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Project description:The lncRNA Sweetheart regulates adaptive cardiac hypertrophy after myocardial injury
| PRJNA824431 | ENA
Project description:NOT PROVIDED; REQUESTED
2021-07-20 | GSE174732 | GEO
Project description:In the previous study, we established a mouse model of cardiac hypertrophy using transverse aortic constriction (TAC) and found that the expression of long non-coding RNAs TINCR was downregulated in myocardial tissue. The present study was designed to determine the potential role of TINCR in the pathogenesis of cardiac hypertrophy. Our results showed that enforced expression of TINCR could attenuate cardiac hypertrophy in TAC mice. Angiotensin II (Ang-II) was found to be associated with reduced TINCR expression and increased hypertrophy in cultured neonatal cardiomyocytes. RNA-binding protein immunoprecipitation assay confirmed that TINCR could directly bind with EZH2 in cardiomyocytes. The results of chromatin immunoprecipitation assay revealed that EZH2 could directly bind to CaMKII promoter region and mediate H3K27me3 modification. Knockdown of TINCR was found to reduce EZH2 occupancy and H3K27me3 binding in the promoter of CaMKII in cardiomyocytes. In addition, enforced expression of TINCR was found to decrease CaMKII expression and attenuate Ang-II-induced cardiomyocyte hypertrophy. Furthermore, our results also showed that Ang-II could increase CaMKII expression in cardiomyocytes, which consequently contributed to cellular hypertrophy. In conclusion, our findings demonstrated that TINCR could attenuate myocardial hypertrophy by epigenetically silencing of CaMKII, which may provide a novel therapeutic strategy for cardiac hypertrophy.
| S-EPMC5564587 | biostudies-other
Project description:RNA m6A modification is the most widely distributed RNA methylation and is closely related to various pathophysiological processes. Although the benefit of regular exercise on the heart has been well recognized, the role of RNA m6A in exercise training and exercise-induced physiological cardiac hypertrophy remains largely unknown. Here, we show that endurance exercise training leads to reduced cardiac mRNA m6A levels. METTL14 is downregulated by exercise, both at the level of RNA m6A and at the protein level. In vivo, wild-type METTL14 overexpression, but not MTase inactive mutant METTL14, blocks exercise-induced physiological cardiac hypertrophy. Cardiac-specific METTL14 knockdown attenuates acute ischemia-reperfusion injury as well as cardiac dysfunction in ischemia-reperfusion remodeling. Mechanistically, silencing METTL14 suppresses Phlpp2 mRNA m6A modifications and activates Akt-S473, in turn regulating cardiomyocyte growth and apoptosis. Our data indicates that METTL14 plays an important role in maintaining cardiac homeostasis. METTL14 downregulation represents a promising therapeutic strategy to attenuate cardiac remodeling.
| S-EPMC9646739 | biostudies-literature
Project description:Cardiovascular diseases rank the top cause of morbidity and mortality worldwide and are usually associated with blood reperfusion after myocardial ischemia/reperfusion injury (MIRI), which often causes severe pathological damages and cardiomyocyte apoptosis. LSINCT5 expression in the plasma of MI patients (n = 53), healthy controls (n = 42) and hypoxia-reoxygenation (HR)-treated cardiomyocyte AC16 cells was examined using qRT-PCR. The effects of LSINCT5 on cell viability and apoptosis were detected by MTT and flow cytometry, respectively. The expression of apoptosis-related proteins Bcl2, Bax and caspase 3 were tested by Western blot. The interaction between LSINCT5 and miR-222 was predicted by bioinformatic analysis. Moreover, changes in viability and apoptosis of AC16 cells co-transfected with siLSINCT5 and miR-222 inhibitor after HR treatment were examined. At last, the expression of proteins in PI3K/AKT pathway, namely PTEN, PI3K and AKT, was examined to analyze the possible pathway participating in LSINCT5-mediated MI/RI. Our study showed that LSINCT5 expression was upregulated in the plasma of MI patients and HR-treated AC16 cells. LSINCT5 overexpression significantly decreased cell viability and apoptosis. Luciferase reporter gene assay and RNA pulldown assay showed that LSINCT5 was a molecular sponge of miR-222. MiR-222 silencing in AC16 cells simulated the phenotypes of MIRI patients and HR-treated cells, indicating that LSINCT5 functions via miR-222 to regulate proliferation and apoptosis of HR-treated AC16 cells. We also showed that proteins of PI3K/AKT signaling pathway were affected in HR-treated AC16 cells, and LSINTC5 knockdown rescued these effects. LncRNA LSINCT5 was upregulated during MI pathogenesis, and LSINCT5 regulated MIRI possibly via a potential LSINCT5/miR-222 axis and PI3K/AKT signaling pathway. Our findings may provide novel evidence for MIRI prevention.
