Right ventricular long noncoding RNA expression in human heart failure.
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ABSTRACT:
SUBMITTER: Di Salvo TG
PROVIDER: S-EPMC4405709 | biostudies-literature | 2015 Mar
REPOSITORIES: biostudies-literature
Publications
Right ventricular long noncoding RNA expression in human heart failure.
Di Salvo Thomas G TG Guo Yan Y Su Yan Ru YR Clark Travis T Brittain Evan E Absi Tarek T Maltais Simon S Hemnes Anna A
Pulmonary circulation 20150301 1
The expression of long noncoding RNAs (lncRNAs) in human heart failure (HF) has not been widely studied. Using RNA sequencing (RNA-Seq), we compared lncRNA expression in 22 explanted human HF hearts with lncRNA expression in 5 unused donor human hearts. We used Cufflinks to identify isoforms and DESeq to identify differentially expressed genes. We identified the noncoding RNAs by cross-reference to Ensembl release 73 (Genome Reference Consortium human genome build 37) and explored possible funct ...[more]
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Project description:BackgroundRight ventricular (RV) dysfunction contributes to mortality in chronic heart failure (HF). However, the molecular mechanisms of RV failure remain poorly understood, and RV myocardial biomarkers have yet to be developed.Methods and resultsWe performed RNA sequencing (RNA-seq) on 22 explanted human HF RVs and 5 unused donor human heart RVs (DON RV) and compared results to those recently reported from 16 explanted human LVs We used Bowtie-Tophat for transcript alignment and transcriptome assembly, DESeq for identification of differentially expressed genes (DEGs) and Ingenuity for exploration of gene ontologies. In the HF RV, RNA-seq identified 130,790 total RNA transcripts including 13,272 protein coding genes, 10,831 long non-coding RNA genes and 8,605 pseudogenes. There were 800-1000 DEGs between DON and HF RV comparison groups with differences concentrated in cytoskeletal, basement membrane, extracellular matrix (ECM), inflammatory mediator, hemostasis, membrane transport and transcription factor genes, lncRNAs and pseudogenes. In an unbiased approach, the top 10 DEGs SERPINA3, SERPINA5, LCN6, LCN10, STEAP4, AKR1C1, STAC2, SPARCL1, VSIG4 and F8 exhibited no overlap in read counts between DON and HF RVs, high sensitivities, specificities, predictive values and areas under the receiver operating characteristic curves. STEAP4, SPARCL1 and VSIG4 were differentially expressed between RVs and LVs, supporting their roles as RV-specific myocardial biomarkers.ConclusionsUnbiased, comprehensive profiling of the RV transcriptome by RNA-seq suggests structural changes and abnormalities in inflammatory processes and yields specific, novel HF RV vs HF LV myocardial biomarkers not previously identified by more limited transcriptome profiling approaches.
| S-EPMC6482959 | biostudies-literature
Project description:BackgroundLong noncoding RNAs (lncRNAs) are non-protein coding transcripts regulating a variety of physiological and pathological functions. However, their implication in heart failure is still largely unknown. The aim of this study is to identify and characterize lncRNAs deregulated in patients affected by ischemic heart failure.MethodsLncRNAs were profiled and validated in left ventricle biopsies of 18 patients affected by non end-stage dilated ischemic cardiomyopathy and 17 matched controls. Further validations were performed in left ventricle samples derived from explanted hearts of end-stage heart failure patients and in a mouse model of cardiac hypertrophy, obtained by transverse aortic constriction. Peripheral blood mononuclear cells of heart failure patients were also analyzed. LncRNA distribution in the heart was assessed by in situ hybridization. Function of the deregulated lncRNA was explored analyzing the expression of the neighbor mRNAs and by gene ontology analysis of the correlating coding transcripts.ResultsFourteen lncRNAs were significantly modulated in non end-stage heart failure patients, identifying a heart failure lncRNA signature. Nine of these lncRNAs (CDKN2B-AS1/ANRIL, EGOT, H19, HOTAIR, LOC285194/TUSC7, RMRP, RNY5, SOX2-OT and SRA1) were also confirmed in end-stage failing hearts. Intriguingly, among the conserved lncRNAs, h19, rmrp and hotair were also induced in a mouse model of heart hypertrophy. CDKN2B-AS1/ANRIL, HOTAIR and LOC285194/TUSC7 showed similar modulation in peripheral blood mononuclear cells and heart tissue, suggesting a potential role as disease biomarkers. Interestingly, RMRP displayed a ubiquitous nuclear distribution, while H19 RNA was more abundant in blood vessels and was both cytoplasmic and nuclear. Gene ontology analysis of the mRNAs displaying a significant correlation in expression with heart failure lncRNAs identified numerous pathways and functions involved in heart failure progression.ConclusionsThese data strongly suggest lncRNA implication in the molecular mechanisms underpinning HF.
