Download or read book Transcriptional Regulation of Cardiac Hypertrophy and Heart Failure written by and published by . This book was released on 2006 with total page 241 pages. Available in PDF, EPUB and Kindle. Book excerpt: Cardiac hypertrophy and dilatation are mediated by neuro-endocrine factors, internal stretch and stress sensitive signaling pathways, which in turn transduce alterations in cardiac gene expression through specific transcription factors. This dissertation will, in the first section, provide direct evidence for transcription factor myocyte enhancer factor 2 (MEF2) in the regulation of cardiac dilation and fibrosis through reprogramming cardiac gene expression; in the second section, introduce a novel secreted factor growth differentiation factor 15 (GDF15) as a cardiac anti-hypertrophic and protective factor. The MEF2 family of transcription factors have been indirectly implicated as a downstream mediator of hypertrophic signaling pathways. In this dissertation, we demonstrate directly that MEF2 induce dilated cardiomyopathy and the lengthening of myocytes without a primary induction of cardiac hypertrophy. Cardiac-specific overexpression of MEF2A or MEF2C showed spontaneous cardiomyopathy, which was not altered by activated calcineurin, or developed more fulminant disease following pressure overload. In cultured cardiomyocytes, MEF2A and MEF2C overexpression induced sarcomeric disorganization and focal elongation. Mechanistically, MEF2A and MEF2C programmed similar alteration in gene expression that included extracellular matrix remodeling, ion handling, and metabolic genes. Indeed, cultured cardiomyocytes overexpressing MEF2A, or adult myocytes from MEF2A transgenic hearts, showed reduced transient outward currents, suggesting a proximal mechanism underlying MEF2-dependent cardiomyopathy. During the analysis of gene reprogramming by MEF2, we noted dramatic induction of GDF15. GDF15 is induced by conditions that promote hypertrophy and dilation. Transgenic mice with cardiac-specific overexpression of GDF15 were normal, but were partially resistant to induced hypertrophy. GDF15 antagonized induced hypertrophy in cultured cardiomyocyte. Transient expression of GDF15 by intravenous adenoviral delivery, or by direct injection of recombinant protein, attenuated ventricular dilation and heart failure in MLP null mice through an endocrine effect. Conversely, Gdf15 null mice showed enhanced cardiac hypertrophic growth, and a pronounced loss in ventricular performance following stimulation. Mechanistically, GDF15 promoted activation of Smad2/3, which was partially responsible for the anti-hypertrophic effects. These results identify GDF15 as a novel endocrine factor that antagonizes the hypertrophic response and loss of ventricular performance.
Download or read book A Proposed Mechanism for Transcriptional Regulation of Cardiac Hypertrophy written by Heidi Mae Medford and published by . This book was released on 2014 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: Conventional medical therapies for treatment of hypertension center around symptom management, and this is due, in part, to limited understanding of the mechanisms responsible for hypertrophy, remodeling, and progression to heart failure. Cardiac hypertrophy can be physiological or pathological. Physiological cardiac hypertrophy occurs in response to exercise and pregnancy, while pathological cardiac hypertrophy results from mechanical stress such as pressure overload induced by hypertension; this form of hypertrophy is irreversible, and can eventually degenerate to heart failure. Approximately 2-5% of circulating glucose enters the hexosamine biosynthesis pathway, and the end result is posttranslational attachment of O-linked attachment of β-N-acetylglucosamine (O-GlcNAc) to cardiac proteins, which is increased in cardiovascular disease and heart failure; O-GlcNAc transferase (OGT) is the enzyme that catalyzes this addition. OGT is a singly encoded protein with three splice variants (110, 103, and 78 kDa), and hypertrophic signaling is blunted by O-GlcNAcylation of proteins by OGT. Although the OGT 110 kDa subunit has been characterized in a variety of cell and tissue types, cardiac OGT function and activity remains poorly understood. The aim of this dissertation was to investigate the roles of O-GlcNAc and OGT in physiological and pathological hypertrophy signaling, as well as their interaction with multiple hypertrophic signaling cascades such as the fetal cardiac gene program (FCGP), as well as histone deacetylase 4 (HDAC4) and CaMKIIδ. The dissertation consists of three original research studies, as well as a recently published literature review describing the role of OGT in heart failure. Through a variety of study designs including Western diet consumption, exercise, and hypertension/pressure overload, we have demonstrated that 110 kDa OGT is essential to the cardiac stress response. This dissertation has firmly established the involvement of the 110 kDa subunit of OGT with FCGP, HDAC4, and CaMKIIδ regulated hypertrophic signaling, as well as implicated OGT as being intricately involved with regulation of calcium signaling proteins. The findings described in this dissertation enhance the understanding of both the function and involvement of OGT in exercise and heart failure, which will promote the development of more effective therapeutic approaches to cardiomyopathy.
