Human Heart Disease Research Articles

P3489Endothelial adenosine-to-inosine RNA editing is indispensable for vascular integrity

Abstract Background Adenosine (A)-to-inosine (I) RNA editing is a powerful upstream regulator of double-stranded RNA (dsRNA) metabolism, its role however in tissue homeostasis remains poorly understood. We have recently reported that RNA editing is dysregulated in human atherosclerotic heart disease, although its role in the maintenance of endothelial cell (EC) function is unknown. Purpose The goal of the present study is to evaluate the role of EC-specific ADAR1 in vascular homeostasis in vivo. Methods Constitutional or inducible EC restricted ADAR1 ablation was achieved by crossing mice carrying a conditional (floxed) ADAR1 allele with either a Tie2-Cre or with a tamoxifen-inducible Cdh5-CreERT2 mouse line. EC function was assessed by the postnatal retinal angiogenesis model and barrier function assays and immunohistochemistry of lung and liver tissues. Cell culture assays, gene-silencing techniques, RT-qPCR, western blot and confocal microscopy were utilized to assess the ADAR1 effects in intracellular endothelial signalling. Results Constitutive endothelial ADAR1 ablation caused prenatal lethality at embryonic stage E13.5, demonstrating an essential role for endothelial ADAR1 in development. Postnatal ADAR1 ablation resulted in reduced vascular outgrowth, reduced vessel branching in the central vascular plexus and decreased filopodial protrusions from ECs at the angiogenic front of the vascular plexus compared with littermate control mice at P5. Furthermore, endothelial ADAR1 ablation in adult mice resulted in sudden death within 6–8 days after activation of Cre recombinase due to development of severe pleural effusions caused by widespread vascular leakage, indicating a disturbance of EC barrier function in lung microvasculature. Mechanistically, ADAR1-mediated RNA editing is essential for the metabolism of endogenous long-to-short dsRNAs, while silencing of endothelial ADAR1 resulted in accumulation of cytoplasmic long dsRNAs. Long dsRNAs are recognised as a danger-associated molecular pattern by the cytosolic innate immune sensing and signalling sensors. Consequently, the cytoplasmic accumulation of endogenous long dsRNAs resulted in activation of innate immune system in ECs, as assessed by the induction of interferon-β. Concomitantly, activation of the cytoplasmic dsRNA sensors resulted in dissociation of beta-catenin from VE-cadherin in EC junctions and endocytosis of VE-cadherin. Conclusion ADAR1-mediated RNA editing of long dsRNAs is essential for the long-to-short dsRNA metabolism and thus suppression of endogenous innate immune sensing and signalling. EC-restricted ADAR1 ablation results in embryonic lethality, impaired retinal angiogenesis at P5 and sudden death in adult mice due to pleural effusions, which all indicate that ADAR1-mediated RNA editing is indispensable for maintenance of vascular barrier integrity.

From embryogenesis to adulthood: Critical role for GATA factors in heart development and function

Cardiac development is governed by a complex network of transcription factors (TFs) that regulate cell fates in a spatiotemporal manner. Among these, the GATA family of zinc finger TFs plays prominent roles in regulating the development of the myocardium, endocardium, and outflow tract. This family comprises six members three of which, GATA4, 5, and 6, are predominantly expressed in cardiac cells where they activate specific downstream gene targets via interactions with one another and with other TFs and signaling molecules. Their critical function in heart formation is evidenced by the phenotypes of animal models lacking these factors and by the broad spectrum of human congenital heart diseases associated with mutations in their genes. Similarly, in the postnatal heart, these proteins play significant and nonredundant roles in cardiac function, regulating adaptive stress responses including cardiomyocyte hypertrophy and survival, as well as endothelial homeostasis and angiogenesis. As such, decreased expression of either GATA4, 5, or 6 results in impaired cardiovascular homeostasis and increased risk of premature and serious cardiovascular events such as hypertension, arrhythmia, aortopathy, and heart failure. Although a great deal of progress has been made in understanding GATA-dependent regulatory processes in the heart, the molecular mechanisms underlying the specificity of GATA factors and their upstream regulation remain incompletely understood. The knowledge and tools developed since their discovery 25 years ago should accelerate progress toward further elucidation of their mechanisms of action in health and disease. This in turn will greatly improve diagnosis and care for the millions of individuals affected by congenital and acquired cardiac disease worldwide.

