scholarly journals miR-208a in Cardiac Hypertrophy and Remodeling

2021 ◽  
Vol 8 ◽  
Author(s):  
Xing-Huai Huang ◽  
Jia-Lu Li ◽  
Xin-Yue Li ◽  
Shu-Xia Wang ◽  
Zhi-Han Jiao ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Heart Development ◽  
Regulatory Networks ◽  
Heart Diseases ◽  
Endocrine Function ◽  
Molecular Networks ◽  
Cardiac Conduction ◽  
Whole Body ◽  
Transgenic Expression ◽  
Hypertrophic Growth

Various stresses, including pressure overload and myocardial stretch, can trigger cardiac remodeling and result in heart diseases. The disorders are associated with high risk of morbidity and mortality and are among the major health problems in the world. MicroRNAs, a class of ~22nt-long small non-coding RNAs, have been found to participate in regulating heart development and function. One of them, miR-208a, a cardiac-specific microRNA, plays key role(s) in modulating gene expression in the heart, and is involved in a broad array of processes in cardiac pathogenesis. Genetic deletion or pharmacological inhibition of miR-208a in rodents attenuated stress-induced cardiac hypertrophy and remodeling. Transgenic expression of miR-208a in the heart was sufficient to cause hypertrophic growth of cardiomyocytes. miR-208a is also a key regulator of cardiac conduction system, either deletion or transgenic expression of miR-208a disturbed heart electrophysiology and could induce arrhythmias. In addition, miR-208a appeared to assist in regulating the expression of fast- and slow-twitch myofiber genes in the heart. Notably, this heart-specific miRNA could also modulate the “endocrine” function of cardiac muscle and govern the systemic energy homeostasis in the whole body. Despite of the critical roles, the underlying regulatory networks involving miR-208a are still elusive. Here, we summarize the progress made in understanding the function and mechanisms of this important miRNA in the heart, and propose several topics to be resolved as well as the hypothetical answers. We speculate that miR-208a may play diverse and even opposite roles by being involved in distinct molecular networks depending on the contexts. A deeper understanding of the precise mechanisms of its action under the conditions of cardiac homeostasis and diseases is needed. The clinical implications of miR-208a are also discussed.

scholarly journals Transcriptome profile of the sinoatrial ring reveals conserved and novel genetic programs of the zebrafish pacemaker

BMC Genomics ◽  
2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Rashid Minhas ◽  
Henry Loeffler-Wirth ◽  
Yusra H. Siddiqui ◽  
Tomasz Obrębski ◽  
Shikha Vashisht ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Heart Development ◽  
Heart Diseases ◽  
Cardiac Conduction ◽  
Molecular Profile ◽  
Signature Genes ◽  
Pacemaker Function ◽  
Genes Encoding ◽  
Electrical Impulses ◽  
Functional Analyses

Abstract Background Sinoatrial Node (SAN) is part of the cardiac conduction system, which controls the rhythmic contraction of the vertebrate heart. The SAN consists of a specialized pacemaker cell population that has the potential to generate electrical impulses. Although the SAN pacemaker has been extensively studied in mammalian and teleost models, including the zebrafish, their molecular nature remains inadequately comprehended. Results To characterize the molecular profile of the zebrafish sinoatrial ring (SAR) and elucidate the mechanism of pacemaker function, we utilized the transgenic line sqet33mi59BEt to isolate cells of the SAR of developing zebrafish embryos and profiled their transcriptome. Our analyses identified novel candidate genes and well-known conserved signaling pathways involved in pacemaker development. We show that, compared to the rest of the heart, the zebrafish SAR overexpresses several mammalian SAN pacemaker signature genes, which include hcn4 as well as those encoding calcium- and potassium-gated channels. Moreover, genes encoding components of the BMP and Wnt signaling pathways, as well as members of the Tbx family, which have previously been implicated in pacemaker development, were also overexpressed in the SAR. Among SAR-overexpressed genes, 24 had human homologues implicated in 104 different ClinVar phenotype entries related to various forms of congenital heart diseases, which suggest the relevance of our transcriptomics resource to studying human heart conditions. Finally, functional analyses of three SAR-overexpressed genes, pard6a, prom2, and atp1a1a.2, uncovered their novel role in heart development and physiology. Conclusion Our results established conserved aspects between zebrafish and mammalian pacemaker function and revealed novel factors implicated in maintaining cardiac rhythm. The transcriptome data generated in this study represents a unique and valuable resource for the study of pacemaker function and associated heart diseases.

