Distinct Epigenomic Features in End-Stage Failing Human Hearts

Movassagh, Mehregan; Choy, Mun-Kit; Knowles, David A.; Cordeddu, Lina; Haider, Syed; Down, Thomas A.; Siggens, Lee; Vujić, Ana; Simeoni, Ilenia; Penkett, Chris; Goddard, Martin; Lió, Píetro; Bennett, Martin R.; Foo, Roger

doi:10.1161/circulationaha.111.040071

Cited by 241 publications

(214 citation statements)

References 58 publications

Supporting

Mentioning

203

Contrasting

Order By: Relevance

“…Emerging data show that aberrant DNA methylation patterns play an important role in cardiovascular disease, including atherogenesis (54), coronary artery disease (44,45), dilated cardiomyopathy (24), and heart failure (29,36,37). Furthermore, DNA methylation regulates the expression of myosin heavy chain 7 (Myh7), a sarcomere protein important for cardiac contractility (8).…”

mentioning

confidence: 99%

cAMP induces hypertrophy and alters DNA methylation in HL-1 cardiomyocytes

Fang

Robinson

Wang-Hu

et al. 2015

American Journal of Physiology-Cell Physiology

View full text Add to dashboard Cite

-cAMP is a highly regulated secondary messenger involved in many biological processes. Chronic activation of the cAMP pathway by catecholamines results in cardiac hypertrophy and fibrosis; however, the mechanism by which elevated cAMP leads to cardiomyopathy is not fully understood. To address this issue, we increased intracellular cAMP levels in HL-1 cardiomyocytes, a cell line derived from adult mouse atrium, using either the stable cAMP analog N 6 ,2=-O-dibutyryladenosine 3=,5=-cyclic monophosphate (DBcAMP) or phosphodiesterase (PDE) inhibitors caffeine and theophylline. Elevated cAMP levels increased cell size and altered expression levels of cardiac genes and micro-RNAs associated with hypertrophic cardiomyopathy (HCM), including Myh6, Myh7, Myh7b, Tnni3, Anp, Bnp, Gata4, Mef2c, Mef2d, Nfatc1, miR208a, and miR208b. In addition, DBcAMP altered the expression of DNA methyltransferases (Dnmts) and Tet methylcytosine dioxygenases (Tets), enzymes that regulate genomic DNA methylation levels. Changes in expression of DNA methylation genes induced by elevated cAMP led to increased global DNA methylation in HL-1 cells. In contrast, inhibition of DNMT activity with 5-azacytidine treatment decreased global DNA methylation levels and blocked the increased expression of several HCM genes (Myh7, Gata4, Mef2c, Nfatc1, Myh7b, Tnni3, and Bnp) observed with DBcAMP treatment. These results demonstrate that cAMP induces cardiomyocyte hypertrophy and altered HCM gene expression in vitro and that DNA methylation patterns mediate the upregulation of HCM genes induced by cAMP. These data identify a previously unknown mechanism by which elevated levels of cAMP lead to increased expression of genes associated with cardiomyocyte hypertrophy.

show abstract

mentioning

confidence: 99%

cAMP induces hypertrophy and alters DNA methylation in HL-1 cardiomyocytes

Fang

Robinson

Wang-Hu

et al. 2015

American Journal of Physiology-Cell Physiology

View full text Add to dashboard Cite

show abstract

“…DNA methylation DNA methylation is the most common epigenetic chromatin modification [39] . Movassagh M et al [40] suggested that there is distinct global pattern of the epigenome leading to regulate the expression of underlying genes. Authors investigated genome-wide maps of DNA methylation and histone-3 lysine-36 trimethylation enrichment for cardiomyopathic and normal human hearts.…”

Section: Histone Acetylationmentioning

confidence: 99%

“…Authors investigated genome-wide maps of DNA methylation and histone-3 lysine-36 trimethylation enrichment for cardiomyopathic and normal human hearts. It has found a sufficient difference in DNA methylation in promoters of up-regulated genes, but not down-regulated genes in end-stage cardiomyopathy [40]. Furthermore, the process of DNA methylation was under regulation through several genetic pathways that are modulating by platelet/ endothelial cell adhesion molecule 1, hypoxia-inducible factor1alpha, angiomotin-like 2, and Rho GTPase activating protein 24 [40,41] .…”

Section: Histone Acetylationmentioning

confidence: 99%

Are Epigenetic Features Essential in Advance of Heart Failure Phenotypes?