Targeting cardiac fibrosis with engineered T cells.

SummaryFibrosis is observed in nearly every form of myocardial disease1. Upon injury, cardiac fibroblasts (CF) in the heart begin to remodel the myocardium via extracellular matrix deposition, resulting in increased tissue stiffness and reduced compliance. Excessive cardiac fibrosis is an important factor in the progression of various forms of cardiac disease and heart failure2. However, clinical interventions and therapies targeting fibrosis remain limited3. In this study, we demonstrate the efficacy of redirected T-cell immunotherapy to specifically target pathologic cardiac fibrosis. We find that cardiac fibroblasts expressing a xenogeneic antigen can be effectively targeted and ablated by adoptive transfer of antigen-specific CD8+ T cells. Through expression analysis of cardiac fibroblast gene signatures from healthy versus diseased human hearts, we identified an endogenous CF target; fibroblast activation protein (FAP). Adoptive transfer of T cells expressing a chimeric antigen receptor (CAR) against FAP, results in a significant reduction in cardiac fibrosis and restoration of function after injury in mice. These results provide the proof-of-principle basis for a novel immunotherapeutic avenue for the treatment of cardiac disease.

Abstract P2013: Genomic Identification Of Key CircRNAs In Healthy And Dilated Cardiomyopathy Human Heart

Heart failure is a leading cause of morbidity and mortality. Dilated cardiomyopathy (DCM) is a primary cause of heart failure and sudden cardiac death worldwide. Therefore, it is important to identify factors that function in both normal and diseased hearts for a better understanding of etiology of DCM. CircRNA is a newly discovered class of RNA molecule and has been found to play a critical role in both physiological and pathological conditions. In this study, we systematically analyzed whole transcriptome data of five normal and five DCM human heart samples to identify putative key circRNAs and predict their potential underlying mechanisms. Our results revealed that many circRNAs produced from known cardiac diseases-related gene loci are dysregulated in DCM, such as circRNAs originated from TTN and RYR2 . Furthermore, our analysis revealed 40 conserved circRNAs that are putatively important in normal or DCM human heart, including 14 circRNAs with potential to act as sponges for DCM-related miRNAs and 4 circRNAs with potential coding ability. Importantly, our results identified that a novel class of circRNA, fusion-circRNAs are originated from MYH6 and MYH7 genes and exhibit most abundant expression in human heart with high conservation between different species. Furthermore, these fusion-circRNAs were dysregulated in DCM and have strong potential to sponge DCM-related miRNAs. In summary, our findings serve as a valuable resource for exploration of the function of circRNAs in human heart diseases.

Abstract 321: RBFOX2 is critical for maintaining alternative polyadenylation patterns in cardiomyoblasts

Background: The RNA binding protein RBFOX2 is implicated in human heart diseases. However, RBFOX2-regulated RNA networks are not well defined. RBFOX2 has a well-characterized role in alternative splicing (AS) while accumulating evidence suggests that RBFOX2 may also have a role in alternative polyadenylation (APA). Recent studies showed that RBFOX2 binds to regions close to poly(A) sites in the 3’UTR of pre-mRNAs. In addition, RBFOX2 binds to the cleavage and polyadenylation specificity factors. Therefore, we aimed to determine whether RBFOX2 has a role in regulating APA. Method: We employed poly(A)click sequencing (PAC-seq) and DPAC (Differential Poly(A) Cluster analysis) computational pipeline to identify differential poly(A) usage and mRNA abundance. We also used nanopore sequencing to identify different spliced variants and the coordinated AS and APA events. Results: We report that knockdown of RBFOX2 in embryonic rat heart derived cells leads to altered alternative polyadenylation (APA) of hundreds of genes. RBFOX2-mediated APA changes impacted both mRNA levels and generation of different gene isoforms. Nanopore sequencing identified full-length transcripts regulated by RBFOX2 and revealed RBFOX2-mediated isoform switches via both APA and AS in cardiac cells. Notably, RBFOX2-regulated APA networks affect genes such as Tpm1 and Tnnt1 involved in cardiac contractility. Identification of RBFOX2-regulated RNA networks provides novel insights into the pathogenesis of heart diseases in which RBFOX2 is involved and pave the way for designing therapeutics. Conclusions: RBFOX2 regulates alternative polyadenylation via splicing dependent and independent mechanisms. RBFOX2-mediated APA affects mRNA levels of contractile genes.

