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ALKBH5 Induces Fibroblast-to-Myofibroblast Transformation During Hypoxia to Protect Against Cardiac Rupture After Myocardial Infarction

ABSTRACT: ALKBH5 Induces Fibroblast-to-Myofibroblast Transformation During Hypoxia to Protect Against Cardiac Rupture After Myocardial Infarction

PROVIDER: PRJNA940140 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR23680500_1.fastq.gz	Fastqsanger.gz
	SRR23680500_2.fastq.gz	Fastqsanger.gz
	SRR23680501_1.fastq.gz	Fastqsanger.gz
	SRR23680501_2.fastq.gz	Fastqsanger.gz
	SRR23680502_1.fastq.gz	Fastqsanger.gz

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ALKBH5 Induces Fibroblast-to-Myofibroblast Transformation During Hypoxia to Protect Against Cardiac Rupture After Myocardial Infarction

Project description:Objectives: To investigate the role of ALKBH5 in fibroblasts during post-myocardial infarction (MI) repair. Background: N6-methyladenosine (m6A) mRNA modification has been shown to play an important role in cardiovascular diseases. The RNA demethylase, AlkB homolog 5 (ALKBH5), is an m6A "eraser" that is responsible for decreased m6A methylation. However, its role in cardiac fibroblasts during the post-MI healing process remains elusive. Methods: MI was mimicked by permanent left anterior descending artery ligation in global ALKBH5-knockout, ALKBH5-knockin, and fibroblast-specific ALKBH5-knockout mice to study the function of ALKBH5 during post-MI collagen repair. Methylated RNA immunoprecipitation sequencing was performed to explore potential ALKBH5 targets. Results: Dramatic alterations in ALKBH5 expression were observed during the early stage post-MI and in hypoxic fibroblasts. Global ALKBH5 knockin reduced infarct size and improved cardiac function after MI. The global and fibroblast-specific ALKBH5-knockout mice both exhibited low survival rates along with poor collagen repair, impaired cardiac function, and cardiac rupture. Both in vivo and in vitro ALKBH5 loss led to impaired fibroblast activation and decreased collagen deposition. Additionally, hypoxia, but not TGF-β1 or Ang II, upregulated ALKBH5 expression in myofibroblasts in a HIF-1α-dependent transcriptional manner. Mechanistically, ALKBH5 promoted the stability of ErbB4 mRNA and the degradation of ST14 mRNA via m6A demethylation. Fibroblast-specific ErbB4 overexpression ameliorated the impaired fibroblast-to-myofibroblast transformation and poor post-MI repair due to ALKBH5 knockout. Conclusions: Fibroblast ALKBH5 positively regulates post-MI healing via post-transcriptional modification and stabilization of ErbB4 mRNA in an m6A-dependent manner. Targeting ALKBH5/ERBB4 may be a potential therapeutic option for post-MI cardiac rupture.

2023-10-01 | GSE226415 | GEO

ALKBH5 induces fibroblast-to-myofibroblast transformation during hypoxia to protect against cardiac rupture after myocardial infarction.

Project description: Not available

| S-EPMC11258655 | biostudies-literature

ALKBH5 is a New Mammalian RNA Demethylase

Project description:N6-methyladenosine (m6A) is the most prevalent internal modification of messenger RNA (mRNA) in higher eukaryotes. Here we report ALKBH5 as a new mammalian demethylase that oxidatively removes the m6A modification in mRNA in vitro and inside cells. This demethylation activity of ALKBH5 significantly affects mRNA export and RNA metabolism as well as the assembly of mRNA processing factors in nuclear speckles. Alkbh5-deficient male mice are characterized by impaired fertility resulting from apoptosis that affects meiotic metaphase-stage spermatocytes. In accordance with this defect, we have identified in mouse testes 1552 differentially expressed genes which cover broad functional categories and include spermatogenesis-related mRNAs involved in the p53 functional interaction network. We show that Alkbh5-deficiency impacts the expression levels of some of these mRNAs, supporting the observed phenotype. The discovery of this new RNA demethylase strongly suggests that the reversible m6A modification plays fundamental and broad functions in mammalian cells. RNA-seq in two cell types

2013-02-15 | E-GEOD-40132 | biostudies-arrayexpress

GMP-compatible extracellular vesicles prevent heart failure after a myocardial infarction through reduction of myofibroblast activation

Project description:Ischemic heart disease is the leading cause of heart failure and mortality in the Western world. Survival after a ST-Elevation Myocardial Infarction (STEMI) has not improved over the last decade, mostly because revascularization with percutaneous coronary intervention (PCI) may, paradoxically, induce myocardial ischemia-reperfusion (MIR) injury. The injury is orchestrated by macrophages and leads to myofibroblast activation and additional scar formation. Here, we have developed a good manufacturing practice compatible protocol for the generation of an immune modulatory extracellular vesicle (EV)-rich product from bone marrow mesenchymal stromal. In blinded, placebo-controlled MIR models in mice and pigs, the EV product preserved the myocardial function in the mice hearts and was cardioprotective in the pig models of MIR. To facilitate translation to the clinic, we have also developed a positron emission tomography (PET)-based system to longitudinally detect in vivo heart myofibroblast activation and, thereby, the scar formation in mice and humans. The PET system showed that the EV-product significantly reduced myofibroblast activation and the scar size in placebo-controlled MIR-injury models in mice. In conclusion, PET-directed EV-treatment might offer an individualized additive treatment to PCI in order to prevent heart failure after STEMI.

