scholarly journals miR-2954 Inhibits PI3K Signaling and Induces Autophagy and Apoptosis in Myocardium Selenium Deficiency

2018 ◽  
Vol 51 (2) ◽  
pp. 778-792 ◽  
Author(s):  
Qi Liu ◽  
Jingzeng Cai ◽  
Yunan Gao ◽  
Jie Yang ◽  
Yafan Gong ◽  
...  
Keyword(s):  
Heart Disease ◽  
Cardiac Injury ◽  
Selenium Deficiency ◽  
Pi3k Pathway ◽  
Keshan Disease ◽  
Protection Mechanism ◽  
Myocardial Diseases ◽  
Self Protection

Background/Aims: Selenium (Se) deficiency can lead to several cardiac diseases, including Keshan disease in humans, mulberry heart disease in pigs and cardiac injury in chickens. MicroRNAs have been a research focus in recent years and have been shown to participate in a new avenue of cell death-autophagy, which can play a significant role in several types of heart disease. Methods: MicroRNAome analysis showed that the expression of miR-2954 was increased in the myocardium of selenium-deficient chickens, and PI3K was predicted to be the target gene. The target relationship between miR-2954 and PI3K was verified with a double fluorescence enzyme assay and RNA Protein Interaction Prediction and molecular docking software. qRT-PCR and western blotting were used to detect the expression of PI3K and related pathway components in selenium-deficient chickens and miR-2954 knockout/overexpression cardiomyocytes. Results: In this study, we observed that miR-2954 overexpression led to inhibition of PI3K pathway in vivo and in vitroled to inhibition of the PI3K pathway in vivo and in vitro. Conclusion: The expression of miR-2954 was increased in selenium-deficient myocardium, whereas overexpression of miR-2954 led to autophagy and apoptosis of myocardial cells during cardiac injury through regulation of the PI3K pathway; whether this phenomenon is a self-protection mechanism of the organism or damage caused by miR-2954 requires further study. Our findings provides new insight apoptosis in cardiomyocytes; additionally, we aim to provide a new direction for the diagnosis and targeted treatment of myocardial diseases.

scholarly journals Direct Cardiac Reprogramming: Advances in Cardiac Regeneration

2015 ◽  
Vol 2015 ◽  
pp. 1-8 ◽  
Author(s):  
Olivia Chen ◽  
Li Qian
Keyword(s):  
Myocardial Infarction ◽  
Heart Disease ◽  
Cell Fate ◽  
Early Stage ◽  
Cardiac Injury ◽  
Cardiac Regeneration ◽  
Scar Tissue ◽  
Coronary Events

Heart disease is one of the lead causes of death worldwide. Many forms of heart disease, including myocardial infarction and pressure-loading cardiomyopathies, result in irreversible cardiomyocyte death. Activated fibroblasts respond to cardiac injury by forming scar tissue, but ultimately this response fails to restore cardiac function. Unfortunately, the human heart has little regenerative ability and long-term outcomes following acute coronary events often include chronic and end-stage heart failure. Building upon years of research aimed at restoring functional cardiomyocytes, recent advances have been made in the direct reprogramming of fibroblasts toward a cardiomyocyte cell fate bothin vitroandin vivo. Several experiments show functional improvements in mouse models of myocardial infarction followingin situgeneration of cardiomyocyte-like cells from endogenous fibroblasts. Though many of these studies are in an early stage, this nascent technology holds promise for future applications in regenerative medicine. In this review, we discuss the history, progress, methods, challenges, and future directions of direct cardiac reprogramming.

scholarly journals iPLA2β Contributes to ER Stress-Induced Apoptosis during Myocardial Ischemia/Reperfusion Injury

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1446
Author(s):  
Tingting Jin ◽  
Jun Lin ◽  
Yingchao Gong ◽  
Xukun Bi ◽  
Shasha Hu ◽  
...  
Keyword(s):  
Cell Death ◽  
Heart Disease ◽  
Myocardial Ischemia ◽  
Ischemic Heart Disease ◽  
Er Stress ◽  
Ischemia Reperfusion ◽  
Myocardial Ischemia Reperfusion ◽  
Induced Apoptosis