Abstract 97: Induction of Hexosamine Biosynthetic Pathway Promotes Cardiac Hypertrophy through Activation of O-GlcNAcylation

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Diem H Tran ◽  
Jianping Li ◽  
Xiaoding Wang ◽  
Herman I May ◽  
Gabriele G Schiattarella ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Biosynthetic Pathway ◽  
Heart Diseases ◽  
Pressure Overload ◽  
Neonatal Rat ◽  
Mice Model ◽  
Hexosamine Biosynthetic Pathway ◽  
Hypertrophic Growth

Background & significance: Heart failure affects approximately 6 million Americans, with 5-year survival of 50%, which is responsible for a huge burden on the US economy and healthcare system. The relevance and significance of the metabolic alteration to the pathogenesis of pressure overload-induced cardiac hypertrophy and heart failure are largely unknown. The hexosamine biosynthetic pathway (HBP) that is linked to metabolism of glucose, fatty acids and amino acids, has been implicated in the pathophysiology of heart diseases. Methods & results: Thoracic aortic constriction (TAC) was performed to induce heart failure by pressure overload in mice. At the in vitro levels, treatment of phenylephrine (PE, 50 μM) was used to induce cellular hypertrophy in neonatal rat ventricular myocytes (NRVM). Our data revealed that all the enzymes of the HBP were upregulated while induction of hypertrophy at both in vivo and in vitro levels. Consistently, the intermediate product of the HBP was elevated in heart by afterload stress, as measured by metabolomics analyses. In the transgenic mice model for Gfat1, the rate-limiting enzyme of the HBP, we found more profound cardiac hypertrophy and cardiac remodeling in response to pressure overload. The increase of O-GlcNAc was also observed. In addition, the regulation of O-GlcNAcylation by specific targeting of two enzymes of the HBP (1 mM Alloxan, an inhibitor of OGT and 10 μM PUGNAc, an inhibitor of OGA) in NRVM suggested an involvement of the mTOR signaling in the activation of O-GlcNAc levels and the hypertrophy response. Targeting of the HBP by either specific siRNA or Gfat1 inhibitor (Azaserine, 5 μM) led to decrease in cellular hypertrophic response. Conclusions: Together, our data strongly suggest that the HBP participates in cardiac hypertrophic growth and pharmacologic targeting of the HBP may represent a novel approach to ameliorate pathological remodeling.

scholarly journals VEGF Contributes to Mesenchymal Stem Cell-Mediated Reversion of Nor1-Dependent Hypertrophy in iPS Cell-Derived Cardiomyocytes

2021 ◽  
Vol 2021 ◽  
pp. 1-19
Author(s):  
Denise Philipp ◽  
Michelle Holthaus ◽  
Vida Basoah ◽  
Kurt Pfannkuche ◽  
Laura Suhr ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cardiac Hypertrophy ◽  
Western Blot ◽  
Microarray Analysis ◽  
Heart Diseases ◽  
Orphan Receptor ◽  
In Vivo Studies ◽  
Dependent Manner ◽  
Ips Cell ◽  
Hypertrophic Growth

Myocardial hypertrophy is present in many heart diseases, representing a strong predictor of adverse cardiovascular outcomes. Regarding therapeutic intervention, mesenchymal stem cells (MSCs) have been suggested to significantly reduce cardiac hypertrophy and progression to heart failure. Preconditioning of MSCs was previously demonstrated to highly improve their paracrine activity resulting in modulation of immune responses and the progression of diseases. Here, we studied the effects of bone marrow-derived preconditioned MSCs on hypertrophied induced pluripotent stem cell-derived cardiomyocytes (iPS-CM) and also sought to identify MSC-derived antihypertrophic molecules. Phenylephrine (PE) was used to induce hypertrophy in murine iPS-CM, and markers of hypertrophy were identified by microarray analysis. Murine MSCs were treated with IFN-γ and IL-1β to enhance their paracrine activity, and transcriptional profiling was performed by microarray analysis. Hypertrophied iPS-CM were subsequently cocultured with preconditioned MSCs or MSC-conditioned medium (CM), respectively. Effects on hypertrophied iPS-CM were studied by cell area quantification, real-time PCR, and western blot. In some experiments, cells were incubated with fractions of MSC-CM obtained by ultrafiltration or by MSC-CM supplemented with inhibitory antibodies. Intracellular and extracellular levels of vascular endothelial growth factor (VEGF) were evaluated by western blot and ELISA. PE-induced hypertrophy in iPS-CM was associated with an upregulation of neuron-derived orphan receptor (Nor1) expression, activation of Akt, and inhibition of both strongly prevented hypertrophy induction in iPS-CM. VEGF secreted by preconditioned MSCs provoked hypertrophy regression in iPS-CM, and a negative correlation between Nor1 expression and hypertrophic growth could be evidenced. Our results demonstrate that Nor1 expression strongly supports hypertrophy in iPS-CM. Moreover, the secretome of preconditioned MSCs triggered regression of hypertrophy in iPS-CM in a VEGF-dependent manner. We suggest that the delivery of the MSC-derived secretome may represent a therapeutic strategy to limit cardiac hypertrophy. However, additional in vivo studies are needed to prove this hypothesis.