Download or read book Epigenetic Mechanisms of Transcriptional Regulation in Cardiac Hypertrophy Using Engineered Heart Tissue written by Alexandra Löser and published by . This book was released on 2018 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt:
Download or read book The Role of PGC 1a in the Transcriptional Regulation of Energy Homeostasis in Cardiac Hypertrophy and Heart Failure written by Houman Ashrafian and published by . This book was released on 2009 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt:
Download or read book Molecular Mechanisms of Cardiac Hypertrophy and Failure written by Richard A. Walsh and published by CRC Press. This book was released on 2005-11-29 with total page 812 pages. Available in PDF, EPUB and Kindle. Book excerpt: This title reviews current knowledge of the mechanisms contributing to heart failure. Editor Richard Walsh and an internationally renowned team of contributors discuss key advances in molecular and cell biology, biochemistry, and pharmacology, focusing on advances that have a direct bearing on current clinical studies. It highlights developments across a broad range of disciplines, with in-depth coverage of each topic providing background and perspective on current literature. By setting new advances in a broader context, this text allows readers to compare different ideas and evaluate their importance in their own areas of research or clinical practice.
Download or read book Heart Hypertrophy and Failure written by Naranjan S. Dhalla and published by Springer Science & Business Media. This book was released on 2012-12-06 with total page 549 pages. Available in PDF, EPUB and Kindle. Book excerpt: Heart Hypertrophy and Failure brings together leading basic scientists and clinicians, presenting improved knowledge of the pathophysiology and treatment of the condition. The result is a synthesis of state-of-the-art information on molecular biology, cellular physiology and structure-function relationships in the cardiovascular system in health and disease. The papers presented describe fundamental mechanisms underlying changes in the cellular machinery during the development of cardiac hypertrophy and heart failure. Audience: Students, scientists, clinical and experimental cardiologists who seek to understand and manage the perplexing problems of hypertrophy and heart failure.
Download or read book Cardiac Regeneration written by Masaki Ieda and published by Springer. This book was released on 2017-10-27 with total page 274 pages. Available in PDF, EPUB and Kindle. Book excerpt: This Volume of the series Cardiac and Vascular Biology offers a comprehensive and exciting, state-of-the-art work on the current options and potentials of cardiac regeneration and repair. Several techniques and approaches have been developed for heart failure repair: direct injection of cells, programming of scar tissue into functional myocardium, and tissue-engineered heart muscle support. The book introduces the rationale for these different approaches in cell-based heart regeneration and discusses the most important considerations for clinical translation. Expert authors discuss when, why, and how heart muscle can be salvaged. The book represents a valuable resource for stem cell researchers, cardiologists, bioengineers, and biomedical scientists studying cardiac function and regeneration.
