Systems analysis reveals down-regulation of a network of pro-survival miRNAs drives the apoptotic response in dilated cardiomyopathy

Isserlin, Ruth; Merico, Daniele; Wang, Dingyan; Vuckovic, Dajana; Bousette, Nicolas; Gramolini, Anthony O.; Bader, Gary D.; Emili, Andrew

doi:10.1039/c4mb00265b

Cited by 22 publications

(21 citation statements)

References 94 publications

(157 reference statements)

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“…The HF‐specific panel of seven circulating miRNAs identified in our study overlaps with published results of other related investigations. Although several investigators report an up‐regulation of miRNAs, more recent publications describe lower levels of miRNAs to be associated with cardiac disease, in concordance with our study . For example, a study of patients with symptomatic HF showed that 24 circulating miRNAs were decreased compared with control subjects, including miR‐26b‐5p, miR‐223‐3p, miR‐16‐5p, miR‐30e‐5p, miR‐423‐5p, miR‐27a‐3p, and miR‐18a‐5p, and Watson et al also found that all of the 5 identified circulating miRNAs were reduced in HF patients …”

Section: Discussionsupporting

confidence: 91%

Signature of circulating microRNAs in patients with acute heart failure

Ovchinnikova

Schmitter

Vegter

et al. 2015

European J of Heart Fail

174

137

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Aims Our aim was to identify circulating microRNAs (miRNAs) associated with acute heart failure (AHF). Methods and results Plasma miRNA profiling included 137 patients with AHF from 3 different cohorts, 20 with chronic heart failure (CHF), 8 with acute exacerbation of COPD, and 41 healthy controls. Levels of circulating miRNAs were measured using quantitative reverse transcription–polymerase chain reaction (qRT–PCR). Plasma levels of miRNAs in patients with AHF were decreased compared with CHF patients or healthy subjects, whereas no significant changes were observed between acute COPD patients and controls. Fifteen miRNAs found in the discovery phase to differ most significantly between healthy controls and patients with AHF were further investigated in an extended cohort of 100 AHF patients at admission and a separate cohort of 18 AHF patients at different time points. Out of these 15 miRNAs, 12 could be confirmed in an additional AHF validation cohort and 7 passed the Bonferroni correction threshold (miR-18a-5p, miR-26b-5p, miR-27a-3p, miR-30e-5p, miR-106a-5p, miR-199a-3p, and miR-652-3p, all P < 0.00005). A further drop in miRNA levels within 48 h after AHF admission was associated with an increased risk of 180-day mortality in a subset of the identified miRNAs. Conclusions Declining levels of circulating miRNAs were associated with increasing acuity of heart failure. Early in-hospital decreasing miRNA levels were predictive for mortality in a subset of miRNAs in patients with AHF. The discovered miRNA panel may serve as a launch-pad for molecular pathway studies to identify new pharmacological targets and miRNA-based therapies

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Section: Discussionsupporting

confidence: 91%

Signature of circulating microRNAs in patients with acute heart failure

Ovchinnikova

Schmitter

Vegter

et al. 2015

European J of Heart Fail

174

137

View full text Add to dashboard Cite

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“…A growing amount of evidence demonstrates that miRNAs can regulate apoptosis [ 38 ]. Thirteen miRNAs, including miR-21, were upregulated in early-stage dilated cardiomyopathy, whereas 11 miRNAs including miR-499 were downregulated [ 39 ]. MiR-499 was also downregulated in cardiomyocytes exposed to anoxia [ 40 ].…”

Section: Discussionmentioning

confidence: 99%

SOX6 and PDCD4 enhance cardiomyocyte apoptosis through LPS-induced miR-499 inhibition

Jia

Wang²,

Shi

et al. 2015

Apoptosis

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Sepsis-induced cardiac apoptosis is one of the major pathogenic factors in myocardial dysfunction. As it enhances numerous proinflammatory factors, lipopolysaccharide (LPS) is considered the principal mediator in this pathological process. However, the detailed mechanisms involved are unclear. In this study, we attempted to explore the mechanisms involved in LPS-induced cardiomyocyte apoptosis. We found that LPS stimulation inhibited microRNA (miR)-499 expression and thereby upregulated the expression of SOX6 and PDCD4 in neonatal rat cardiomyocytes. We demonstrate that SOX6 and PDCD4 are target genes of miR-499, and they enhance LPS-induced cardiomyocyte apoptosis by activating the BCL-2 family pathway. The apoptosis process enhanced by overexpression of SOX6 or PDCD4, was rescued by the cardiac-abundant miR-499. Overexpression of miR-499 protected the cardiomyocytes against LPS-induced apoptosis. In brief, our results demonstrate the existence of a miR-499-SOX6/PDCD4-BCL-2 family pathway in cardiomyocytes in response to LPS stimulation.Electronic supplementary materialThe online version of this article (doi:10.1007/s10495-015-1201-6) contains supplementary material, which is available to authorized users.