scholarly journals Transcriptome Profile of the Sinoatrial Ring Reveals Conserved and Novel Genetic Programs of the Zebrafish Pacemaker

2020 ◽  
Author(s):  
Rashid Minhas ◽  
Henry Loeffler-Wirth ◽  
Yusra Siddiqui ◽  
Tomasz Obrebski ◽  
Shikha Vhashist ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Heart Development ◽  
Heart Diseases ◽  
Cardiac Conduction ◽  
Molecular Profile ◽  
Signature Genes ◽  
Pacemaker Function ◽  
Genes Encoding ◽  
Electrical Impulses ◽  
Functional Analyses

Abstract Background: Sinoatrial Node (SAN) is part of the cardiac conduction system, which controls the rhythmic contraction of the vertebrate heart. The SAN consists of a specialized pacemaker cell population that has the potential to generate electrical impulses. Although the SAN pacemaker has been extensively studied in mammalian and teleost models, including the zebrafish, their molecular nature remains inadequately comprehended. Results: To characterize the molecular profile of the SAR and elucidate the mechanism of pacemaker function, we utilized the zebrafish transgenic line sqet33mi59BEt to isolate cells of the sinoatrial ring (SAR) of developing zebrafish embryos and profiled their transcriptome. Our analyses identified novel candidate genes and well-known conserved signaling pathways involved in pacemaker development. We show that, compared to the rest of the heart, the zebrafish SAR overexpresses several mammalian SAN pacemaker signature genes, which include hcn4 as well as those encoding calcium- and potassium-gated channels. Moreover, genes encoding components of the BMP and Wnt signaling pathways, as well as members of the Tbx family, which have previously been implicated in pacemaker development, were also overexpressed in the SAR. Among SAR-overexpressed genes, 24 had human homologues implicated in 104 different ClinVar phenotype entries related to various forms of congenital heart diseases, which suggest the relevance of our transcriptomics resource to studying human heart conditions. Finally, functional analyses of three SAR-overexpressed genes, pard6a, prom2, and atp1a1a.2, uncovered their novel role in heart development and physiology. Conclusion: Our results established conserved aspects between zebrafish and mammalian pacemaker function and revealed novel factors implicated in maintaining cardiac rhythm. The transcriptome data generated in this study represents a unique and valuable resource for the study of pacemaker function and associated heart diseases.

scholarly journals Processed By-Products from Soy Beverage (Okara) as Sustainable Ingredients for Nile Tilapia (O. niloticus) Juveniles: Effects on Nutrient Utilization and Muscle Quality

Animals ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 590
Author(s):  
Glenise B. Voss ◽  
Vera Sousa ◽  
Paulo Rema ◽  
Manuela. E. Pintado ◽  
Luísa M. P. Valente
Keyword(s):  
Nile Tilapia ◽  
Lactobacillus Rhamnosus ◽  
Protein Digestibility ◽  
Nutrient Utilization ◽  
Nutrient Digestibility ◽  
Fish Growth ◽  
Muscle Quality ◽  
Whole Body ◽  
Hypertrophic Growth ◽  
Bifidobacterium Animalis

The apparent digestibility coefficients (ADCs) of differently processed okara meals were assessed in Nile tilapia diets: dried okara not autoclaved (FOK), dried okara autoclaved (AOK), okara hydrolyzed with Alcalase (ALOK) or Cynara cardunculus proteases (CYOK), and hydrolyzed okara fermented with lactic bacteria: Lactobacillus rhamnosus R11 (CYR11OK) or Bifidobacterium animalis ssp. lactis Bb12 (CYB12OK). Okara processing significantly affected nutrient digestibility: dry matter ADC was highest in CYR11OK (80%) and lowest in FOK (40%). The lowest protein digestibility was observed in CYR11OK (72%), and the highest in AOK (97%) and CYOK (91%), evidencing the effectiveness of the autoclave and the use of C. cardunculus proteases to increase okara protein bioavailability. The inclusion of up to 20% of AOK or CYOK did not affect fish growth, nutrient utilization, or whole body composition of Nile tilapia. The flesh quality (color, pH, water activity, cohesiveness, elasticity and resilience) was not affected by the dietary incorporation of AOK or CYOK. Fish fed with AOK diets stand out for their high density of muscle fibers, particularly in AOK20, which can explain their high muscle firmness and may result in further hypertrophic growth. Altogether, results suggest that hydrolyzed or autoclaved okara are valuable ingredients for Nile tilapia diets.