Abstract 658: RNF20/40 Regulates Cardiomyocyte Maturation

Between birth and adulthood, cardiomyocytes (CMs) undergo profound changes in size, ultrastructure, metabolism, and gene expression, a process collectively referred to as CM maturation. Although highly coordinated, the transcriptional network that governs this process is not understood. This lack of understanding is a barrier to cardiac regenerative medicine, where our current inability to mature CMs differentiated from non-myocytes limits their use for disease modeling or replacement therapy. In addition, disruption of maturation by abnormal hemodynamic loads in neonates who have undergone surgery to correct congenital heart defects likely contributes to their high incidence of heart failure in adulthood. A sound understanding of the regulatory network governing CM maturation will inspire hypothesis driven attempts to surmount these challenges. In mice, a key hallmark of CM maturation is sarcomere isoform switching, including the well documented neonatal switch from Myosin Heavy Chain 7 (Myh7) to Myosin Heavy Chain 6 (Myh6). We have conducted and validated an in vivo high throughput CRISPR screen for transcriptional regulators of CM maturation, using the Myh7/6 isoform switch as the readout. Two top candidates from this screen, Rnf20 and Rnf40, form a complex which deposits the epigenetic mark H2bub1 (histone-2B mono-ubiquitinated on lysine 120). Defects in RNF20/40 and H2Bub1 regulation have been associated with human congenital heart disease, but their mechanistic function in the heart has not been studied. We performed ChIP and RNA-sequencing experiments in control and RNF loss-of-function models to characterize the role of H2Bub1 in transcriptional control of CM maturation. The resulting mechanistic insights into how gene expression is coordinately controlled during maturation will inform efforts to improve CM production protocols and develop targeted therapies.

Exogenous WNT5A and WNT11 proteins rescue CITED2 dysfunction in mouse embryonic stem cells and zebrafish morphants

Mutations and inadequate methylation profiles of CITED2 are associated with human congenital heart disease (CHD). In mouse, Cited2 is necessary for embryogenesis, particularly for heart development, and its depletion in embryonic stem cells (ESC) impairs cardiac differentiation. We have now determined that Cited2 depletion in ESC affects the expression of transcription factors and cardiopoietic genes involved in early mesoderm and cardiac specification. Interestingly, the supplementation of the secretome prepared from ESC overexpressing CITED2, during the onset of differentiation, rescued the cardiogenic defects of Cited2-depleted ESC. In addition, we demonstrate that the proteins WNT5A and WNT11 held the potential for rescue. We also validated the zebrafish as a model to investigate cited2 function during development. Indeed, the microinjection of morpholinos targeting cited2 transcripts caused developmental defects recapitulating those of mice knockout models, including the increased propensity for cardiac defects and severe death rate. Importantly, the co-injection of anti-cited2 morpholinos with either CITED2 or WNT5A and WNT11 recombinant proteins corrected the developmental defects of Cited2-morphants. This study argues that defects caused by the dysfunction of Cited2 at early stages of development, including heart anomalies, may be remediable by supplementation of exogenous molecules, offering the opportunity to develop novel therapeutic strategies aiming to prevent CHD.

Antioxidants and Atherosclerosis: Mechanistic Aspects.

