Common MicroRNA Signatures in Cardiac Hypertrophic and Atrophic Remodeling Induced by Changes in Hemodynamic Load

El‐Armouche, Ali; Schwoerer, Alexander Peter; Neuber, Christiane; Emmons, Julius; Biermann, D.; Christalla, Thomas; Grundhoff, Adam; Eschenhagen, Thomas; Zimmermann, Wolfram H.; Ehmke, Heimo

doi:10.1371/journal.pone.0014263

Cited by 32 publications

(25 citation statements)

References 40 publications

(66 reference statements)

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“…Many of the induced and repressed miRs were regulated in the same direction in fetal, hypertrophic, and failing human hearts, consistent with the known reactivation of the fetal gene program with stress (18,51). Also noted were unique subsets of miRs dysregulated with each disease state: hypertrophy, ischemic heart disease, and dilated cardiomyopathy.…”

supporting

confidence: 56%

Dynamic microRNA expression during the transition from right ventricular hypertrophy to failure

Reddy¹,

Zhao²,

Hu³

et al. 2012

Physiological Genomics

100

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microRNA expression during the transition from right ventricular hypertrophy to failure. Physiol Genomics 44: 562-575, 2012. First published March 27, 2012 doi:10.1152/physiolgenomics.00163.2011 are small, noncoding RNAs that are emerging as crucial regulators of cardiac remodeling in left ventricular hypertrophy (LVH) and failure (LVF). However, there are no data on their role in right ventricular hypertrophy (RVH) and failure (RVF). This is a critical question given that the RV is uniquely at risk in patients with congenital right-sided obstructive lesions and in those with systemic RVs. We have developed a murine model of RVH and RVF using pulmonary artery constriction (PAC). miR microarray analysis of RV from PAC vs. control demonstrates altered miR expression with gene targets associated with cardiomyocyte survival and growth during hypertrophy (miR 199a-3p) and reactivation of the fetal gene program during heart failure (miR-208b). The transition from hypertrophy to heart failure is characterized by apoptosis and fibrosis (miRs-34, 21, 1). Most are similar to LVH/LVF. However, there are several key differences between RV and LV: four miRs (34a, 28, 148a, and 93) were upregulated in RVH/RVF that are downregulated or unchanged in LVH/LVF. Furthermore, there is a corresponding downregulation of their putative target genes involving cell survival, proliferation, metabolism, extracellular matrix turnover, and impaired proteosomal function. The current study demonstrates, for the first time, alterations in miRs during the process of RV remodeling and the gene regulatory pathways leading to RVH and RVF. Many of these alterations are similar to those in the afterload-stressed LV. miRs differentially regulated between the RV and LV may contribute to the RVs increased susceptibility to heart failure. heart failure; right ventricle CARDIAC REMODELING IN RESPONSE to stress results from activation and repression of genes encoding proteins that regulate cardiac contractility and structure. As novel mechanisms of remodeling are uncovered to understand the basic mechanisms of disease, an additional layer of regulation mediated by stress-responsive microRNAs (miRs) has emerged. miRs are small, noncoding RNAs of 18 -25 nucleotides that regulate gene expression by degradation or translational suppression of mRNA. miRs have retained sequence conservation across species, indicating a strong evolutionary role in fundamental biologic processes. Since the discovery of the first miR in 1993, their role in cell differentiation, proliferation, apoptosis, and stress responses has been elucidated. Their role in cardiovascular development, left ventricular hypertrophy (LVH), and heart failure is only now being understood. (8, 13).Van Rooij et al. (56) elucidated the miR expression profile in LVH in a model of thoracic aortic constriction. Many of the induced and repressed miRs were regulated in the same direction in fetal, hypertrophic, and failing human hearts, consistent with the known reactivation of the fetal gene program with st...

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supporting

confidence: 56%

Dynamic microRNA expression during the transition from right ventricular hypertrophy to failure

Reddy¹,

Zhao²,

Hu³

et al. 2012

Physiological Genomics

100

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“…Based on the previous studies, it can be concluded that associations with CVDs have been shown for some of herein identified miRNAs (as is the case for miR-483-5p showing the relationship with angiogenesis 29 or miR-224 showing altered expression profile in myocardial hypertrophy). 30 Moreover, miRNA function is often associated with the effect on the course of neoplasia. Although similar association studies are also conducted for miRNAs relation to phenotype and pathophysiology of the cardiovascular system, they are far less numerous.…”

mentioning

confidence: 99%

In‑silico identification of cardiovascular disease‑related SNPs affecting predicted microRNA target sites

