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Targeting Cytoplasmic SAM by Expressing Slc25a26 Inhibits Protein Synthesis in Cardiac Hypertrophy via SAMTOR/mTOR signaling

ABSTRACT: Excess protein synthesis is the major pathological manifestation of cardiac hypertrophy; however, the underlying mechanism remains elusive. Here we found that a SAM transporter Slc25a26 translocated to mitochondria during cardiac hypertrophy. Silencing Slc25a26 aggravated phenylephrine-induced cardiomyocyte hypertrophy in neonatal rat ventricular myocytes. Transcriptome analysis revealed a specific regulation of ribosome genes by Slc25a26. Puromycin incorporation assay showed a negative regulation of protein synthesis rate by Slc25a26. The translational regulation was independent of ribosome assembly, but abolished by mTOR inhibitor rapamycin. Administration of SAM, or silencing Samtor, reversed the inhibitory impact of Slc25a26 on protein synthesis. AAV9-mediated Slc25a26 overexpression in mouse heart increased the SAM level in mitochondria, but reduced that in nucleus and cytoplasm. Transaortic-constriction-induced hypertrophic pathologies, including pathological gene induction, cardiomyocyte enlargement, myocardial remodeling and heart dysfunction were significantly alleviated by Slc25a26 overexpression. Our data demonstrate a crucial role of subcellular SAM homeostasis in translational control during cardiac hypertrophy.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE173737 | GEO | 2022/01/05

REPOSITORIES: GEO

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AAV9-medated cardiac expression of lncRNA CARDINAL ameliorate TAC induced hypertrophy

Project description:Pathological cardiac hypertrophy is featured by enhanced protein synthesis. Translation inhibition is effective in treating cardiac hypertrophy, yet with systematic side effect. We identified a cardiac-enriched LncRNA CARDINAL, when over-expressed in cardiomyocyte using AAV9 driven by cTNT promoter, ameliorate transaortic constriction (TAC) induced hypertrophy.

2024-04-22 | GSE210983 | GEO

Deletion of cardiac-enriched lncRNA CARDINAL exacerbate TAC induced hypertrophy

Project description:Pathological cardiac hypertrophy is featured by enhanced protein synthesis. Translation inhibition is effective in treating cardiac hypertrophy, yet with systematic side effect. We identified a cardiac-enriched LncRNA CARDINAL, when deleted, exacerbate transaortic constriction (TAC) induced hypertrophy.

2024-04-22 | GSE210982 | GEO

NAP1L5 is required for translation activation during cardiomyocyte hypertrophy

Project description:Pathological growth of cardiomyocytes during hypertrophy is characterized by excess protein synthesis; however, the regulatory mechanism remains largely unknown. Using a neonatal rat ventricular myocyte (NRVMs) model, here we find that the expression of nucleosome assembly protein 1 like 5 (Nap1l5) is upregulated in phenylephrine (PE)-induced hypertrophy. Knockdown of Nap1l5 expression by siRNA significantly blocks cell size enlargement and pathological gene induction after PE treatment. In contrast, Adenovirus-mediated Nap1l5 overexpression significantly aggravates the pro-hypertrophic effects of PE on NRVMs. RNA-seq analysis reveals that Nap1l5 knockdown reverses the pro-hypertrophic transcriptome reprogramming after PE treatment. Whereas immune response is dominantly enriched in the upregulated genes, oxidative phosphorylation, cardiac muscle contraction and ribosome related pathways are remarkably enriched in the down-regulated genes. Although PRC2 and PRC1 are involved in Nap1l5-mediated gene regulation, Nap1l5 does not directly alter the levels of global histone methylations. However, puromycin incorporation assay shows that Nap1l5 is both necessary and sufficient to drive the increased protein synthesis rate in cardiomyocyte hypertrophy. This is attributable to a direct regulation of ribosome assembly by Nap1l5. Our findings demonstrate a previously unrecognized role of Nap1l5 in translation control during cardiac hypertrophy.

2022-10-09 | GSE185699 | GEO

The role of microRNA-204 in pressure overload-induced cardiac hypertrophy

Project description:microRNAs regulate cardiac hypertrophy development, which predicts the risk of heart failure. Here we investigate the role of microRNA-204-5p (miR-204) in developing cardiac hypertrophy and cardiac dysfunction following transaortic constriction. To determine the role of miR-204, we determined the transcriptomic profile of hearts following transaortic constriction.