Atherosclerosis is a chronic inflammatory disease which is a major cause of coronary heart disease and stroke in humans. It is characterized by intimal plaques and cholesterol accumulation in arterial walls. The side effects of currently prescribed synthetic drugs and their high cost in the treatment of atherosclerosis has prompted the use of alternative herbal medicines, dietary supplements, and antioxidants associated with fewer adverse effects for the treatment of atherosclerosis. This article aims to present the activity mechanisms of antioxidants on atherosclerosis along with a review of the most prevalent medicinal plants employed against this multifactorial disease. The wide-ranging information in this review article was obtained from scientific databases including PubMed, Web of Science, Scopus, Science Direct and Google Scholar. Natural and synthetic antioxidants have a crucial role in the prevention and treatment of atherosclerosis through different mechanisms. These include: The inhibition of low density lipoprotein (LDL) oxidation, the reduction of reactive oxygen species (ROS) generation, the inhibition of cytokine secretion, the prevention of atherosclerotic plaque formation and platelet aggregation, the preclusion of mononuclear cell infiltration, the improvement of endothelial dysfunction and vasodilation, the augmentation of nitric oxide (NO) bioavailability, the modulation of the expression of adhesion molecules such as vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) on endothelial cells, and the suppression of foam cell formation.

Postnatal Cardiac Development and Regenerative Potential in Large Mammals.

The neonatal capacity for cardiac regeneration in mice is well studied and has been used to develop many potential strategies for adult cardiac regenerative repair following injury. However, translating these findings from rodents to designing regenerative therapeutics for adult human heart disease remains elusive. Large mammals including pigs, dogs, and sheep are widely used as animal models of humans in preclinical trials of new cardiac drugs and devices. However, very little is known about the fundamental cardiac cell biology and the timing of postnatal cardiac events that influence cardiomyocyte proliferation in these animals. There is emerging evidence that external physiological and environmental cues could be the key to understanding cardiomyocyte proliferative behavior. In this review, we survey available literature on postnatal development in various large mammal models to offer a perspective on the physiological and cellular characteristics that could be regulating cardiomyocyte proliferation. Similarities and differences between developmental milestones, cardiomyocyte maturational events, as well as environmental cues regulating cardiac development, are discussed for various large mammals, with a focus on postnatal cardiac regenerative potential and translatability to the human heart.

Widespread Translational Control of Fibrosis in the Human Heart by RNA-Binding Proteins.

Fibrosis is a common pathology in many cardiac disorders and is driven by the activation of resident fibroblasts. The global posttranscriptional mechanisms underlying fibroblast-to-myofibroblast conversion in the heart have not been explored. Genome-wide changes of RNA transcription and translation during human cardiac fibroblast activation were monitored with RNA sequencing and ribosome profiling. We then used RNA-binding protein-based analyses to identify translational regulators of fibrogenic genes. The integration with cardiac ribosome occupancy levels of 30 dilated cardiomyopathy patients demonstrates that these posttranscriptional mechanisms are also active in the diseased fibrotic human heart. We generated nucleotide-resolution translatome data during the transforming growth factor β1-driven cellular transition of human cardiac fibroblasts to myofibroblasts. This identified dynamic changes of RNA transcription and translation at several time points during the fibrotic response, revealing transient and early-responder genes. Remarkably, about one-third of all changes in gene expression in activated fibroblasts are subject to translational regulation, and dynamic variation in ribosome occupancy affects protein abundance independent of RNA levels. Targets of RNA-binding proteins were strongly enriched in posttranscriptionally regulated genes, suggesting genes such as MBNL2 can act as translational activators or repressors. Ribosome occupancy in the hearts of patients with dilated cardiomyopathy suggested the same posttranscriptional regulatory network was underlying cardiac fibrosis. Key network hubs include RNA-binding proteins such as Pumilio RNA binding family member 2 (PUM2) and Quaking (QKI) that work in concert to regulate the translation of target transcripts in human diseased hearts. Furthermore, silencing of both PUM2 and QKI inhibits the transition of fibroblasts toward profibrotic myofibroblasts in response to transforming growth factor β1. We reveal widespread translational effects of transforming growth factor β1 and define novel posttranscriptional regulatory networks that control the fibroblast-to-myofibroblast transition. These networks are active in human heart disease, and silencing of hub genes limits fibroblast activation. Our findings show the central importance of translational control in fibrosis and highlight novel pathogenic mechanisms in heart failure.

Genetic Polymorphism of β-Casein Gene in Polish Red Cattle-Preliminary Study of A1 and A2 Frequency in Genetic Conservation Herd.