Download or read book Gene Activity Patterns Associated with Pathological Cardiac Hypertrophy are Mediated by Specific Chromatin Modifying Factors written by Lisa Hsiu Chuan Chang and published by . This book was released on 2013 with total page 528 pages. Available in PDF, EPUB and Kindle. Book excerpt: Pathological cardiac hypertrophy is an initial compensatory response of the heart to a range of intrinsic stimuli including arterial hypertension, myocardial infarction and cardiomyopathy whereby prolonged stress often results in congestive heart failure and sudden death. This condition is commonly associated with the reactivation of the foetal gene program. Recent work has uncovered the importance of chromatin remodeling in the control of gene expression in heart disease. We used a transverse aortic constricted (TAC) mouse model to induce hypertrophy. The increased expression of Nppa, Nppb and embryonic Myh7 were inversely correlated with reduced expression of the adult Myh6 and Atp2a2 genes in TAC animals. We examined the regulatory complexes associated with hypertrophy and changes in the transcriptional response using strategies that allowed us to immunopurify soluble chromatin fractions. Chromatin immunopurifications were performed on the left ventricles of SHAM and TAC cardiac tissues. Quantification of the immunopurified chromatin indicated a unique pattern of binding on the promoters of Nppa, Nppb, Myh6 and Myh7 genes. Our findings suggested that the ATP-dependent chromatin remodeling complex, SWI/SNF, could act in a coordinated fashion with histone acetyltransferase (HAT) or histone deacetylase (HDAC) complexes to regulate the expression of these genes in the hypertrophic heart. SWI/SNF complex serves as a co-regulator in the development of pathological cardiac hypertrophy. We observed enrichment of SWI/SNF subunit BRM and p300 HAT during the reactivation of the foetal gene program on the promoters of upregulated Nppa, Nppb and Myh7 genes. We also observed the recruitment of the SWI/SNF subunit BRG1 and HDAC2 on the Myh6 gene which was consistent with its suppressed gene expression in the hypertrophic heart. The data presented indicate that components of SWI/SNF machinery are associated with diverse regulatory mechanism and the suppression and activation of gene expression. Suppression of HDACs is known to blunt pressure-overload cardiac hypertrophy. However, the molecular mechanism behind this blockade remains unclear. We used a broad-spectrum HDAC inhibitor, Trichostatin A (TSA) to investigate hypertrophy prevention in a mouse model of TAC. TSA treatment resulted in the downregulation of Nppa, Nppb and embryonic Myh7 which was intrinsically highly expressed in the hypertrophic heart. The observed changes in gene expression were found to be associated with concurrent release of BRM, H3K9/14 acetylation and recruitment of BRG1, HDAC2 on suppressed Nppa, Nppb and Myh6 gene promoters in the TSA treated TAC animals. This study described the reciprocoal association of SWI/SNF subunits, BRG1 and BRM, with histone modifications correlated with the regulation of cardiac gene transcription in pathological hypertrophy and their regulatory function in response to TSA exposure. To determine changes in the expression of genes mediated by pathological cardiac hypertrophy, we used a global approach using RNA-Seq. In recent years, high-throughput technologies have been developed and rapidly improved to interrogate several aspects of cellular processes. RNA-Seq was used to map global mRNA expression profile, providing a more sensitive approach than microarrays. It allowed the identification of rare transcripts and gene isoforms which the array approach was unable to detect. This was followed by further investigation using bioinformatics resources such as gene enrichment analysis, pathways, and regulatory network analysis. This enabled us to classify the differentially expressed genes and transcript isoforms into functional categories. A major challenge in deciphering the molecular mechanism associated with the development and prevention of cardiac hypertrophy is the identification of regulatory determinants that are thought to regulate gene expression. We have identified that SWI/SNF chromatin remodeling complex, more specifically, BRM was associated with HAT whereas BRG1 was associated with HDAC2 in correlation with gene expression. Further investigation of regulatory determinants mediated gene expression would need to be carried out to provide a useful framework for understanding and distinguishing the regulatory function of SWI/SNF in pathological cardiac hypertrophy. These studies could lead to more precise understanding of heart disease and potential new strategy to personalised therapies to prevent or reverse cardiac hypertrophy and in turn, cardiac failure.
