of chlorinated dioxins in ground beef are first reviewed to form a basis for a clear understanding of the health implications of chlorinated dioxins in the human food chain and why it is necessary to monitor the level of dioxins in animal food products, especially ground beef. The methods of collection, sampling, and processing of ground beef, and the methods of sample clean up prior to the analysis, are reviewed. Emphasis is laid on the new techniques that are available and that might be effective in the analysis of chlorinated dioxins in ground beef. Among these new methods and techniques are: the synergistic combination of ELISA/GC/MS, direct sample introduction to /GC/MS-MS, automated clean-up method, and the supercritical fluid extraction methods. The possible treatments of results from each method and technique are discussed and their respective efficiencies are compared. Finally, quality control and quality assurance parameters are evaluated for levels of accuracy, reproducibility, and precision.

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P2X7 Receptor–Mediated Inflammation in Cardiovascular Disease

Frontiers in Pharmacology ◽

10.3389/fphar.2021.654425 ◽

2021 ◽

Vol 12 ◽

Author(s):

Junteng Zhou ◽

Zhichao Zhou ◽

Xiaojing Liu ◽

Hai-Yan Yin ◽

Yong Tang ◽

...

Keyword(s):

Cardiovascular Disease ◽

Cardiovascular Diseases ◽

P2x7 Receptor ◽

Cardiac Fibrosis ◽

Inflammatory Responses ◽

Interleukin 1 ◽

Experimental Studies ◽

Therapeutic Interventions ◽

Receptor Protein ◽

Inflammasome Activation

Purinergic P2X7 receptor, a nonselective cation channel, is highly expressed in immune cells as well as cardiac smooth muscle cells and endothelial cells. Its activation exhibits to mediate nucleotide-binding domain (NOD)-like receptor protein 3 (NLRP3) inflammasome activation, resulting in the release of interleukin-1 beta (IL-1β) and interleukin-18 (IL-18), and pyroptosis, thus triggering inflammatory response. These pathological mechanisms lead to the deterioration of various cardiovascular diseases, including atherosclerosis, arrhythmia, myocardial infarction, pulmonary vascular remodeling, and cardiac fibrosis. All these worsening cardiac phenotypes are proven to be attenuated after the P2X7 receptor inhibition in experimental studies. The present review aimed to summarize key aspects of P2X7 receptor–mediated inflammation and pyroptosis in cardiovascular diseases. The main focus is on the evidence addressing the involvement of the P2X7 receptor in the inflammatory responses to the occurrence and development of cardiovascular disease and therapeutic interventions.

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Improvement of Cardiac Fibrosis Biomarkers through Inflammation Inhibition by Green Tea and Decaffeinated Light Roasted Green Coffee Extract Combination Administration in Metabolic Syndrome Rat Model

F1000Research ◽

10.12688/f1000research.55468.1 ◽

2021 ◽

Vol 10 ◽

pp. 1013

Author(s):

Mifetika Lukitasari ◽

Mohammad Saifur Rohman ◽

Dwi Adi Nugroho ◽

Nila Aisyah Wahyuni ◽

Mukhamad Nur Kholis ◽

...

Keyword(s):

Gene Expression ◽

Metabolic Syndrome ◽

Green Tea ◽

Rat Model ◽

Cardiac Fibrosis ◽

Significant Risk ◽

Green Coffee ◽

The Metabolic Syndrome ◽

Tnf Α ◽

Tgf Β1

Background: Metabolic syndrome is a significant risk factor for cardiovascular diseases. Green tea and green coffee extracts, antioxidant and anti-inflammatory agents may participate in metabolic syndrome-induced cardiac fibrosis alleviation. However, the effect of combination of those extracts still needs exploration. Therefore, this study investigated the effect of green tea and decaffeinated light roasted green coffee extracts and their combination in metabolic syndrome-induced cardiac fibrosis rats. Methods: Metabolic syndrome rat model was i1nduced through high-fat high sucrose diets feeding for 8 weeks and injection of low dose streptozotocin at the 2nd week. The metabolic syndrome rats were divided into 4 experimental groups metabolic syndrome rats (MS); metabolic syndrome rats treated with 300 mg/ kg b.w green tea extract (GT); metabolic syndrome rats treated with 200 mg/ kg b.w decaffeinated light roasted green coffee extract (GC); metabolic syndrome rats treated with the combination of the two extracts (CE); and a normal control (NC) group was added. Angiotensin 2 level was analyzed by ELISA method. Gene expression of NF-κB, TNF-α, IL-6, Tgf-β1, Rac-1, and α-sma were analyzed by touchdown polymerase chain reaction methods. Results: Metabolic syndrome rats treated with green tea and decaffeinated light roasted green coffee significantly decreased angiotensin-2 serum level and cardiac inflammation and fibrosis gene expression level (NF-κB, TNF-α, IL-6, Tgf-β1, Rac-1, and α-sma). More significant alleviation was observed in the combination group. Conclusion: This study suggested that combination of green tea and decaffeinated light roasted green coffee extracts showed better improvement in metabolic syndrome-induced cardiac fibrosis rat model compared to that of single extract administration through inflammation inhibition

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Environmental pollutants-dependent molecular pathways and carcinogenesis

Biodiscovery ◽

10.3897/biodiscovery.22.e29242 ◽

2019 ◽

Vol 22 ◽

Author(s):

Myriam El Helou ◽

Pascale A. Cohen ◽

Mona Diab-Assaf ◽

Sandra Ghayad

Keyword(s):

Gene Expression ◽

Environmental Pollutants ◽

Environmental Chemicals ◽

Gene Repair ◽

Hormone Production ◽

Aryl Hydrocarbon ◽

Repair Mechanisms ◽

Cellular Signal ◽

And Function ◽

G Protein Coupled

Exposure to environmental pollutants can modulate many biological and molecular processes such as gene expression, gene repair mechanisms, hormone production and function and inflammation, resulting in adverse effects on human health including the occurrence and development of different types of cancer. Carcinogenesis is a complex and long process, taking place in multiple stages and is affected by multiple factors. Some environmental molecules are genotoxic, able to damage the DNA or to induce mutations and changes in gene expression acting as initiators of carcinogenesis. Other molecules called xenoestrogens can promote carcinogenesis by their mitogenic effects by possessing estrogenic-like activities and consequently acting as endocrine disruptors causing multiple alterations in cellular signal transduction pathways. In this review, we focus on recent research on environmental chemicals-driven molecular functions in human cancers. For this purpose, we will be discussing the case of two receptors in mediating environmental pollutants effects: the established nuclear receptor, the Aryl hydrocarbon receptor (AhR) and the emerging membrane receptor, G-protein coupled estrogen receptor 1 (GPER1).

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