Simple SummaryCurrently, milk and dairy products are considered nutritious foods because they contain bioactive constituents. However, in some cases, milk consumption might cause health-related issues, such as allergic reactions. Among all of the proteins present in milk, caseins deserve special attention. A genetic variant called β-casein is recognized as a potential cause of some health implications. However, although milk protein characteristics have been widely covered, a significant majority of published research focus on one cattle breed: Holstein There are numerous local breeds that have not been widely analyzed to date. One such breed is a dual-purpose breed called Polish Red.Although there is growing interest in Red cow’s milk in Poland, to date there are few reports investigating the characteristics of milk components in the studied population. Particular emphasis on milk proteins is advised, since β-casein is a source of bioactive peptides named β-casomorphins. β-casomorphin 7, which originates mostly from β-casein variants A1, may be a significant risk factor in human ischemic heart disease, arteriosclerosis, type I diabetes, sudden infant death syndrome, and autism. The aim of the present study was to identify CSN2 polymorphism gene in exon 7 using the genomic sequence from GenBank (M55158), g.8101C>A, (codon 67). Blood samples were collected from 201 Polish Red cattle (24 males and 177 females). The genotype of β-casein was determined using PCR-ACRS. The frequency of β-casein A2 in Polish Red population was 0.47. β-casein A2 frequency in Polish Red bulls and in cows was 0.58 and 0.37, respectively.

A feline orthologue of the human MYH7 c.5647G>A (p.(Glu1883Lys)) variant causes hypertrophic cardiomyopathy in a Domestic Shorthair cat.

Hypertrophic cardiomyopathy (HCM) is the most common inherited human heart disease. The same disease has a high prevalence in cats, where it is also suspected to be inherited. More than 1500 variants in MYBPC3, MYH7 and other sarcomeric genes are associated with human HCM, while in cats, only two causative variants in MYBPC3 are currently known. Here, we describe an adult Domestic Shorthair cat with arterial thromboembolism and heart failure that was diagnosed with HCM on necropsy. Sequencing of the coding regions of MYBPC3 and MYH7 revealed 21 variants, of which the MYH7 c.5647G>A (p.(Glu1883Lys)) variant was further analysed, because its orthologous variant had already been reported in a human patient with HCM, but with limited causal evidence. This variant affects the highly conserved assembly competence domain, is predicted in silico to be damaging and was found only once in population databases. Recently, functional studies have confirmed its predicted damaging effect and a paralogous variant in MYH6 has been associated with cardiac disease in humans as well. This report of an orthologous variant in a cat with HCM and its absence in 200 additional cats provides further evidence for its disease-causing nature. As the first report of feline HCM caused by a variant in MYH7, this study also emphasises this gene as a candidate gene for future studies in cats and highlights the similarity between human and feline HCM.

Oligogenic inheritance of a human heart disease involving a genetic modifier.

Complex genetic mechanisms are thought to underlie many human diseases, yet experimental proof of this model has been elusive. Here, we show that a human cardiac anomaly can be caused by a combination of rare, inherited heterozygous mutations. Whole-exome sequencing of a nuclear family revealed that three offspring with childhood-onset cardiomyopathy had inherited three missense single-nucleotide variants in the MKL2, MYH7, and NKX2-5 genes. The MYH7 and MKL2 variants were inherited from the affected, asymptomatic father and the rare NKX2-5 variant (minor allele frequency, 0.0012) from the unaffected mother. We used CRISPR-Cas9 to generate mice encoding the orthologous variants and found that compound heterozygosity for all three variants recapitulated the human disease phenotype. Analysis of murine hearts and human induced pluripotent stem cell-derived cardiomyocytes provided histologic and molecular evidence for the NKX2-5 variant's contribution as a genetic modifier.

Myocarditis in Humans and in Experimental Animal Models.