Expression of cyclin D1 and CDK4 causes hypertrophic growth of cardiomyocytes in culture: a possible implication for cardiac hypertrophy

2002 ◽  
Vol 296 (2) ◽  
pp. 274-280 ◽  
Author(s):  
Mimi Tamamori-Adachi ◽  
Hiroshi Ito ◽  
Kiyoshi Nobori ◽  
Kentaro Hayashida ◽  
Junya Kawauchi ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Cyclin D1 ◽  
Hypertrophic Growth

Abstract P320: The Gut Microbial Metabolite Butyrate Suppresses Cardiac Hypertrophy Via An Epigenetic Mechanism

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Masahiko Umei ◽  
Hiroshi Akazawa ◽  
Akiko Saga-Kamo ◽  
Hiroki Yagi ◽  
Qing Liu ◽  
...  
Keyword(s):  
Heart Failure ◽  
Fatty Acid ◽  
Cardiac Hypertrophy ◽  
Short Chain Fatty Acid ◽  
Chain Fatty Acid ◽  
Epigenetic Mechanism ◽  
Neonatal Rat ◽  
Short Chain ◽  
Rat Cardiomyocytes ◽  
Hypertrophic Growth

Introduction: Short-chain fatty acids (SCFA) are one of the gut microbial metabolites that can influence host health and disease. We previously reported that gut dysbiosis is associated with heart failure, and that the proportion of butyrate-producing bacteria is decreased in the gut of patients with heart failure. Purpose: We investigated the molecular mechanism of butyrate in the development of cardiac hypertrophy. Methods and Results: Single-cell transcriptome analysis and co-expression network analysis revealed that G protein-coupled receptors for short-chain fatty acid receptors were not expressed in cardiomyocytes and that Olfr78 was expressed in vascular smooth muscle cells in the heart. On the other hand, treatment with butyrate inhibited ET1-induced and isoproterenol (ISO)-induced hypertrophic growth in cultured neonatal rat cardiomyocytes. Moreover, butyrate increased the acetylation levels of histone H3, suggesting the inhibitory effect of butyrate on HDAC. In addition, butyrate caused the degradation of HDAC2 and up-regulation of Inpp5f, encoding inositol polyphosphate-5-phosphatase f, leading to a significant decrease in the phosphorylation levels of Akt and glycogen synthase kinase 3β (GSK3β). Finally, intraperitoneal injection of butyrate inhibited ISO-induced cardiac hypertrophy in mice. These results suggest that butyrate protects against hypertrophic responses via suppression of the Akt-GSK3β pathway through HDAC inhibition. Conclusion: In the heart, there were no known short-chain fatty acid receptors in cardiomyocytes. However, butyrate was shown to have an epigenetic mechanism in suppressing effect on cardiomyocyte hypertrophy via suppression of HDAC2-Akt-GSK3β axis. Our results uncover a potential link between dysbiosis of intestinal microbiota and the development of cardiac hypertrophy.

Prenatal ethanol exposure impairs the conduction delay at the atrioventricular junction in the looping heart

2021 ◽  
Author(s):  
Shan Ling ◽  
Michael W Jenkins ◽  
Michiko Watanabe ◽  
Stephanie M Ford ◽  
Andrew M Rollins
Keyword(s):  
Heart Development ◽  
Molecular Mechanisms ◽  
Early Stage ◽  
Heart Defects ◽  
Ethanol Exposure ◽  
Cardiac Conduction ◽  
Conduction Delay ◽  
Prenatal Ethanol Exposure ◽  
Endocardial Cushions ◽  
Atrioventricular Junction

The etiology of ethanol-related congenital heart defects has been the focus of much study, but most research has concentrated on cellular and molecular mechanisms. We have shown with optical coherence tomography (OCT) that ethanol exposure led to increased retrograde flow and smaller atrioventricular (AV) cushions compared to controls. Since AV cushions play a role in patterning the conduction delay at the atrioventricular junction (AVJ), this study aims to investigate whether ethanol exposure alters the AVJ conduction in early looping hearts and whether this alteration is related to the decreased cushion size. Quail embryos were exposed to a single dose of ethanol at gastrulation, and Hamburger-Hamilton stage 19 - 20 hearts were dissected for imaging. Cardiac conduction was measured using an optical mapping microscope and we imaged the endocardial cushions using OCT. Our results showed that, compared with controls, ethanol-exposed embryos exhibited abnormally fast AVJ conduction and reduced cushion size. However, this increased conduction velocity (CV) did not strictly correlate with decreased cushion volume and thickness. By matching the CV map to the cushion size map, we found that the slowest conduction location was consistently at the atrial side of the AVJ, which had the thinner cushions, not at the thickest cushion location at the ventricular side as expected. Our findings reveal regional differences in the AVJ myocardium even at this early stage in heart development. These findings reveal the early steps leading to the heterogeneity and complexity of conduction at the mature AVJ, a site where arrhythmias can be initiated.