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Project description:Background: No medical therapies exist to treat right ventricular (RV) remodeling and RV failure (RVF), in large part because molecular pathways that are specifically activated in pathologic human RV remodeling remain poorly defined. Murine models have suggested involvement of Wnt signaling, but this has not been well-defined in human RVF. Methods: Using a candidate gene approach, we sought to identify genes specifically expressed in human pathologic RV remodeling by assessing the expression of 28 WNT-related genes in the RVs of three groups: explanted nonfailing donors (NF, n = 29), explanted dilated and ischemic cardiomyopathy, obtained at the time of cardiac transplantation, either with preserved RV function (pRV, n = 78) or with RVF (n = 35). Results: We identified the noncanonical WNT receptor ROR2 as transcriptionally strongly upregulated in RVF compared to pRV and NF (Benjamini-Hochberg adjusted P < 0.05). ROR2 protein expression correlated linearly to mRNA expression (R 2 = 0.41, P = 8.1 × 10-18) among all RVs, and to higher right atrial to pulmonary capillary wedge ratio in RVF (R 2 = 0.40, P = 3.0 × 10-5). Utilizing Masson's trichrome and ROR2 immunohistochemistry, we identified preferential ROR2 protein expression in fibrotic regions by both cardiomyocytes and noncardiomyocytes. We compared RVF with high and low ROR2 expression, and found that high ROR2 expression was associated with increased expression of the WNT5A/ROR2/Ca2+ responsive protease calpain-μ, cleavage of its target FLNA, and FLNA phosphorylation, another marker of activation downstream of ROR2. ROR2 protein expression as a continuous variable, correlated strongly to expression of calpain-μ (R 2 = 0.25), total FLNA (R 2 = 0.67), calpain cleaved FLNA (R 2 = 0.32) and FLNA phosphorylation (R 2 = 0.62, P < 0.05 for all). Conclusion: We demonstrate robust reactivation of a fetal WNT gene program, specifically its noncanonical arm, in human RVF characterized by activation of ROR2/calpain mediated cytoskeleton protein cleavage.
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Project description:Little is known about the right ventricular (RV) proteome in human heart failure (HF), including possible differences compared to the left ventricular (LV) proteome. We used 2-dimensional differential in-gel electrophoresis (pH: 4-7, 10-150 kDa), followed by liquid chromatography tandem mass spectrometry, to compare the RV and LV proteomes in 12 explanted human hearts. We used Western blotting and multiple-reaction monitoring for protein verification and RNA sequencing for messenger RNA and protein expression correlation. In all 12 hearts, the right ventricles (RVs) demonstrated differential expression of 11 proteins relative to the left ventricles (LVs), including lesser expression of CRYM, TPM1, CLU, TXNL1, and COQ9 and greater expression of TNNI3, SAAI, ERP29, ACTN2, HSPB2, and NDUFS3. Principal-components analysis did not suggest RV-versus-LV proteome partitioning. In the nonischemic RVs (n = 6), 7 proteins were differentially expressed relative to the ischemic RVs (n = 6), including increased expression of CRYM, B7Z964, desmin, ANXA5, and MIME and decreased expression of SERPINA1 and ANT3. Principal-components analysis demonstrated partitioning of the nonischemic and ischemic RV proteomes, and gene ontology analysis identified differences in hemostasis and atherosclerosis-associated networks. There were no proteomic differences between RVs with echocardiographic dysfunction (n = 8) and those with normal function (n = 4). Messenger RNA and protein expression did not correlate consistently, suggesting a major role for RV posttranscriptional protein expression regulation. Differences in contractile, cytoskeletal, metabolic, signaling, and survival pathways exist between the RV and the LV in HF and may be related to the underlying HF etiology and differential posttranscriptional regulation.