Myocarditis is defined as an inflammation of the cardiac muscle. In humans, various infectious and non-infectious triggers induce myocarditis with a broad spectrum of histological presentations and clinical symptoms of the disease. Myocarditis often resolves spontaneously, but some patients develop heart failure and require organ transplantation. The need to understand cellular and molecular mechanisms of inflammatory heart diseases led to the development of mouse models for experimental myocarditis. It has been shown that pathogenic agents inducing myocarditis in humans can often trigger the disease in mice. Due to multiple etiologies of inflammatory heart diseases in humans, a number of different experimental approaches have been developed to induce myocarditis in mice. Accordingly, experimental myocarditis in mice can be induced by infection with cardiotropic agents, such as coxsackievirus B3 and protozoan parasite Trypanosoma cruzi or by activating autoimmune responses against heart-specific antigens. In certain models, myocarditis is followed by the phenotype of dilated cardiomyopathy and the end stage of heart failure. This review describes the most commonly used mouse models of experimental myocarditis with a focus on the role of the innate and adaptive immune systems in induction and progression of the disease. The review discusses also advantages and limitations of individual mouse models in the context of the clinical manifestation and the course of the disease in humans. Finally, animal-free alternatives in myocarditis research are outlined.

TBX20 - an important target gene for the prevention and treatment of cardiovascular diseases

The T-Box transcription factor family plays a crucial role during heart development. A large amount of clinical evidence showed TBX 1, 2, 5, 18, 20 proteins to be strongly associated with human congenital heart diseases including atrial septal defect, mitral valve disease, and tetralogy of Fallot. Among these, TBX20 has attracted much attention. This article gives a brief review for the progress made in the research on TBX20 and cardiovascular disease.

Intronic Polymorphisms in Gene of Second Heart Field as Risk Factors for Human Congenital Heart Disease in a Chinese Population.

Transcriptional factors and signaling factors in the second heart field (SHF) contribute to cardiac development. However, the associations of intronic gene variants in the SHF with congenital heart disease (CHD) remain ununderstood. Ten single nucleotide polymorphisms (SNPs) from our previous sequencing data were selected and then genotyped in 383 CHD patients and 384 healthy controls in a Chinese population. Genotype analyses revealed that minor alleles in TBX1: rs12165908 C > G [odds ratio (OR) = 2.64; 95% confidence interval (CI) = 1.87-3.73, p = 3.03 × 10-8] and GATA6: rs143085291 C > T (OR = 2.49; 95% CI = 1.18-5.29, p = 0.01) increased CHD risk significantly. Meanwhile, FGF10: rs78454549 T > C and GATA4: rs13275657 A>G polymorphisms were significantly associated with increased risk of simple CHDs. The minor allele C in GATA4: rs17153694 T > C increased the risk of tetralogy of Fallot, whereas minor alleles in TBX1: rs41298006 G>A, FGF10: rs75629618 C>T, FGF10: rs10461755 G>A, FGF10: rs75632187 A>G, and FGF10: rs12518964 G > A were associated with increased risk of single ventricle. The minor allele T in rs143085291 in GATA6 enhancer decreased the transcription level in luciferase assay. Our findings suggest that intronic SNPs in transcriptional factors and signaling factors in the SHF are significantly associated with increased risk of different CHD types.

Role of Intra‐cardiac Neurohumoral Factors in Human Chronic Ischemic Heart Disease

BackgroundA transient myocardial ischemia results in the destruction of typical metabolic cascades and leaves structural “traces” in the cardiomyocytes and myocardial interstitial components. Those structural “traces” are microscopically determined by disseminated micro‐focal alterations of the ultrastructure of the cardiomyocytes along with increased interstitial fibrosis. However, cardiac sympathetic nerve terminals are more sensitive to transient myocardial ischemia than the cardiomyocytes. The present study performed ultramicroscopic characterizations of sympathetic nerve terminals in human ischemic heart disease.MethodsLeft ventricular myocardial biopsies were taken from patients with chronic ischemic heart disease and examined under transmission electron microscopy (TEM) using the electron‐histochemical method. Ultrastructural details of alterations in cardiac sympathetic nerve terminals were analyzed to assess their role in the fibrosis development and the damage to cardiomyocytes.ResultsIn patients, the decrease in vesicles of sympathetic nerve terminals and the polymorphism of their secretory granules indicate decreased neo‐synthesis of neurotransmitters as well as their up‐take. We also found that glycocalyx is dissociated and micro‐configurated and cell membranes are lysed. These structural observations imply that the neurotransmitter release into the peri‐cellular space activates functions of mast cells, endothelial cells, fibroblasts, contributing to cardiomyocyte damage and the development of myocardial fibrosis.ConclusionThese results suggest that the accumulation of endogenous cardiac neurotransmitters in the myocardial interstitium may lead to the progressive damage to cardiomyocytes and the development of cardiac fibrosis in human ischemic heart disease. Understanding mechanisms of the regulation of endogenous cardiac neurohumoral factors, especially those involved in the initiation, progression and resolution of cardiac fibrosis is crucial to prevent the ventricular cardiomyocyte damage and to design anti‐fibrosis treatment strategies for patients with chronic ischemic heart disease.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Research progress of relationship between GATA family gene mutations with congenital heart diseases