2021-10-11 | GSE185595 | GEO

Loss of mouse P2Y6 nucleotide receptor is associated with physiological macrocardia and amplified pathological cardiac hypertrophy

Project description:The study of the mechanisms leading to cardiac hypertrophy is essential to better understand cardiac development and regeneration. Pathological conditions such as ischemia or pressure overload can induce a release of extracellular nucleotides within the heart. We recently investigated the potential role of nucleotide P2Y receptors in cardiac development. We showed that adult P2Y4-null mice displayed microcardia resulting from defective cardiac angiogenesis. Here we show that loss of another P2Y subtype called P2Y6, a UDP receptor, was associated with a macrocardia phenotype and amplified pathological cardiac hypertrophy. Cardiomyocyte proliferation and size were increased in vivo in hearts of P2Y6-null neonates, resulting in enhanced post-natal heart growth. We then observed that loss of P2Y6 receptor enhanced pathological cardiac hypertrophy induced after isoproterenol injection. We identified an inhibitory effect of UDP on in vitro isoproterenol-induced cardiomyocyte hyperplasia and hypertrophy. The present study identifies mouse P2Y6 receptor as a regulator of cardiac development and cardiomyocyte function. P2Y6 receptor could constitute a therapeutic target to regulate cardiac hypertrophy.

2016-12-19 | GSE76215 | GEO

Transcription profiling of hearts from mice heterozygous for Gata4 mutation (G4D) to investigate the significance of Gata4 in regulating postnatal heart function and in regulating the hypertrophic response of the heart to pathological stress.

Project description:An important event in the pathogenesis of heart failure is the development of pathological cardiac hypertrophy. In cultured cardiac cardiomyocytes, the transcription factor Gata4 is required for agonist-induced cardiomyocyte hypertrophy. We hypothesized that in the intact organism Gata4 is an important regulator of postnatal heart function and of the hypertrophic response of the heart to pathological stress. To test this hypothesis, we studied mice heterozygous for deletion of the second exon of Gata4 (G4D). At baseline, G4D mice had mild systolic and diastolic dysfunction associated with reduced heart weight and decreased cardiomyocyte number. After transverse aortic constriction (TAC), G4D mice developed overt heart failure and eccentric cardiac hypertrophy, associated with significantly increased fibrosis and cardiomyocyte apoptosis. Inhibition of apoptosis by overexpression of the insulin-like growth factor 1 receptor prevented TAC-induced heart failure in G4D mice. Unlike WT-TAC controls, G4D-TAC cardiomyocytes hypertrophied by increasing in length more than width. Gene expression profiling revealed upregulation of genes associated with apoptosis and fibrosis, including members of the TGF? pathway. Our data demonstrate that Gata4 is essential for cardiac function in the postnatal heart. After pressure overload, Gata4 regulates the pattern of cardiomyocyte hypertrophy and protects the heart from load-induced failure. Experiment Overall Design: We reasoned that if Gata4 was a crucial regulator of pathways necessary for cardiac hypertrophy, then modest reductions of Gata4 activity should result in an observable cardiac phenotype. To test this hypothesis, we used gene targeted mice that express reduced levels of Gata4. We characterized these mice at baseline and after pressure Experiment Overall Design: overload.

2007-11-13 | E-GEOD-5500 | biostudies-arrayexpress

Genome wide TFIIB binding during postnatal and pressure-induced cardiac hypertrophy

Project description:Purpose: To identify the differential TFIIB bindingl patterns during postnatal cardiac growth, pressure-induced cardiac hypertrophy and adult mouse hearts Methods: Hearts were extracted from 1-2day old C57 mice, from mice subjecetd to Transaortic coarctation or adult mice. The hearts were sent to Active Motif for TFIIB- ChIP-Seq. Results: In accordance with previosly published data (Sayed D, et. al. JBC, 2013 Jan 25;288(4):2546-58) with genome wide polII and H3K9ac status during cardiac hypertrophy (GSE50637), Denovo TFIIB recruitment was restricted to speclaized genes with cardiac hypertrophy. Hearts were extracted from 1-2day old C57 mice, from mice subjecetd to Transaortic coarctation or adult mice. The hearts were sent to Active Motif for TFIIB- ChIP-Seq.