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“…We previously reported quantitative changes in protein and cognate mRNA expression levels in cardiac ventricular tissue at different time points in the development of DCM in R9C-PLN mice representing clear clinical stages in the progression to HF (5). We showed that the latter maladaptive response was driven by elevated activity of MAPK signaling by the protein kinases p38 and JNK, in part through down-regulation of prosurvival microRNAs (6). However, the underlying upstream and downstream signaling events preceding HF were not fully explored.…”

Section: Phospholamban (Pln) Plays a Central Role In Camentioning

confidence: 99%

Global phosphoproteomic profiling reveals perturbed signaling in a mouse model of dilated cardiomyopathy

Kuzmanov

Guo

Buchsbaum

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Phospholamban (PLN) plays a central role in Ca2+ homeostasis in cardiac myocytes through regulation of the sarco(endo)plasmic reticulum Ca 2+ -ATPase 2A (SERCA2A) Ca 2+ pump. An inherited mutation converting arginine residue 9 in PLN to cysteine (R9C) results in dilated cardiomyopathy (DCM) in humans and transgenic mice, but the downstream signaling defects leading to decompensation and heart failure are poorly understood. Here we used precision mass spectrometry to study the global phosphorylation dynamics of 1,887 cardiac phosphoproteins in early affected heart tissue in a transgenic R9C mouse model of DCM compared with wild-type littermates. Dysregulated phosphorylation sites were quantified after affinity capture and identification of 3,908 phosphopeptides from fractionated whole-heart homogenates. Global statistical enrichment analysis of the differential phosphoprotein patterns revealed selective perturbation of signaling pathways regulating cardiovascular activity in early stages of DCM. Strikingly, dysregulated signaling through the Notch-1 receptor, recently linked to cardiomyogenesis and embryonic cardiac stem cell development and differentiation but never directly implicated in DCM before, was a prominently perturbed pathway. We verified alterations in Notch-1 downstream components in early symptomatic R9C transgenic mouse cardiomyocytes compared with wild type by immunoblot analysis and confocal immunofluorescence microscopy. These data reveal unexpected connections between stress-regulated cell signaling networks, specific protein kinases, and downstream effectors essential for proper cardiac function.phospholamban | proteomic | bioinformatics | heart disease | signaling C ardiovascular diseases (CVDs) leading to systolic/diastolic heart failure (HF), such as hypertensive/diabetic heart disease, stroke, and vascular atherosclerosis, are leading causes of death in the developed world (1). Many CVDs are associated with genetic predispositions. For example, in humans, the arginine to cysteine (R9C) substitution in phospholamban (PLN) has been shown to result in dilated cardiomyopathy (DCM) presenting in adolescence, leading to rapid deterioration of heart function and premature death (2). However, the etiology and molecular mechanisms of progression of DCM and other CVDs leading to HF are complex and still poorly understood, further complicating clinical assessment and management. From a biological and clinical perspective, the identification and characterization of clinically relevant, potentially druggable, pathways driving the maladaptive response in affected heart tissue are key challenges to improved diagnostic and therapeutic tools for earlier detection and preventative treatment of both inherited and chronic CVDs.Cardiac muscle contraction is controlled by Ca 2+ flux and signaling relays, which are perturbed in HF. Internal stores of Ca 2+ required for the proper functioning of cardiomyocytes (CMs) are normally maintained through the function of the sarco(endo)plasmic reticulum Ca 2+ -ATPase 2 ...

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Systems analysis reveals down-regulation of a network of pro-survival miRNAs drives the apoptotic response in dilated cardiomyopathy

Cited by 22 publications

References 94 publications

Signature of circulating microRNAs in patients with acute heart failure

Signature of circulating microRNAs in patients with acute heart failure

SOX6 and PDCD4 enhance cardiomyocyte apoptosis through LPS-induced miR-499 inhibition

Global phosphoproteomic profiling reveals perturbed signaling in a mouse model of dilated cardiomyopathy

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