2026-06-12 | PXD064567 | Pride

Myofibroblast-specific 5-HT2B Mediates Adverse Remodeling Following Myocardial Infarction

Project description:Myofibroblast-specific 5-HT2B Mediates Adverse Remodeling Following Myocardial Infarction

| PRJNA661561 | ENA

Nuclear envelope rupture causes RNA polymerase loss in LMNA cardiomyopathy

Project description:Localized rupture of the nuclear envelope has been reported in various pathologies, including cancer, neurodegenerative disease, myocardial infarction, as well as dilated cardiomyopathy caused by Lamin A/C gene mutations (LMNA-DCM). Whether and how nuclear rupture contributes to disease remains unclear. Here, we report that nuclear rupture causes global transcriptional deficiency in a mouse model of LMNA-DCM. We observed that ruptured nuclei lost chromatin-bound RNA polymerase II, leading to downregulation of numerous genes essential for cardiomyocyte structure and function. Notably, over one third of ruptured nuclei resealed and regained transcription. Resealing involved the ESCRT-III membrane remodeling complex and was cardioprotective, as its blockade increased rupture frequency and accelerated cardiomyopathy. However, resealing was ineffective: resealed nuclei re-ruptured at twice the resealing rate and ten-fold faster than the de novo rupture rate. A mathematical model predicted a steady accumulation of ruptured nuclei despite ongoing resealing. Consistently, a human LMNA-mutant heart contained numerous ruptured nuclei at the time of disease presentation. These findings link nuclear rupture to organ deterioration through global transcriptional deficiency and suggested rupture repair as a critical modifier of nuclear rupture-associated conditions.

2026-04-03 | GSE325163 | GEO

Endogenous Smad7 restrains myofibroblast activation and protects from post-infarction heart failure by suppressing TGF-b signaling and by directly inhibiting Erbb2

Project description:Repair of the infarcted heart requires TGFβ-Smad3 signaling in cardiac myofibroblasts. However, TGF-β-driven myofibroblast activation needs to be tightly regulated in order to prevent excessive fibrosis and adverse remodeling that may precipitate heart failure. We hypothesized that induction of the inhibitory Smad, Smad7 may restrain infarct myofibroblast activation, and we examined the molecular mechanisms of Smad7 actions. In a mouse model of non-reperfused infarction, Smad3 activation triggered Smad7 synthesis in β-SMA+ infarct myofibroblasts, but not in β-SMA-/PDGFRα+ fibroblasts. Myofibroblast-specific Smad7 loss increased heart failure-related mortality, worsened dysfunction, and accentuated fibrosis in the infarct border zone and in the papillary muscles. Smad7 attenuated myofibroblast activation and reduced synthesis of structural and matricellular extracellular matrix proteins. Smad7 actions on TGF-β cascades involved de-activation of Smad2/3 and non-Smad pathways, without any effects on TGF-β receptor activity. Unbiased transcriptomic and proteomic analysis identified receptor tyrosine kinase signaling as a major target of Smad7. Smad7 interacted with Erbb2 in a TGF-independent manner and restrained Erbb1/Erbb2 activation, suppressing fibroblast expression of fibrogenic proteases, integrins and CD44. Smad7 induction in myofibroblasts serves as an endogenous TGF-β-induced negative feedback mechanism that inhibits post-infarction fibrosis by restraining Smad-dependent and Smad-independent TGF-β responses, and by suppressing TGF-independent fibrogenic actions of Erbb2.

2021-11-11 | GSE185767 | GEO

Cardiac pericytes contribute to myofibroblast expansion and vascular maturation following myocardial infarction

Project description:Cardiac pericytes contribute to myofibroblast expansion and vascular maturation following myocardial infarction

| PRJNA922047 | ENA

RNA-Seq of injured mouse hearts depleted for myofibroblast Yap [I]

Project description:A myofibroblast specific tamoxifen inducible Cre was used to assess the contribution of Yap in the mouse heart after myocardial infarction

2022-10-29 | GSE163269 | GEO

ALKBH5

Project description:ALKBH5

| PRJNA932008 | ENA