scholarly journals Piezo1-Mediated Mechanotransduction Promotes Cardiac Hypertrophy by Impairing Calcium Homeostasis to Activate Calpain/Calcineurin Signaling

Hypertension ◽  
2021 ◽  
Author(s):  
Yuhao Zhang ◽  
Sheng-an Su ◽  
Wudi Li ◽  
Yuankun Ma ◽  
Jian Shen ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Ion Channel ◽  
Calcium Homeostasis ◽  
Pressure Overload ◽  
Cell Physiology ◽  
Hypertrophic Growth ◽  
Molecular Features ◽  
Mechanosensitive Ion Channel

Hemodynamic overload induces pathological cardiac hypertrophy, which is an independent risk factor for intractable heart failure in long run. Beyond neurohumoral regulation, mechanotransduction has been recently recognized as a major regulator of cardiac hypertrophy under a myriad of conditions. However, the identification and molecular features of mechanotransducer on cardiomyocytes are largely sparse. For the first time, we identified Piezo1 (Piezo type mechanosensitive ion channel component 1), a novel mechanosensitive ion channel with preference to Ca 2+ was remarkably upregulated under pressure overload and enriched near T-tubule and intercalated disc of cardiomyocyte. By applying cardiac conditional Piezo1 knockout mice (Piezo1 fl/fl Myh6Cre+, Piezo1 Cko ) undergoing transverse aortic constriction, we demonstrated that Piezo1 was required for the development of cardiac hypertrophy and subsequent adverse remodeling. Activation of Piezo1 by external mechanical stretch or agonist Yoda1 lead to the enlargement of cardiomyocytes in vitro, which was blocked by Piezo1 silencing or Yoda1 analog Dooku1 or Piezo1 inhibitor GsMTx4. Mechanistically, Piezo1 perturbed calcium homeostasis, mediating extracellular Ca 2+ influx and intracellular Ca 2+ overload, thereby increased the activation of Ca 2+ -dependent signaling, calcineurin, and calpain. Inhibition of calcineurin or calpain could abolished Yoda1 induced upregulation of hypertrophy markers and the hypertrophic growth of cardiomyocytes in vitro. From a comprehensive view of the cardiac transcriptome, most of Piezo1 affected genes were highly enriched in muscle cell physiology, tight junction, and corresponding signaling. This study characterizes an undefined role of Piezo1 in pressure overload induced cardiac hypertrophy. It may partially decipher the differential role of calcium under pathophysiological condition, implying a promising therapeutic target for cardiac dysfunction.

scholarly journals ISCA1 Deficiency Induces Iron Metabolism Disorder and Myocardial Oncosis in Rat

2021 ◽  
Author(s):  
Yahao Ling ◽  
Xinlan Yang ◽  
Xu Zhang ◽  
Feifei Guan ◽  
Xiaolong Qi ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Iron Metabolism ◽  
Heart Development ◽  
Cardiac Development ◽  
Heart Diseases ◽  
Pathological Process ◽  
Metabolism Disorder ◽  
Abnormal Metabolism ◽  
Validation Experiments

Abstract The effects of multiple mitochondrial dysfunction (MMD) on heart, a highly mitochondria-dependent tissue, is still unclear. This study was the first to verify the effect of ISCA1 gene deficiency, which has been shown to cause multiple mitochondrial dysfunction syndromes type 5 (MMDS5), on cardiac development in vivo, that is cardiomyocytes suffer from energy shortage due to abnormal metabolism of iron ion, which leads to oncosis and eventually HF and body death. Subsequently, we determine a new interacting molecule for ISCA1, six-transmembrane epithelial antigen of prostate 3 (STEAP3), which acts as a reductase in the reduction of Fe3+ to Fe2+. Forward and reverse validation experiments demonstrated that STEAP3 plays an important role in iron metabolism and energy generation impairment induced by ISCA1 deficiency. This result provides theoretical basis for understanding of MMDS pathogenesis, especially on heart development and the pathological process of heart diseases, and finally provides new clues for searching of clinical therapeutic targets.

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