Both calcium-independent phospholipase A2 beta (iPLA2β) and endoplasmic reticulum (ER) stress regulate important pathophysiological processes including inflammation, calcium homeostasis and apoptosis. However, their roles in ischemic heart disease are poorly understood. Here, we show that the expression of iPLA2β is increased during myocardial ischemia/reperfusion (I/R) injury, concomitant with the induction of ER stress and the upregulation of cell death. We further show that the levels of iPLA2β in serum collected from acute myocardial infarction (AMI) patients and in samples collected from both in vivo and in vitro I/R injury models are significantly elevated. Further, iPLA2β knockout mice and siRNA mediated iPLA2β knockdown are employed to evaluate the ER stress and cell apoptosis during I/R injury. Additionally, cell surface protein biotinylation and immunofluorescence assays are used to trace and locate iPLA2β. Our data demonstrate the increase of iPLA2β augments ER stress and enhances cardiomyocyte apoptosis during I/R injury in vitro and in vivo. Inhibition of iPLA2β ameliorates ER stress and decreases cell death. Mechanistically, iPLA2β promotes ER stress and apoptosis by translocating to ER upon myocardial I/R injury. Together, our study suggests iPLA2β contributes to ER stress-induced apoptosis during myocardial I/R injury, which may serve as a potential therapeutic target against ischemic heart disease.

scholarly journals Multimodal Diagnostics of Microrheologic Alterations in Blood of Coronary Heart Disease and Diabetic Patients

Diagnostics ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 76
Author(s):  
Anastasia Maslianitsyna ◽  
Petr Ermolinskiy ◽  
Andrei Lugovtsov ◽  
Alexandra Pigurenko ◽  
Maria Sasonko ◽  
...  
Keyword(s):  
Coronary Heart Disease ◽  
Heart Disease ◽  
Red Blood Cells ◽  
Blood Cells ◽  
Optical Methods ◽  
Diabetic Patients ◽  
Aggregation Index ◽  
Significant Difference

Coronary heart disease (CHD) has serious implications for human health and needs to be diagnosed as early as possible. In this article in vivo and in vitro optical methods are used to study blood properties related to the aggregation of red blood cells in patients with CHD and comorbidities such as type 2 diabetes mellitus (T2DM). The results show not only a significant difference of the aggregation in patients compared to healthy people, but also a correspondence between in vivo and in vitro parameters. Red blood cells aggregate in CHD patients faster and more numerously; in particular the aggregation index increases by 20 ± 7%. The presence of T2DM also significantly elevates aggregation in CHD patients. This work demonstrates multimodal diagnostics and monitoring of patients with socially significant pathologies.

scholarly journals FGF1ΔHBS prevents diabetic cardiomyopathy by maintaining mitochondrial homeostasis and reducing oxidative stress via AMPK/Nur77 suppression

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Dezhong Wang ◽  
Yuan Yin ◽  
Shuyi Wang ◽  
Tianyang Zhao ◽  
Fanghua Gong ◽  
...  
Keyword(s):  
Diabetic Cardiomyopathy ◽  
Metabolic Regulation ◽  
Cardiac Injury ◽  
Serum Levels ◽  
Ros Generation ◽  
Dependent Manner ◽  
Cardiac Tissues ◽  
Beneficial Effects

AbstractAs a classically known mitogen, fibroblast growth factor 1 (FGF1) has been found to exert other pleiotropic functions such as metabolic regulation and myocardial protection. Here, we show that serum levels of FGF1 were decreased and positively correlated with fraction shortening in diabetic cardiomyopathy (DCM) patients, indicating that FGF1 is a potential therapeutic target for DCM. We found that treatment with a FGF1 variant (FGF1∆HBS) with reduced proliferative potency prevented diabetes-induced cardiac injury and remodeling and restored cardiac function. RNA-Seq results obtained from the cardiac tissues of db/db mice showed significant increase in the expression levels of anti-oxidative genes and decrease of Nur77 by FGF1∆HBS treatment. Both in vivo and in vitro studies indicate that FGF1∆HBS exerted these beneficial effects by markedly reducing mitochondrial fragmentation, reactive oxygen species (ROS) generation and cytochrome c leakage and enhancing mitochondrial respiration rate and β-oxidation in a 5’ AMP-activated protein kinase (AMPK)/Nur77-dependent manner, all of which were not observed in the AMPK null mice. The favorable metabolic activity and reduced proliferative properties of FGF1∆HBS testify to its promising potential for use in the treatment of DCM and other metabolic disorders.