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| S-EPMC5778995 | biostudies-literature
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2015-04-02 | E-GEOD-67492 | biostudies-arrayexpress
Project description:AimThe severity of cardiac impairment in acute heart failure (AHF) predicts outcome, but challenges remain to identify prognostically important non-invasive parameters of cardiac function. Left ventricular ejection fraction (LVEF) is relevant, but only in those with reduced LV systolic function. We aimed to assess the standard and advanced parameters of left and right ventricular (RV) function from echocardiography in predicting long-term outcomes in AHF.MethodsA total of 418 consecutive AHF patients presenting over 12 months were prospectively recruited and underwent bedside echocardiography within 24 h of recruitment. We retrospectively assessed 8 RV and 5 LV echo parameters of the cardiac systolic function to predict 2-year mortality, using both guideline-directed and study-specific cutoffs, based on the maximum Youden indices via ROC analysis. For the RV, these were the tricuspid annular plane systolic excursion, RV fractional area change, tissue Doppler imaging (TDI) peak tricuspid annular systolic wave velocity, both peak- and end-systolic RV free wall global longitudinal strain (RV GLS) and strain rate (mean RV GLSR), RV ejection fraction (RVEF) derived from a 2D ellipsoid model and the ratio of the TAPSE to systolic pulmonary artery pressure (SPAP). For the LV, these were the LVEF, mitral regurgitant ΔP/Δt (MR dP/dt), the lateral mitral annular TDI peak systolic wave velocity, LV GLS, and the LV GLSR.ResultsA total of 7/8 parameters of RV systolic function were predictive of 2-year outcome, with study cutoffs like international guidelines. A cutoff of < -1.8 s-1 mean RV GLSR was associated with worse outcome compared to > -1.8 s-1 [HR 2.13 95% CI 1.33-3.40 (p = 0.002)]. TAPSE:SPAP of > 0.027 cm/mmHg (vs. < 0.027 cm/mmHg) predicted worse outcome [HR 2.12 95% CI 1.53-2.92 (p < 0.001)]. A 3-way comparison of 2-year mortality by LVEF from the European Society of Cardiology (ESC) guideline criteria of LVEF > 50, 41-49, and < 40% was not prognostic [38.6% vs. 30.9 vs. 43.9% (p = 0.10)]. Of the 5 parameters of LV systolic function, only an MR dP/dt cutoff of < 570 mmHg was predictive of adverse outcome [HR 1.63 95% CI 1.01-2.62 (p = 0.047)].ConclusionWith cutoffs broadly like the ESC guidelines, we identified RV dysfunction to be associated with adverse prognosis, whereas LVEF could not identify patients at risk.
| S-EPMC9157539 | biostudies-literature
Project description:AimTo evaluate the long-term prognostic significance of right ventricular (RV) deformation and RV-arterial coupling in a cohort of patients with heart failure (HF) due to severe aortic stenosis (AS) candidate for trans-catheter aortic valve implantation (TAVI).MethodsThe study is a retrospective analysis of 56 patients undergoing echocardiography before TAVI execution. RV function was defined by tricuspid annular plane systolic excursion (TAPSE), fractional area change (FAC), peak systolic myocardial velocity by tissue Doppler imaging (RVSm) and RV longitudinal strain (RVLS). RV-arterial coupling were defined as TAPSE and RVLS normalized for systolic pulmonary artery pressure (sPAP) to obtain afterload-independent parameters: TAPSE/sPAP and RVLS/sPAP, respectively. All-cause mortality was the primary endpoint of survival analysis; composite of death and hospitalization for HF was the secondary endpoint.ResultsAll patients underwent TAVI from femoral access. Mean age was 81.6±6.3 years and left ventricular ejection fraction was preserved in most patients (51±15%). At 10 years, using Cox regression analysis adjusted for the parameters related to prognosis at univariate analysis, we found that only pre-procedural RVLS was independently associated with all-cause mortality (aHR 1.53, 95% CI 1.10-2.12, P=0.011). RVLS (aHR 7.542, 95% CI 1.325-42.921, P=0.023), sPAP (aHR 1.421, 95% CI 1.045-1.932, P=0.025), TAPSE/sPAP (aHR 4.977, 95% CI 5.425-21.99, P=0.044) and RVLS/sPAP (aHR 2.333, 95% CI 3.9677-12.999, P=0.046) were independently associated with the secondary endpoint.ConclusionsAmong patients with HF due to severe AS undergoing TAVI, deformation imaging (i.e., RVLS) and RV-arterial coupling (i.e., TAPSE/sPAP and RVLS/sPAP) provide better risk stratification at long-term follow up of 10 years than other RV echocardiographic parameters.