| S-EPMC8568755 | biostudies-literature
Project description:Cardiac hypertrophy (CH) is closely related to a range of cardiovascular diseases, including heart failure and sudden cardiac death. The present study aimed to elucidate the role of long non-coding RNA (lncRNA) ZEB2 antisense RNA 1 (ZEB2-AS1) in regulating the hypertrophic process of cardiomyocytes and the potential underlying mechanism. An in vivo CH mouse model was established by performing transverse aortic constriction procedures. An in vitro CH model was established in primary cardiomyocytes isolated from mice by phenylephrine (PE) treatment. The relative protein levels of BNP, ANP and PTEN in cells with different groups (CH group and control group) were determined by western blotting. Relative expression levels of ZEB2-AS1, natriuretic peptide A (ANP) and brain natriuretic peptide (BNP) were determined in both in vivo and in vitro CH models. The regulatory effects of ZEB2-AS1/phosphatase and tensin homolog (PTEN) on cell surface area, and the relative expression levels of ANP and BNP were explored. ZEB2-AS1, ANP and BNP expression levels were increased in both in vivo and in vitro CH models compared with the sham and negative control groups, respectively. ZEB2-AS1 knockdown decreased cell surface area, and downregulated ANP and BNP expression levels in PE-treated primary cardiomyocytes. Similarly, PTEN overexpression reduced cell surface area, and downregulated ANP and BNP expression levels in PE-treated primary cardiomyocytes. Moreover, PTEN reversed the regulatory effects of ZEB2-AS1 on hypertrophic cardiomyocytes. Therefore, the present study suggested that lncRNA ZEB2-AS1 may influence the progression of CH by downregulating PTEN.
| S-EPMC7507051 | biostudies-literature
Project description:BackgroundAcetyltransferase p300 is essential for cardiac development and is thought to be involved in cardiac myocyte growth through MEF2- and GATA4-dependent transcription. However, the importance of p300 in the modulation of cardiac growth in vivo is unknown.Methods and resultsPressure overload induced by transverse aortic coarctation, postnatal physiological growth, and human heart failure were associated with large increases in p300. Minimal transgenic overexpression of p300 (1.5- to 3.5-fold) induced striking myocyte and cardiac hypertrophy. Both mortality and cardiac mass were directly related to p300 protein dosage. Heterozygous loss of a single p300 allele reduced pressure overload-induced hypertrophy by approximately 50% and rescued the hypertrophic phenotype of p300 overexpressers. Increased p300 expression had no effect on total histone deacetylase activity but was associated with proportional increases in p300 acetyltransferase activity and acetylation of the p300 substrates histone 3 and GATA-4. Remarkably, a doubling of p300 levels was associated with the de novo acetylation of MEF2. Consistent with this, genes specifically upregulated in p300 transgenic hearts were highly enriched for MEF2 binding sites.ConclusionsSmall increments in p300 are necessary and sufficient to drive myocardial hypertrophy, possibly through acetylation of MEF2 and upstream of signals promoting phosphorylation or nuclear export of histone deacetylases. We propose that induction of myocardial p300 content is a primary rate-limiting event in the response to hemodynamic loading in vivo and that p300 availability drives and constrains adaptive myocardial growth. Specific reduction of p300 content or activity may diminish stress-induced hypertrophy and forestall the development of heart failure.