scholarly journals Phosphorylation of Serine 303 Is a Prerequisite for the Stress-Inducible SUMO Modification of Heat Shock Factor 1

2003 ◽  
Vol 23 (8) ◽  
pp. 2953-2968 ◽  
Author(s):  
Ville Hietakangas ◽  
Johanna K. Ahlskog ◽  
Annika M. Jakobsson ◽  
Maria Hellesuo ◽  
Niko M. Sahlberg ◽  
...  
Keyword(s):  
Heat Shock ◽  
Phosphorylation Site ◽  
Stress Granules ◽  
Heat Shock Factor ◽  
Transcriptional Level ◽  
Heat Shock Factor 1 ◽  
Protection Mechanism ◽  
Sumo Modification

ABSTRACT The heat shock response, which is accompanied by a rapid and robust upregulation of heat shock proteins (Hsps), is a highly conserved protection mechanism against protein-damaging stress. Hsp induction is mainly regulated at transcriptional level by stress-inducible heat shock factor 1 (HSF1). Upon activation, HSF1 trimerizes, binds to DNA, concentrates in the nuclear stress granules, and undergoes a marked multisite phosphorylation, which correlates with its transcriptional activity. In this study, we show that HSF1 is modified by SUMO-1 and SUMO-2 in a stress-inducible manner. Sumoylation is rapidly and transiently enhanced on lysine 298, located in the regulatory domain of HSF1, adjacent to several critical phosphorylation sites. Sumoylation analyses of HSF1 phosphorylation site mutants reveal that specifically the phosphorylation-deficient S303 mutant remains devoid of SUMO modification in vivo and the mutant mimicking phosphorylation of S303 promotes HSF1 sumoylation in vitro, indicating that S303 phosphorylation is required for K298 sumoylation. This finding is further supported by phosphopeptide mapping and analysis with S303/7 phosphospecific antibodies, which demonstrate that serine 303 is a target for strong heat-inducible phosphorylation, corresponding to the inducible HSF1 sumoylation. A transient phosphorylation-dependent colocalization of HSF1 and SUMO-1 in nuclear stress granules provides evidence for a strictly regulated subnuclear interplay between HSF1 and SUMO.

scholarly journals Anti-CD63 antibodies suppress IgE-dependent allergic reactions in vitro and in vivo

2005 ◽  
Vol 201 (3) ◽  
pp. 385-396 ◽  
Author(s):  
Stefan Kraft ◽  
Tony Fleming ◽  
James M. Billingsley ◽  
Shih-Yao Lin ◽  
Marie-Hélène Jouvin ◽  
...  
Keyword(s):  
Pi3k Pathway ◽  
Therapeutic Agents ◽  
Allergic Reactions ◽  
Ecm Proteins ◽  
Broad Array ◽  
High Affinity Ige Receptor ◽  
Nonadherent Cells ◽  
Tetraspanin Cd63

High-affinity IgE receptor (FcεRI) cross-linking on mast cells (MCs) induces secretion of preformed allergy mediators (degranulation) and synthesis of lipid mediators and cytokines. Degranulation produces many symptoms of immediate-type allergic reactions and is modulated by adhesion to surfaces coated with specific extracellular matrix (ECM) proteins. The signals involved in this modulation are mostly unknown and their contribution to allergic reactions in vivo is unclear. Here we report the generation of monoclonal antibodies that potently suppress FcεRI-induced degranulation, but not leukotriene synthesis. We identified the antibody target as the tetraspanin CD63. Tetraspanins are membrane molecules that form multimolecular complexes with a broad array of molecules including ECM protein-binding β integrins. We found that anti-CD63 inhibits MC adhesion to fibronectin and vitronectin. Furthermore, anti-CD63 inhibits FcεRI-mediated degranulation in cells adherent to those ECM proteins but not in nonadherent cells. Thus the inhibition of degranulation by anti-CD63 correlates with its effect on adhesion. In support of a mechanistic linkage between the two types of inhibition, anti-CD63 had no effect on FcεRI-induced global tyrosine phosphorylation and calcium mobilization but impaired the Gab2–PI3K pathway that is known to be essential for both degranulation and adhesion. Finally, we showed that these antibodies inhibited FcεRI-mediated allergic reactions in vivo. These properties raise the possibility that anti-CD63 could be used as therapeutic agents in MC-dependent diseases.

