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1.
Circ Res ; 124(2): 292-305, 2019 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-30582455

RESUMO

RATIONALE: The Hippo pathway plays an important role in determining organ size through regulation of cell proliferation and apoptosis. Hippo inactivation and consequent activation of YAP (Yes-associated protein), a transcription cofactor, have been proposed as a strategy to promote myocardial regeneration after myocardial infarction. However, the long-term effects of Hippo deficiency on cardiac function under stress remain unknown. OBJECTIVE: We investigated the long-term effect of Hippo deficiency on cardiac function in the presence of pressure overload (PO). METHODS AND RESULTS: We used mice with cardiac-specific homozygous knockout of WW45 (WW45cKO), in which activation of Mst1 (Mammalian sterile 20-like 1) and Lats2 (large tumor suppressor kinase 2), the upstream kinases of the Hippo pathway, is effectively suppressed because of the absence of the scaffolding protein. We used male mice at 3 to 4 month of age in all animal experiments. We subjected WW45cKO mice to transverse aortic constriction for up to 12 weeks. WW45cKO mice exhibited higher levels of nuclear YAP in cardiomyocytes during PO. Unexpectedly, the progression of cardiac dysfunction induced by PO was exacerbated in WW45cKO mice, despite decreased apoptosis and activated cardiomyocyte cell cycle reentry. WW45cKO mice exhibited cardiomyocyte sarcomere disarray and upregulation of TEAD1 (transcriptional enhancer factor) target genes involved in cardiomyocyte dedifferentiation during PO. Genetic and pharmacological inactivation of the YAP-TEAD1 pathway reduced the PO-induced cardiac dysfunction in WW45cKO mice and attenuated cardiomyocyte dedifferentiation. Furthermore, the YAP-TEAD1 pathway upregulated OSM (oncostatin M) and OSM receptors, which played an essential role in mediating cardiomyocyte dedifferentiation. OSM also upregulated YAP and TEAD1 and promoted cardiomyocyte dedifferentiation, indicating the existence of a positive feedback mechanism consisting of YAP, TEAD1, and OSM. CONCLUSIONS: Although activation of YAP promotes cardiomyocyte regeneration after cardiac injury, it induces cardiomyocyte dedifferentiation and heart failure in the long-term in the presence of PO through activation of the YAP-TEAD1-OSM positive feedback mechanism.


Assuntos
Proteínas de Ciclo Celular/deficiência , Desdiferenciação Celular , Insuficiência Cardíaca/metabolismo , Miócitos Cardíacos/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Disfunção Ventricular Esquerda/metabolismo , Função Ventricular Esquerda , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Apoptose , Ciclo Celular , Proteínas de Ciclo Celular/genética , Células Cultivadas , Proteínas de Ligação a DNA/metabolismo , Modelos Animais de Doenças , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/patologia , Insuficiência Cardíaca/fisiopatologia , Via de Sinalização Hippo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miócitos Cardíacos/patologia , Oncostatina M/metabolismo , Fosfoproteínas/metabolismo , Ratos Wistar , Transdução de Sinais , Fatores de Transcrição de Domínio TEA , Fatores de Transcrição/metabolismo , Disfunção Ventricular Esquerda/genética , Disfunção Ventricular Esquerda/patologia , Disfunção Ventricular Esquerda/fisiopatologia , Proteínas de Sinalização YAP
2.
Physiol Rev ; 91(3): 827-87, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21742789

RESUMO

MicroRNAs (miRNAs) are a class of posttranscriptional regulators that have recently introduced an additional level of intricacy to our understanding of gene regulation. There are currently over 10,000 miRNAs that have been identified in a range of species including metazoa, mycetozoa, viridiplantae, and viruses, of which 940, to date, are found in humans. It is estimated that more than 60% of human protein-coding genes harbor miRNA target sites in their 3' untranslated region and, thus, are potentially regulated by these molecules in health and disease. This review will first briefly describe the discovery, structure, and mode of function of miRNAs in mammalian cells, before elaborating on their roles and significance during development and pathogenesis in the various mammalian organs, while attempting to reconcile their functions with our existing knowledge of their targets. Finally, we will summarize some of the advances made in utilizing miRNAs in therapeutics.