Download or read book Protein Translation Regulation in Cardiac Hypertrophy and Heart Failure written by Yifan Wang and published by . This book was released on 2023 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: Cardiac hypertrophy is an adaptive process during hemodynamic stress induced by various pathophysiological conditions. During this process, individual myocyte grows bigger in size under complex and multi-layered regulations, which required a large amount of de novo protein synthesis. It has already been well-established back in the 1960s and 70s that protein synthesis is induced early on during induced hypertrophic stress, which is a dominating factor leading to hypertrophic myocytes and hearts. Over the years, scientists have extensively investigated different regulatory steps in cardiac hypertrophy, such as signaling pathways, transcription regulation, and metabolism. However, translation remained poorly studied. Moreover, recent discoveries on transcriptome/translatome mismatch brought these questions to our attention, as it is challenging the prevalent interpretation of the central dogma. Therefore, there's a dire need to achieve a deeper understanding of translation regulation in cardiac hypertrophy to fill the knowledge gap and coordinate the conflict and discrepancies between the knowns and the novel discoveries. In this thesis, we discussed protein translation regulation in cardiac hypertrophy in many different aspects, including toolkits to study translation, translation efficiency, translation capacity, and the emerging field of spatial-temporal regulation of translation machinery. Aiming to obtain a comprehensive understanding of translation regulation in cardiac hypertrophy, we combined novel mouse and cell culture models with cutting-edge technologies including deep RNA sequencing and proteomics to investigate the translatome landscape and underlying molecular mechanisms. We identified striking remodeling of the translatome and nascent proteome during hypertrophic stress with an emphasis on ribosome biogenesis. We identified a long non-coding RNA (lncRNA) named Myocardial Infarction Associated Transcript (Miat) as a critical regulator of translation during cardiac hypertrophy. For molecular mechanisms, we demonstrated Miat interacts with a nucleolar protein nucleolin (NCL) to mediate ribosome biogenesis. We also discovered important regulatory roles of Miat in nucleolar (center of ribosome biogenesis) dynamics and transportation of translation machinery. Taken together, this thesis gave a holistic and comprehensive depiction of translation regulation in pathological cardia hypertrophy with a well-characterized lncRNA mediating multiple aspects of the translation process and translation machineries. Our study filled the knowledge gap in our understanding of cardiac hypertrophy and gave inspirations on protein synthesis regulation in heart, which could be generalized to many other non-cardiac contexts and lead to a paradigm shift. Our discoveries shed light on current clinical resolutions of cardiac hypertrophy and may potentially lead to the development of novel therapies.
Download or read book Cardiac Hypertrophy and Failure written by Bernard Swynghedauw and published by . This book was released on 1990 with total page 718 pages. Available in PDF, EPUB and Kindle. Book excerpt: Cardiac insufficiency, a major cause of premature mortality, is a key focus of medical and pharmaceutical research. This book aims to bring clinicians and researchers up-to-date on recent biophysical, cellular physiological and molecular biological developments and their clinical applications.
Download or read book Cardiac Adaptation in Heart Failure written by J. Holtz and published by Springer Science & Business Media. This book was released on 2012-12-06 with total page 344 pages. Available in PDF, EPUB and Kindle. Book excerpt: Traditionally, cardiac hypertrophy is regarded as an adaptation of the heart to permanent mechanical overload. Regardless of the fact that many different and often unknown primary causes can result in heart failure, mechanical overload and myocardial hypertrophy is found in almost all forms of manifest chronic heart failure (apart from failure due to extramyocardial hindrances to inflow or to relaxation). However, the reactive enlargement of myocardial mass in response to an enhanced hemodynamic burden appears to be a double-edged sword. Obviously, the hypertrophy helps to reduce the enhanced ventricular wall stress in heart failure by adding contractile units to the overdistended chamber wall. However, in recent years it became clear that this adaptive hypertrophic process is rather complex and may include problematic facets. The adaptive hypertrophy includes proliferation of the nonmyocyte cardiac cells as well as substantial alterations in the phenotype of the growing myocytes due to differential changes in gene expression.
Download or read book Cardiac Mechanotransduction written by Matti Weckström and published by Springer Science & Business Media. This book was released on 2007-12-22 with total page 158 pages. Available in PDF, EPUB and Kindle. Book excerpt: This book presents a multidisciplinary approach to cardiac mechanotransduction. The chapters depict the many faces of the topic, from membrane and ion channel level to mechanics, biochemical signaling and regulation via hormone systems. Cardiac Mechanotransduction is of interest to basic life sciences, like physiology, biochemistry and pharmacology, but also to clinicians working with heart-related problems, such as cardiologists and internists.