Endothelium-dependent vasorelaxing activity of wine and other grape products

1993 ◽  
Vol 265 (2) ◽  
pp. H774-H778 ◽  
Author(s):  
D. F. Fitzpatrick ◽  
S. L. Hirschfield ◽  
R. G. Coffey
Keyword(s):  
Coronary Heart Disease ◽  
Heart Disease ◽  
Vascular Function ◽  
Vascular Tissue ◽  
Grape Skin ◽  
Grape Skins ◽  
Grape Juices ◽  
Patent Coronary Artery

Current interest in the presumed benefits of wine in protecting against coronary heart disease prompted us to investigate possible effects of various grape products on vascular function in vitro. Certain wines, grape juices, and grape skin extracts relaxed precontracted smooth muscle of intact rat aortic rings but had no effect on aortas in which the endothelium had been removed. Quercitin and tannic acid, compounds known to be present in grape skins, also produced endothelium-dependent relaxation; two other grape skin compounds, resveratrol and malvidin, did not relax the rings. Phenylephrine-induced contractions were attenuated by prior exposure of aortic rings to grape skin extracts. The extracts also increased guanosine 3',5'-cyclic monophosphate (cGMP) levels in intact vascular tissue, and both relaxation and the increase in cGMP were reversed by NG-monomethyl-L-arginine and NG-nitro-L-arginine, competitive inhibitors of the synthesis of the endothelium-derived relaxing factor, nitric oxide (NO). The vasorelaxation induced by grape products therefore appears to be mediated by the NO-cGMP pathway. If such responses occur in vivo, they could conceivably help to maintain a patent coronary artery and thereby possibly contribute to a reduced incidence of coronary heart disease.

scholarly journals Mending a broken heart: In vitro, in vivo and in silico models of congenital heart disease

2021 ◽  
Vol 14 (3) ◽  
pp. dmm047522
Author(s):  
Abdul Jalil Rufaihah ◽  
Ching Kit Chen ◽  
Choon Hwai Yap ◽  
Citra N. Z. Mattar
Keyword(s):  
Congenital Heart Disease ◽  
Heart Disease ◽  
Congenital Heart ◽  
Computational Models ◽  
Developing Heart ◽  
Heterogenous Group ◽  
In Silico Models ◽  
Large Animals

ABSTRACTBirth defects contribute to ∼0.3% of global infant mortality in the first month of life, and congenital heart disease (CHD) is the most common birth defect among newborns worldwide. Despite the significant impact on human health, most treatments available for this heterogenous group of disorders are palliative at best. For this reason, the complex process of cardiogenesis, governed by multiple interlinked and dose-dependent pathways, is well investigated. Tissue, animal and, more recently, computerized models of the developing heart have facilitated important discoveries that are helping us to understand the genetic, epigenetic and mechanobiological contributors to CHD aetiology. In this Review, we discuss the strengths and limitations of different models of normal and abnormal cardiogenesis, ranging from single-cell systems and 3D cardiac organoids, to small and large animals and organ-level computational models. These investigative tools have revealed a diversity of pathogenic mechanisms that contribute to CHD, including genetic pathways, epigenetic regulators and shear wall stresses, paving the way for new strategies for screening and non-surgical treatment of CHD. As we discuss in this Review, one of the most-valuable advances in recent years has been the creation of highly personalized platforms with which to study individual diseases in clinically relevant settings.

scholarly journals Antioxidant Effects of Eryngium carlinae in Diabetic Rats

2018 ◽  
Vol 6 (5) ◽  
Author(s):  
Diana García-Cerrillo ◽  
Ruth Noriega-Cisneros ◽  
Donovan Peña-Montes ◽  
Maribel Huerta-Cervantes ◽  
Mónica Silva-Ríos ◽  
...  
Keyword(s):  
Metabolic Diseases ◽  
Systemic Disease ◽  
Cardiac Injury ◽  
Thiobarbituric Acid ◽  
Diabetic Rats ◽  
Cardiovascular Risks ◽  
Thiobarbituric Acid Reactive Substances ◽  
Antioxidant Effects