| S-EPMC7486529 | biostudies-literature
Project description:Right ventricular heart failure (RVF) associated with pulmonary hypertension (PH) is characterized by a distinct gene expression pattern when compared with functional compensatory hypertrophy. Carvedilol treatment after RVF has been established reduces right ventricle (RV) hypertrophy and improves the RV function. In addition, carvedilol treatment has been shown to alter the gene expression of select genes. We sought to identify, on a genome-wide basis, the effect of carvedilol on gene expression. RVF was induced in male Sprague-Dawley rats by the combination of VEGF-receptor blockade and chronic hypoxia; thereafter, one group was treated with carvedilol. RNA was isolated from the RV and subjected to microarray analysis. A prediction analysis of the carvedilol-treated RVs showed that carvedilol treated RVs most resembled in their expression pattern the RVF pattern. However, an analysis beyond the boundaries of the prediction set revealed a small set of genes associated with carvedilol reversal of RVF. Pathway analysis of this set of genes revealed expression changes of genes involved in cardiac hypertrophy, mitochondrial dysfunction, protein ubiquitination, and sphingolipid metabolism. Genes encoding proteins in the cardiac hypertrophy and protein ubiquitination pathways were downregulated in the RV by carvedilol, while genes encoding proteins in the mitochondrial dysfunction and sphingolipid metabolism pathways were upregulated by carvedilol. Male Sprague-Dawley rats (Harlan Laboratories Inc., Indianapolis, IN) weighing 200g were injected subcutaneously with SU5416 suspended in 0.5% (w/v) carboxymethylcellulose sodium, 0.9% (w/v) sodium chloride, 0.4% (w/v) polysorbate 80, and 0.9% (v/v) benzyl alcohol in deionized water. Rats were given a single injection of SU5416 (20 mg/kg) at the beginning of the 6-week experiment. The animals were then exposed to chronic hypoxia (simulated altitude of 5,000 m in a nitrogen dilution chamber) for four weeks; thereafter the animals were kept at the altitude of Richmond, VA (sea level) for another two weeks. Hypoxia-only rats were exposed to chronic hypoxia for four weeks. Carvedilol (15 mg/kg; Sigma-Aldrich, St. Louis, MO) was dissolved in 20% dimethyl sulfoxide and water and administered once daily per oral gavage for 4 weeks, beginning after return to room air breathing. Six rats per treatment group were randomly assigned. Rats were euthanized with Euthanasia-III Solution (390 mg/ml pentobarbital sodium, 50 mg/ml phenytoin sodium; Med-Pharmex, Inc., Pomona, CA) and hearts were removed. The RV was dissected from the LV and both ventricles were snap-frozen in liquid nitrogen. Total RNA was isolated from approximately 30 mg of snap-frozen rat heart tissue using the Qiagen RNeasy Mini Kit (Qiagen, Valencia, CA). Hearts were homogenized with Buffer RLT and beta-mercaptoethanol in an MP FastPrepM-BM-.-24 Lysing Matrix D tube (MP Biomedicals LLC, Solon, OH), and then RNA was isolated and purified following the manufacturerM-bM-^@M-^Ys protocol. RNA concentration was determined using a NanoDrop ND-1000 (Thermo Fisher Scientific, Wilmington, DE). All samples had an A260/A280 ratio between 1.9 and 2.1. The amplification and hybridization process is as follows. 500 ng of total RNA was amplified and labeled with Cyanine-5 and 500 ng of universal rat reference RNA (Stratagene, Santa Clara, CA) was amplified and labeled with Cyanine-3 using the Agilent QuickAmp Labeling kit (Agilent Technologies Inc., Santa Clara, CA) to produce labeled cRNA following the manufacturerM-bM-^@M-^Ys protocol. After amplification and labeling, the dye incorporation was determined using a NanoDrop ND-1000 spectrophotometer (Thermo Fisher Scientific, Wilmington, DE). All ratios were greater than 8.0 pmole dye per mg cRNA per the manufacturerM-bM-^@M-^Ys recommendation. 825 ng of sample and 825 ng of reference RNA were combined and incubated with an Agilent Whole Rat Genome 4x44k microarray slide (Agilent Technologies Inc., Wilmington, DE) for 17 hours at 65M-BM-0C. Following hybridization, slides were washed following the manufacturerM-bM-^@M-^Ys protocol and scanned using an Axon GenePix 4200A scanner (Axon Instruments, Union City, CA) at a resolution of 5 mM. The raw data were generated using GenePix Pro 5.0 software (Axon Instruments, Union City, CA). Raw expression data files were uploaded into R and normalized using the Bioconductor marray package by the Lowess normalization algorithm, then exported to BRB Array Tools for analysis.
2013-05-06 | E-GEOD-42579 | biostudies-arrayexpress