| S-EPMC2726266 | biostudies-literature
Project description:Cardiac hypertrophy is closely correlated with diverse cardiovascular diseases, augmenting the risk of heart failure and sudden death. Long non-coding RNAs (lncRNAs) have been studied in cardiac hypertrophy for their regulatory function. LncRNA MEG3 has been reported in human cancers. Whereas, it is unknown whether MEG3 regulates the growth of cardiac hypertrophy. Therefore, this study aims to investigate the specific role of MEG3 in the progression of cardiac hypertrophy. Here, we found that MEG3 contributed to the pathogenesis of cardiac hypertrophy. MEG3 expression was remarkably strengthened in the mice heart which undergone the transverse aortic constriction (TAC). Moreover, qRT-PCR analysis revealed that MEG3 was upregulated in the cardiomyocytes which were treated with Ang-II. Silenced MEG3 inhibited the increasing size of hypertrophic cardiomyocytes and reversed other hypertrophic responses. Mechanically, MEG3 could affect cardiac hypertrophy by regulating gene expression. Mechanically, we found that MEG3 could be upregulated by the transcription factor STAT3 and could regulate miR-361-5p and HDAC9 by acting as a ceRNA. Finally, rescue assays were made to do further confirmation. All our findings revealed that STAT3-inducetd upregulation of lncRNA MEG3 controls cardiac hypertrophy by regulating miR-362-5p/HDAC9 axis.
| S-EPMC6346020 | biostudies-literature
Project description:Cardiac hypertrophy accompanied by maladaptive cardiac remodeling is the uppermost risk factor for the development of heart failure. Long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) have various biological functions, and their vital role in the regulation of cardiac hypertrophy still needs to be explored. In this study, we demonstrated that lncRNA Plscr4 was upregulated in hypertrophic mice hearts and in angiotensin II (Ang II)-treated cardiomyocytes. Next, we observed that overexpression of Plscr4 attenuated Ang II-induced cardiomyocyte hypertrophy. Conversely, the inhibition of Plscr4 gave rise to cardiomyocyte hypertrophy. Furthermore, overexpression of Plscr4 attenuated TAC (transverse aortic constriction)-induced cardiac hypertrophy. Finally, we demonstrated that Plscr4 acted as an endogenous sponge of miR-214 and forced expression of Plscr4 downregulated miR-214 expression to promote Mfn2 and attenuate hypertrophy. In contrast, knockdown of Plscr4 upregulated miR-214 to induce cardiomyocyte hypertrophy. Additionally, luciferase assay showed that miR-214 was the direct target of Plscr4, and overexpression of miR-214 counteracted the anti-hypertrophy effect of Plscr4. Collectively, these findings identify Plscr4 as a negative regulator of cardiac hypertrophy in vivo and in vitro due to its regulation of the miR-214-Mfn2 axis, suggesting that Plscr4 might act as a therapeutic target for the treatment of cardiac hypertrophy and heart failure.
| S-EPMC5862136 | biostudies-literature
Project description:The combinatorial effect of genetic variants is often assumed to be additive. Although genetic variation can clearly interact non-additively, methods to uncover epistatic relationships remain in their infancy. We develop low-signal signed iterative random forests to elucidate the complex genetic architecture of cardiac hypertrophy. We derive deep learning-based estimates of left ventricular mass from the cardiac MRI scans of 29,661 individuals enrolled in the UK Biobank. We report epistatic genetic variation including variants close to CCDC141, IGF1R, TTN, and TNKS. Several loci not prioritized by univariate genome-wide association analysis are identified. Functional genomic and integrative enrichment analyses reveal a complex gene regulatory network in which genes mapped from these loci share biological processes and myogenic regulatory factors. Through a network analysis of transcriptomic data from 313 explanted human hearts, we show that these interactions are preserved at the level of the cardiac transcriptome. We assess causality of epistatic effects via RNA silencing of gene-gene interactions in human induced pluripotent stem cell-derived cardiomyocytes. Finally, single-cell morphology analysis using a novel high-throughput microfluidic system shows that cardiomyocyte hypertrophy is non-additively modifiable by specific pairwise interactions between CCDC141 and both TTN and IGF1R. Our results expand the scope of genetic regulation of cardiac structure to epistasis.
| S-EPMC10659487 | biostudies-literature