Nejvíce citovaný článek - PubMed ID 36426889
Myocardial m6A regulators in postnatal development: effect of sex
Fat mass and obesity-associated (FTO) protein, a key enzyme integral to the dynamic regulation of epitranscriptomic modifications in RNAs, significantly influences crucial RNA lifecycle processes, including splicing, export, decay, and translation. The role of FTO in altering the epitranscriptome manifests across a spectrum of physiological and pathological conditions. This review aims to consolidate current understanding regarding the implications of FTO in health and disease, with a special emphasis on its involvement in obesity and non-communicable diseases associated with obesity, such as diabetes, cardiovascular disease, and cancer. It also summarizes the established molecules with FTO-inhibiting activity. Given the extensive impact of FTO on both physiology and pathophysiology, this overview provides illustrative insights into its roles, rather than an exhaustive account. A proper understanding of FTO function in human diseases could lead to new treatment approaches, potentially unlocking novel avenues for addressing both metabolic disorders and malignancies. The evolving insights into FTO's regulatory mechanisms hold great promise for future advancements in disease treatment and prevention.
Fasting is a common dietary intervention known for its protective effects against metabolic and cardiovascular diseases. While its effects are mostly systemic, understanding tissue-specific changes in the heart is crucial for the identification of the mechanisms underlying fasting-induced cardioprotection. In this study, we performed a proteomic analysis of the fasting heart and attempted to clarify the molecular basis of fasting-induced cardioprotection. Our investigation identified a total of 4,652 proteins, with 127 exhibiting downregulation and 118 showing upregulation after fasting. Annotation analysis highlighted significant changes in processes such as lipid metabolism, the peroxisome pathway, and reactive oxygen species metabolism. Notably, the HIF-1 signaling pathway emerged as one of the focal points, with various HIF-1 targets exhibiting differential responses to fasting. Further experiments demonstrated downregulation of HIF-1α at both transcript and protein levels. Intriguingly, while gene expression of Egln3 decreased, its protein product PHD3 remained unaffected by fasting. The unchanged levels of pro-inflammatory cytokines indicated that the observed reduction in Hif1a expression did not stem from a decrease in basal inflammation. These findings underscore the complex regulation of the well-established cardioprotective HIF-1 signaling within the heart during 3-day fasting.
In 2023, six decades have elapsed since the first experimental work on the heart muscle was published, in which a member of the Institute of Physiology of the Czech Academy of Sciences participated as an author; Professor Otakar Poupa was the founder and protagonist of this research domain. Sixty years - more than half of the century - is certainly significant enough anniversary that is worth looking back and reflecting on what was achieved during sometimes very complicated periods of life. It represents the history of an entire generation of experimental cardiologists; it is possible to learn from its successes and mistakes. The objective of this review is to succinctly illuminate the scientific trajectory of an experimental cardiological department over a 60-year span, from its inaugural publication to the present. The old truth - historia magistra vitae - is still valid. Keywords: Heart, Adaptation, Development, Hypoxia, Protection.
- MeSH
- akademie a ústavy * dějiny MeSH
- biomedicínský výzkum * dějiny trendy MeSH
- dějiny 20. století MeSH
- dějiny 21. století MeSH
- fyziologie dějiny MeSH
- kardiologie dějiny trendy MeSH
- lidé MeSH
- srdce fyziologie MeSH
- zvířata MeSH
- Check Tag
- dějiny 20. století MeSH
- dějiny 21. století MeSH
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- historické články MeSH
- přehledy MeSH
- Geografické názvy
- Česká republika MeSH
RNA modifications affect key stages of the RNA life cycle, including splicing, export, decay, and translation. Epitranscriptomic regulations therefore significantly influence cellular physiology and pathophysiology. Here, we selected some of the most abundant modifications and reviewed their roles in the heart and in cardiovascular diseases: N6-methyladenosine (m6A), N6,2'-O-dimethyladenosine (m6Am), N1-methyladenosine (m1A), pseudouridine (?), 5 methylcytidine (m5C), and inosine (I). Dysregulation of epitranscriptomic machinery affecting these modifications vastly changes the cardiac phenotype and is linked with many cardiovascular diseases such as myocardial infarction, cardiomyopathies, or heart failure. Thus, a deeper understanding of these epitranscriptomic changes and their regulatory mechanisms can enhance our knowledge of the molecular underpinnings of prevalent cardiac diseases, potentially paving the way for novel therapeutic strategies. Keywords: Epitranscriptomics, RNA modifications, Epigenetics, m6A, RNA, Heart.