Kamiński¹,

Kamińska²,

Skorupa³

et al. 2013

Polish Archives of Internal Medicine

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IntroductIon MicroRNAs (miRNAs) are small RNAs that play an important role in the regulation of gene expression. miRNA dysregulation has been associated with phenotypic changes, including cardiovascular diseases (CVDs).objEctIvES The aim of the study was to obtain a list of single nucleotide polymorphisms (SNPs) related to CVDs, with computationally predicted effect on miRNA binding sites, which would verify the hypothesis that miRNA dysregulation can lead to the development of CVDs. MAtErIALS And MEthodSSNPs, CVDs, and miRNAs were the 3 factors subjected to analysis. Based on the publicly available databases, we created a set of SNPs associated with the phenotype of interest and of SNPs located in known miRNA binding sites. We then merged the records assigned by the same SNP, which allowed us to indicate miRNA target sites, whose variants may be associated with CVDs. The results were supplemented with the additional data such as miRNA and mRNA coexpression, differences in the expression between various tissues, and Expression Quantitative Trait Locus analysis. Only in-silico methods, on the basis of publically available information tools and databases, were used. rESuLtS We obtained a list of 47 entries, constituting unique miRNA-SNP allele-phenotype linkages. concLuSIonS Computational approach supports the hypothesis of the linkage between alterations in miRNA function and numerous CVDs. Given the high frequency of SNP incidence, this pathomechanism may be common in the population. Although the obtained results need to be further experimentally validated, limiting the number of interactions to the most probable ones will facilitate the identification of clinically significant associations. potential therapeutic agents for the treatment of CVDs has been proposed. 6 Although genome-wide association studies (GWAS) indicate numerous connections between single nucleotide polymorphisms (SNPs) and phenotypes, leading to the conclusion that these genetic variants are able to significantly affect the course of CVD, 7 they do not provide direct information on the possible mechanisms by which these modulations occur. Given the association of multiple polymorphisms with CVDs, the presence of functional SNPs in noncoding intron sequences, 8 and the effect of miRNAs on gene transcription, we hypothesize that SNPs within miRNA binding site, by destroying the existing or creating novel target sites or by changing miRNA binding strength, may change its effects on gene expression, which results in the onset or change in the course of CVD. In this paper, based on an in-silico analysis, we would like to determine whether there exist miRNAs associated with CVDs by the coexistence of SNPs interfering with their function, and, if so, to indicate the specific ones. KEy WordSIn silico is, apart from in vivo or in vitro, one of the experimental techniques. It represents a modern approach to research, based on the use of computing power to perform mathematical analyses of a large amount of data and the creation of complex datab...

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“…Cardiac atrophy was induced in syngeneic male Lewis rats (270±5 g, n= 34, Charles River, Sulzfeld, Germany) by heterotopic abdominal heart transplantation as previously described [12,14,21,22,29,40,41,45,46]. The donor heart was harvested under deep anaesthesia (thiopental-sodium, 100 mg/kg body weight) and was transplanted into the abdominal cavity of the recipient rat under isoflurane anaesthesia (2-2.5 %).…”

Section: Animal Modelmentioning

confidence: 99%

“…The transplanted (atrophic) and the orthotopic (control) hearts of the recipient animal were removed in deep anaesthesia (thiopental-sodium, 100 mg/kg body weight) 2 weeks after transplantation. An unloading period of 2 weeks was chosen to induce a stable cardiac atrophy in accordance with previous studies [12,14,40,41] while avoiding the detrimental effects of prolonged unloading on cardiac excitation-contraction coupling and contractility [21,22,29,45]. For all experiments, the orthotopic hearts served as corresponding controls.…”

Section: Animal Modelmentioning

confidence: 99%

Enhanced Ca2+ influx through cardiac L-type Ca2+ channels maintains the systolic Ca2+ transient in early cardiac atrophy induced by mechanical unloading

Biermann¹,

Bernhardt²,

Neef³

et al. 2014

Thorac cardiovasc Surg

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Cardiac atrophy as a consequence of mechanical unloading develops following exposure to microgravity or prolonged bed rest. It also plays a central role in the reverse remodelling induced by left ventricular unloading in patients with heart failure. Surprisingly, the intracellular Ca 2+ transients which are pivotal to electromechanical coupling and to cardiac plasticity were repeatedly found to remain unaffected in early cardiac atrophy. To elucidate the mechanisms underlying the preservation of the Ca 2+ transients, we investigated Ca 2+ cycling in cardiomyocytes from mechanically unloaded (heterotopic abdominal heart transplantation) and control (orthotopic) hearts in syngeneic Lewis rats. Following 2 weeks of unloading, sarcoplasmic reticulum (SR) Ca 2+ content was reduced by~55 %. Atrophic cardiac myocytes also showed a much lower frequency of spontaneous diastolic Ca 2+ sparks and a diminished systolic Ca 2+ release, even though the expression of ryanodine receptors was increased by~30 %. In contrast, current clamp recordings revealed prolonged action potentials in endocardial as well as epicardial myocytes which were associated with a two to fourfold higher sarcolemmal Ca 2+ influx under action potential clamp. In addition, Cav1.2 subunits which form the pore of L-type

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Common MicroRNA Signatures in Cardiac Hypertrophic and Atrophic Remodeling Induced by Changes in Hemodynamic Load

Cited by 32 publications

References 40 publications

Dynamic microRNA expression during the transition from right ventricular hypertrophy to failure

Dynamic microRNA expression during the transition from right ventricular hypertrophy to failure

In‑silico identification of cardiovascular disease‑related SNPs affecting predicted microRNA target sites

Enhanced Ca2+ influx through cardiac L-type Ca2+ channels maintains the systolic Ca2+ transient in early cardiac atrophy induced by mechanical unloading

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