Berezin

2016

Journal of Cardiology and Therapy

View full text Add to dashboard Cite

“…This increased LV dilation is called eccentric hypertrophy. In cardiac hypertrophy, neurohormones, inflammatory cytokines and other peptides and growth factors can reactivate groups of genes that are not expressed postnatally, called fetal gene program, through many intracellular signaling pathways (1,6,25). This is accompanied by a decreased activation of genes that are normally expressed in the adult heart.…”

Section: Hypertrophy and Remodelingmentioning

confidence: 99%

“…The assessment of LV diastolic function is often performed by echocardiography using parameters such as transmitral and pulmonary venous inflow patterns (25). E-wave (E) is the transmitral inflow during early diastolic filling and A-wave (A) is the inflow during late diastolic filling.…”

Section: Assessment Of Cardiac Functionmentioning

confidence: 99%

Assessment of Ventricular Function in Normal and Failing Hearts Using 4D Flow CMR

Zajac¹

View full text Add to dashboard Cite

Front cover: Multicolor drawing of the heart and the outflow by Dr. Staffan Wirell, handed to me the day I became a PhD student. Permission to print. ABSTRACTHeart failure is a common disorder and a major cause of illness and death in the population, creating an enormous health-care burden. It is a complex condition, representing the end-point of many cardiovascular diseases. In general heart failure progresses slowly over time and once it is diagnosed it has a poor prognosis which is comparable with that of many types of cancer.The heart has an ability to adapt in response to long lasting increases in hemodynamic demand; the heart conforms its shape and size in order to maintain adequate cardiac output. This process is called remodeling and can be triggered by pathologies such as hypertension or valvular disease. When the myocardial remodeling is maintained chronically it becomes maladaptive and is associated with an increased risk of heart failure.In many cases, heart failure is associated with left bundle branch block (LBBB). This electrical disturbance leads to dyssynchronous left ventricular (LV) contraction and relaxation which may contribute to cardiac dysfunction and ultimately heart failure. Mechanical dyssynchrony can be treated with cardiac resynchronization therapy (CRT). However, many heart failure patients do not demonstrate clinical improvement despite CRT.Blood flow plays an important role in the normal development of the fetal heart. However, flow-induced forces may also induce changes in the heart cells that could lead to pathological remodeling in the adult heart. Until recently, measurement tools have been inadequate in describing the complex three-dimensional and time-varying characteristics of blood flow within the beating heart. 4D (3D + time) flow cardiovascular magnetic resonance (CMR) enables acquisition of three-dimensional, three-directional, time-resolved velocity data from which visualization and quantification of the blood flow patterns over a complete cardiac cycle can be performed. In this thesis, novel 4D Flow CMR based methods are used to study the intraventricular blood flow in healthy subjects and heart failure patients with and without ventricular dyssynchrony in order to gain new knowledge of the ventricular function.Different flow components were assessed in normal heart ventricles. It was found that inflowing blood that passes directly to outflow during the same heartbeat (the Direct Flow component) was larger and possessed more kinetic energy (KE) than other flow components. Diastolic flow through the normal heart appears to create favorable conditions for effective systolic ejection. This organized blood flow pattern within the normal LV is altered in heart failure patients and is associated with decreased preservation of KE which might be unfavorable for efficient LV ejection. Inefficient flow of blood through the heart may influence diastolic wall stress, and thus contribute to pathological myocardial remodeling.In dyssynchronous LVs of heart failure patients with LBB...

show abstract

Distinct Epigenomic Features in End-Stage Failing Human Hearts

Cited by 241 publications

References 58 publications

cAMP induces hypertrophy and alters DNA methylation in HL-1 cardiomyocytes

cAMP induces hypertrophy and alters DNA methylation in HL-1 cardiomyocytes

Are Epigenetic Features Essential in Advance of Heart Failure Phenotypes?

Assessment of Ventricular Function in Normal and Failing Hearts Using 4D Flow CMR

Contact Info

Product

Resources

About