- MeSH
- adenosin analogy a deriváty metabolismus MeSH
- epigeneze genetická * MeSH
- lidé MeSH
- myokard metabolismus MeSH
- posttranskripční úpravy RNA MeSH
- transkriptom MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
- Názvy látek
- adenosin MeSH
Cardiac tolerance to ischaemia can be increased by dietary interventions such as fasting, which is associated with significant changes in myocardial gene expression. Among the possible mechanisms of how gene expression may be altered are epigenetic modifications of RNA - epitranscriptomics. N6-methyladenosine (m6A) and N6,2'-O-dimethyladenosine (m6Am) are two of the most prevalent modifications in mRNA. These methylations are reversible and regulated by proteins called writers, erasers, readers, and m6A-repelled proteins. We analysed 33 of these epitranscriptomic regulators in rat hearts after cardioprotective 3-day fasting using RT-qPCR, Western blot, and targeted proteomic analysis. We found that the most of these regulators were changed on mRNA or protein levels in fasting hearts, including up-regulation of both demethylases - FTO and ALKBH5. In accordance, decreased methylation (m6A+m6Am) levels were detected in cardiac total RNA after fasting. We also identified altered methylation levels in Nox4 and Hdac1 transcripts, both of which play a role in the cytoprotective action of ketone bodies produced during fasting. Furthermore, we investigated the impact of inhibiting demethylases ALKBH5 and FTO in adult rat primary cardiomyocytes (AVCMs). Our findings indicate that inhibiting these demethylases reduced the hypoxic tolerance of AVCMs isolated from fasting rats. This study showed that the complex epitranscriptomic machinery around m6A and m6Am modifications is regulated in the fasting hearts and might play an important role in cardiac adaptation to fasting, a well-known cardioprotective intervention.
- Klíčová slova
- ALKBH5, FTO, Fasting, epitranscriptomics, heart, m6A, m6Am,
- MeSH
- adenosin * genetika metabolismus MeSH
- krysa rodu Rattus MeSH
- messenger RNA genetika MeSH
- omezení příjmu potravy MeSH
- proteomika * MeSH
- RNA metabolismus MeSH
- zvířata MeSH
- Check Tag
- krysa rodu Rattus MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- adenosin * MeSH
- messenger RNA MeSH
- RNA MeSH
Epitranscriptomic modifications have recently emerged into the spotlight of researchers due to their vast regulatory effects on gene expression and thereby cellular physiology and pathophysiology. N6,2'-O-dimethyladenosine (m6Am) is one of the most prevalent chemical marks on RNA and is dynamically regulated by writers (PCIF1, METTL4) and erasers (FTO). The presence or absence of m6Am in RNA affects mRNA stability, regulates transcription, and modulates pre-mRNA splicing. Nevertheless, its functions in the heart are poorly known. This review summarizes the current knowledge and gaps about m6Am modification and its regulators in cardiac biology. It also points out technical challenges and lists the currently available techniques to measure m6Am. A better understanding of epitranscriptomic modifications is needed to improve our knowledge of the molecular regulations in the heart which may lead to novel cardioprotective strategies.
- Klíčová slova
- N6,2‘-O-dimethyladenosine, N6-methyladenosine, epitranscriptomics, heart, m6A, m6Am,
- MeSH
- adenosin * metabolismus MeSH
- biologie MeSH
- messenger RNA genetika MeSH
- metylace DNA * MeSH
- RNA metabolismus MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
- Názvy látek
- adenosin * MeSH
- messenger RNA MeSH
- RNA MeSH
The rapidly developing research field of epitranscriptomics has recently emerged into the spotlight of researchers due to its vast regulatory effects on gene expression and thereby cellular physiology and pathophysiology. N6-methyladenosine (m6A) and N6,2'-O-dimethyladenosine (m6Am) are among the most prevalent and well-characterized modified nucleosides in eukaryotic RNA. Both of these modifications are dynamically regulated by a complex set of epitranscriptomic regulators called writers, readers, and erasers. Altered levels of m6A and also several regulatory proteins were already associated with diabetic tissues. This review summarizes the current knowledge and gaps about m6A and m6Am modifications and their respective regulators in the pathophysiology of diabetes mellitus. It focuses mainly on the more prevalent type 2 diabetes mellitus (T2DM) and its treatment by metformin, the first-line antidiabetic agent. A better understanding of epitranscriptomic modifications in this highly prevalent disease deserves further investigation and might reveal clinically relevant discoveries in the future.
- Klíčová slova
- RNA, T2DM, diabetes, epigenetics, epitranscriptomics, m6A, m6Am, type 2 diabetes mellitus,
- MeSH
- adenosin metabolismus MeSH
- diabetes mellitus 2. typu * genetika MeSH
- lidé MeSH
- messenger RNA metabolismus MeSH
- posttranskripční úpravy RNA MeSH
- RNA genetika metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
- Názvy látek
- adenosin MeSH
- messenger RNA MeSH
- RNA MeSH