2014-11-17 | E-GEOD-56813 | biostudies-arrayexpress

Transcription profiling of mouse IL-18 knockouts vs. wild types treated with pressure overload to examine cardiac hypertrophy

Project description:Pressure overload-induced cardiac hypertrophy was examined in IL-18 knockout and littermate control mice. Experiment Overall Design: 4 groups with RNA pooled from 5-6 per group. Role of IL-18 on gene expression in cardiac hypertrophy induced by pressure overload (transaortic constriction)

2008-06-13 | E-GEOD-5129 | biostudies-arrayexpress

CDC-like Kinase 4 Deficiency Contributes to Pathological Cardiac Hypertrophy by Modulating NEXN Phosphorylation

Project description:Kinase-catalyzed phosphorylation plays crucial roles in numerous biological processes. CDC-like kinases (CLKs) are a group of evolutionarily conserved dual-specificity kinases that have been implicated in RNA splicing, glucose metabolism, diet-induced thermogenesis and so on. However, it is still largely unknown whether CLKs are involved in pathologic cardiac hypertrophy. This study aimed to investigate the role of CLKs in pathologic cardiac hypertrophy and the underlying mechanisms. Using small RNA interference, we discovered that defects in CLK4, but not CLK1, CLK2 or CLK3, were associated with the pathogenesis of pathological cardiomyocyte hypertrophy, while overexpression of CLK4 exerted resistance to isoproterenol-induced pathological cardiomyocyte hypertrophy. Moreover, the expression of CLK4 was significantly reduced in the failed myocardia of mice subjected to either transverse aortic constriction or isoproterenol infusion. Through the Cre/loxP system, we constructed cardiac-specific Clk4-knockout (Clk4-cKO) mice, which manifested pathological myocardial hypertrophy with progressive left ventricular systolic dysfunction and heart dilation. Phosphoproteomic analysis revealed significant changes in phosphorylation of sarcomere-related proteins in Clk4-cKO mice. Further experiments identified nexilin (NEXN), an F-actin binding protein, as the direct substrate of CLK4, and overexpression of a phosphorylation-mimic mutant of NEXN was sufficient to reverse the hypertrophic growth of cardiomyocytes induced by Clk4 knockdown. Importantly, restoring the phosphorylated NEXN significantly ameliorated the myocardial hypertrophy in Clk4-cKO mice. CLK4 phosphorylates NEXN to regulate the development of pathological cardiac hypertrophy. CLK4 may serve as a potential intervention target for the prevention and treatment of heart failure.

2022-07-05 | PXD029682 | Pride

miRNA-99 family diverges physiological cardiac hypertrophy to pathological cardiac hypertrophy

Project description:Purpose: The physiological cardiac hypertrophy is an adaptive condition that does not associate with myocyte cell death while pathological hypertrophy is a maladaptive condition associated with myocyte cell death. Alpha-2 macroglobulin (Î±-2M) an acute phase protein induces cardiac hypertrophy via the ERK1,2 and PI3K/Akt signaling. This study is aimed at exploring the miRNome of Î±-2M induced hypertrophied cardiomyocytes and to understand the role of miRNAs in determination of pathological and physiological hypertrophy. Methods: Hypertrophy was induced in H9c2 cardiomyoblasts using alpha-2 macroglobulin. The induction of hypertrophy is confirmed by microscopy and gene expression studies. Subsequently, the total RNA was isolated and small RNA sequencing was executed in Illumina HiSeq 2000. Results: Analysis of small RNA reads revealed the differential expression of a large set of miRNAs during hypertrophy. Among the differentially expressed candidates, miR-99 family (miR-99a, miR-99b and miR-100) showed significant downregulation upon Î±-2M treatment while isoproterenol treatment (pathological hypertrophy) upregulated their expression. The binding site for Egr1 transcription factor was identified in the promoter region of miR-99 family, and interestingly all miRNAs with Egr1 binding site proven by ChIP-Seq were downregulated during physiological hypertrophy Conclusions: The results proved Egr-1 mediated regulation of miR-99 family determines the uniqueness of pathological and physiological hypertrophy. Upregulated miR-99 expression during pathological hypertrophy suggests that it can be a valuable diagnostic marker and potential therapeutic target for cardiac hypertrophy and heart failure. Small RNA profiles of control and hypertrophied cardiomyocyte H9c2 cells were generated by deep sequencing using Illumina HiSeq 2000

2015-11-01 | E-GEOD-73597 | biostudies-arrayexpress

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