Download or read book Signal Transduction and Cardiac Hypertrophy written by Naranjan S. Dhalla and published by Springer Science & Business Media. This book was released on 2012-12-06 with total page 778 pages. Available in PDF, EPUB and Kindle. Book excerpt: Cellular signaling in cardiac muscle refers to the myriad of stimuli and responses that direct and control the physiological operation of this organ. Our understand ing of these complex signaling cascades has increased dramatically over the past few decades with the advent of molecular tools for their dissection. Moreover, this infor mation is beginning to provide tangible targets towards manipulating cardiac func tion in the setting of cardiovascular disease. The mechanisms and factors that regulate cardiac cell growth are of particular interest as both adaptive and maladaptive responses can occur during cardiac hypertrophy. Cardiac hypertrophy describes the increase in individual cardiac myocyte size that is accomplished through the series and/or parallel addition of sarcomeres. The ability of cardiac muscle to increase in size through hyperplasia becomes highly restricted or negligible shortly after birth. Consequently, the increase in heart size associated with development and growth of an individual occurs through hypertrophy. In response to a chronic increase in workload, cardiac muscle cells can dramatically increase in size to face their increasing contractile demands. While this plasticity is clearly a ben eficial response under many conditions, it can be highly deleterious and inappropri ate under others. For example, cardiac hypertrophy associated with endurance exercise clearly enhances athletic performance. In contrast, the hypertrophy associated with chronic hypertension, stenotic or regurgitant heart valves, or following a myocardial infarction often continues far beyond the period where this adaptive response is ben eficial.
Download or read book Molecular Approaches to Heart Failure Therapy written by Gerd Hasenfuss and published by Springer Science & Business Media. This book was released on 2000 with total page 382 pages. Available in PDF, EPUB and Kindle. Book excerpt: This book provides an approach to discussing new targets for molecular strategies in heart failure therapy. On the basis of most recent data, international experts in this field elaborate on the most relevant pathophysiological alterations in heart failure on a molecular level and discuss potential strategies. These include technical aspects of gene transfer, gene transfer approaches to treating pump failure and arrhythmias, and gene transfer to prevent apoptosis. Furthermore, the topics myocyte transplantation and cell cycle regulation are discussed.The book contains twenty-one chapters including state-of-the-art review articles as well as original papers.
Download or read book Cardiac Hypertrophy From Compensation to Decompensation and Pharmacological Interventions written by Hai-Gang Zhang and published by Frontiers Media SA. This book was released on 2021-06-28 with total page 110 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Download or read book The Hypertrophied Heart written by Nobuakira Takeda and published by Springer Science & Business Media. This book was released on 2012-12-06 with total page 490 pages. Available in PDF, EPUB and Kindle. Book excerpt: Whenever the heart is challenged with an increased work load for a prolonged period, it responds by increasing its muscle mass--a phenomenon known as cardiac hypertrophy. Although cardiac hypertrophy is commonly seen under physiological conditions such as development and exercise, a wide variety of pathological situa tions such as hypertension (pressure overload), valvular defects (volume overload), myocardial infarction (muscle loss), and cardiomyopathy (muscle disease) are also known to result in cardiac hypertrophy. Various hormones such as catecholamines, thyroid hormones, angiotensin II, endothelin, and growth factors have also been shown to induce cardiac hypertrophy. Although the exact mechanisms underlying or pathological forrns of cardiac hypertrophy are poorly under the physiological stood, an increase in the intraventricular pressure is believed to represent the major stimulus for the development of cardiac hypertrophy. In this regard, stretching of the cardiac muscle has been shown to induce the hypertrophic response, but the role of metabolic influences in this process cannot be ruled out. Furthermore, different hormones and other interventions in the absence of stretch have been observed to stimulate protein synthesis in both isolated cardiomyocyte and vascular myocyte preparations. Nonetheless, it is becoming dear that receptor as well as phospholipid linked signal transduction pathways are activated in some specific manner depend ing upon the initial hypertrophic stimulus, and these then result in an increase in the size and mass of cardiomyocytes.
Download or read book Epigenetics in Cardiac Disease written by Johannes Backs and published by Springer. This book was released on 2016-11-21 with total page 322 pages. Available in PDF, EPUB and Kindle. Book excerpt: This book describes important advances in our understanding of how environmental conditions affect cardiac gene expression through epigenetic mechanisms. Further, it discusses the roles of chromatin modifications (in particular DNA methylation and histone modifications) and of chromatin regulators in the context of cardiac diseases. The book provides readers with an overview of our current understanding of epigenetic regulation in the heart, and will stimulate further research in this exciting field. Edited and written by internationally respected experts, it addresses the needs of professors, students and researchers working in the fields of cardiac biology and epigenetics.