The GATA transcription factor family is a type of transcription regulatory factors containing zinc finger structure, in which GATA4, GATA5 and GATA6 play a key role in the process of heart development and functional maturity.A large number of studies have confirmed that the GATA transcription factor family is not only involved in the the heart development, but also its mutations are related to the occurrence of human congenital heart diseases(CHD). This article mainly reviews the relationship between GATA family with heart development, and the relationship between GATA family gene mutation with congenital heart diseases. Key words: GATA transcription factor; Congenital heart disease; Gene mutation

Is Grassfed Meat and Dairy Better for Human and Environmental Health?

The health of livestock, humans, and environments is tied to plant diversity—and associated phytochemical richness—across landscapes. Health is enhanced when livestock forage on phytochemically rich landscapes, is reduced when livestock forage on simple mixture or monoculture pastures or consume high-grain rations in feedlots, and is greatly reduced for people who eat highly processed diets. Circumstantial evidence supports the hypothesis that phytochemical richness of herbivore diets enhances biochemical richness of meat and dairy, which is linked with human and environmental health. Among many roles they play in health, phytochemicals in herbivore diets protect meat and dairy from protein oxidation and lipid peroxidation that cause low-grade systemic inflammation implicated in heart disease and cancer in humans. Yet, epidemiological and ecological studies critical of red meat consumption do not discriminate among meats from livestock fed high-grain rations as opposed to livestock foraging on landscapes of increasing phytochemical richness. The global shift away from phytochemically and biochemically rich wholesome foods to highly processed diets enabled 2.1 billion people to become overweight or obese and increased the incidence of type II diabetes, heart disease, and cancer. Unimpeded, these trends will add to a projected substantial increase in greenhouse gas emissions (GHGE) from producing food and clearing land by 2050. While agriculture contributes one quarter of GHGE, livestock can play a sizable role in climate mitigation. Of 80 ways to alleviate climate change, regenerative agriculture—managed grazing, silvopasture, tree intercropping, conservation agriculture, and farmland restoration—jointly rank number one as ways to sequester GHG. Mitigating the impacts of people in the Anthropocene can be enabled through diet to improve human and environmental health, but that will require profound changes in society. People will have to learn we are members of nature's communities. What we do to them, we do to ourselves. Only by nurturing them can we nurture ourselves.

Distribution of Gadolinium in Rat Heart Studied by Fast Field Cycling Relaxometry and Imaging SIMS.

Research on microcirculatory alterations in human heart disease is essential to understand the genesis of myocardial contractile dysfunction and its evolution towards heart failure. The use of contrast agents in magnetic resonance imaging is an important tool in medical diagnostics related to this dysfunction. Contrast agents significantly improve the imaging by enhancing the nuclear magnetic relaxation rates of water protons in the tissues where they are distributed. Gadolinium complexes are widely employed in clinical practice due to their high magnetic moment and relatively long electronic relaxation time. In this study, the behavior of gadolinium ion as a contrast agent was investigated by two complementary methods, relaxometry and secondary ion mass spectrometry. The study examined the distribution of blood flow within the microvascular network in ex vivo Langendorff isolated rat heart models, perfused with Omniscan® contrast agent. The combined use of secondary ion mass spectrometry and relaxometry allowed for both a qualitative mapping of agent distribution as well as the quantification of gadolinium ion concentration and persistence. This combination of a chemical mapping and temporal analysis of the molar concentration of gadolinium ion in heart tissue allows for new insights on the biomolecular mechanisms underlying the microcirculatory alterations in heart disease.