Metabolic diseases have increased considerably such as diabetes mellitus (DM). Since diabetes is a systemic disease, it implies high cardiovascular risks. It has been widely established that cardiac injury is related to mitochondrial dysfunction through increment of reactive oxygen species (ROS). Synthetic antioxidants can have important side effects; therefore natural sources may represent a better option. Traditional Mexican medicine has been using Eryngium carlinae (EC) for medical treatment. Also our group showed that hexanic extract possesses in vitro antioxidant capacity. Experimental diabetes in Wistar rats was generated by streptozotocin (STZ) and hexanic extract of EC was supplied for 7 weeks (30 mg/kg). Cholesterol, triacylglycerides, glucose, and thiobarbituric acid reactive substances (TBARS) levels were determined in serum. Mitochondria from left ventricle were used in the quantification of TBARS, reduced glutathione, nitric oxide (NO) levels and activity of superoxide dismutase (SOD) enzyme was performed.  Biochemical parameters of glucose and triacylglycerides, as well as TBARS levels in serum show a significant reduction in diabetic group supplied with EC hexanic extract. Thus, we can conclude that the EC hexanic extract possesses antioxidant activity in vitro, and in vivo, by reducing glucose and triacylglycerides levels during hyperglycemia, which may eventually reduce the risk of developing diabetic cardiomyopathy.

Abstract 15142: Endogenous Cardiac Stem Cells’ Activation in Response to Injury Potentiates Their Regenerative Ability

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Andrew J Smith ◽  
Iolanda Aquila ◽  
Beverley J Henning ◽  
Mariangela Scalise ◽  
Bernardo Nadal-Ginard ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cardiac Injury ◽  
Fold Increase ◽  
Cardiac Stem Cells ◽  
Post Injury ◽  
Activated State ◽  
Potential Benefits ◽  
Therapeutic Avenue

The identification of resident, endogenous cardiac stem cells (eCSCs) has re-shaped our understanding of cardiac cellular physiology, while offering a significant potential therapeutic avenue. The biology of these cells must be better understood to harness their potential benefits. We used an acute dose (s.c.; 5mgkg-1) of isoproterenol (ISO) to induce diffuse cardiac injury, with associated eCSC activation, in rats. As peak eCSC activation was at 24 hours post ISO-injury, c-kitpos eCSCs were isolated, characterised and their potential for growth and regenerative potential was assessed in vitro and in vivo, respectively. Activated eCSCs showed increased cell cycling activity (51+1% in S- or G2/M phases vs. 9+2% of quiescent), Ki67 expression (56+7% vs. 10+1%) and TERT expression (14-fold increase vs. quiescent). When directly harvested in culture, activated eCSCs showed augmented proliferation, clonogenicity and cardiosphere formation compared to quiescent eCSCs. Activated eCSCs showed increases in expression of numerous growth factors, particularly HGF, IGF-1, TGF-β, periostin, PDGF-AA and VEGF-A. Furthermore, significant alterations were found in the miRnome, notably increased miR-146b and -221, and decreased miR-192 and -351. ISO+5FU was administrated to mice to induce a model of chronic dilated cardiomyopathy, which is characterized by the ablation of eCSCs and the absence of cardiomyocyte replenishment. In these mice with chronic heart failure, freshly isolated quiescent eCSCs or activated eCSCs (2d post-ISO) were injected through the tail vein. 28 days after injection, activated but not quiescent eCSCs re-populated the resident CSC pool, promoted robust new cardiomyocyte formation and improved cardiac function when compared to saline-treated mice. Dual-labelling with BrdU and EdU at selected stages after ISO injury determined that activated eCSCs returned to a quiescent level by 10 weeks post-injury. In conclusion, CSCs rapidly switch from a quiescent to an activated state to match the myocardial needs for myocyte replacement after injury and then spontaneously go back to quiescence. Harnessing the molecules regulating this process may open up future novel approaches for effective myocardial regeneration.

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