Assuntos
Doença/genética , Regulação da Expressão Gênica no Desenvolvimento , Regulação da Expressão Gênica , Mamíferos/metabolismo , MicroRNAs/metabolismo , Animais , Células Sanguíneas/fisiologia , Encéfalo/metabolismo , Tratamento Farmacológico/tendências , Regulação Neoplásica da Expressão Gênica , Humanos , Rim/metabolismo , Leucemia/metabolismo , Fígado/metabolismo , Pulmão/metabolismo , Linfoma/metabolismo , MicroRNAs/sangue , MicroRNAs/uso terapêutico , Músculo Esquelético/metabolismo , Miocárdio/metabolismo , Neovascularização Fisiológica/fisiologia , Pâncreas/metabolismo , Pele/metabolismo
3.
Circ Res ; 117(10): 891-904, 2015 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-26333362

RESUMO

RATIONALE: In Drosophila, the Hippo signaling pathway negatively regulates organ size by suppressing cell proliferation and survival through the inhibition of Yorkie, a transcriptional cofactor. Yes-associated protein (YAP), the mammalian homolog of Yorkie, promotes cardiomyocyte growth and survival in postnatal hearts. However, the underlying mechanism responsible for the beneficial effect of YAP in cardiomyocytes remains unclear. OBJECTIVES: We investigated whether miR-206, a microRNA known to promote hypertrophy in skeletal muscle, mediates the effect of YAP on promotion of survival and hypertrophy in cardiomyocytes. METHODS AND RESULTS: Microarray analysis indicated that YAP increased miR-206 expression in cardiomyocytes. Increased miR-206 expression induced cardiac hypertrophy and inhibited cell death in cultured cardiomyocytes, similar to that of YAP. Downregulation of endogenous miR-206 in cardiomyocytes attenuated YAP-induced cardiac hypertrophy and survival, suggesting that miR-206 plays a critical role in mediating YAP function. Cardiac-specific overexpression of miR-206 in mice induced hypertrophy and protected the heart from ischemia/reperfusion injury, whereas suppression of miR-206 exacerbated ischemia/reperfusion injury and prevented pressure overload-induced cardiac hypertrophy. miR-206 negatively regulates Forkhead box protein P1 expression in cardiomyocytes and overexpression of Forkhead box protein P1 attenuated miR-206-induced cardiac hypertrophy and survival, suggesting that Forkhead box protein P1 is a functional target of miR-206. CONCLUSIONS: YAP increases the abundance of miR-206, which in turn plays an essential role in mediating hypertrophy and survival by silencing Forkhead box protein P1 in cardiomyocytes.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Reguladoras de Apoptose/metabolismo , Cardiomegalia/metabolismo , MicroRNAs/metabolismo , Infarto do Miocárdio/metabolismo , Traumatismo por Reperfusão Miocárdica/metabolismo , Miócitos Cardíacos/metabolismo , Fosfoproteínas/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Animais Recém-Nascidos , Proteínas Reguladoras de Apoptose/genética , Cardiomegalia/genética , Cardiomegalia/patologia , Proteínas de Ciclo Celular , Sobrevivência Celular , Células Cultivadas , Modelos Animais de Doenças , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Regulação da Expressão Gênica , Camundongos Transgênicos , MicroRNAs/genética , Infarto do Miocárdio/genética , Infarto do Miocárdio/patologia , Infarto do Miocárdio/prevenção & controle , Traumatismo por Reperfusão Miocárdica/genética , Traumatismo por Reperfusão Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Miócitos Cardíacos/patologia , Estresse Oxidativo , Fosfoproteínas/genética , Interferência de RNA , Ratos Wistar , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Transdução de Sinais , Transfecção , Remodelação Ventricular , Proteínas de Sinalização YAP
4.
Circ Res ; 116(2): 264-78, 2015 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-25332205

RESUMO

RATIONALE: Both fusion and fission contribute to mitochondrial quality control. How unopposed fusion affects survival of cardiomyocytes and left ventricular function in the heart is poorly understood. OBJECTIVE: We investigated the role of dynamin-related protein 1 (Drp1), a GTPase that mediates mitochondrial fission, in mediating mitochondrial autophagy, ventricular function, and stress resistance in the heart. METHODS AND RESULTS: Drp1 downregulation induced mitochondrial elongation, accumulation of damaged mitochondria, and increased apoptosis in cardiomyocytes at baseline. Drp1 downregulation also suppressed autophagosome formation and autophagic flux at baseline and in response to glucose deprivation in cardiomyocytes. The lack of lysosomal translocation of mitochondrially targeted Keima indicates that Drp1 downregulation suppressed mitochondrial autophagy. Mitochondrial elongation and accumulation of damaged mitochondria were also observed in tamoxifen-inducible cardiac-specific Drp1 knockout mice. After Drp1 downregulation, cardiac-specific Drp1 knockout mice developed left ventricular dysfunction, preceded by mitochondrial dysfunction, and died within 13 weeks. Autophagic flux is significantly suppressed in cardiac-specific Drp1 knockout mice. Although left ventricular function in cardiac-specific Drp1 heterozygous knockout mice was normal at 12 weeks of age, left ventricular function decreased more severely after 48 hours of fasting, and the infarct size/area at risk after ischemia/reperfusion was significantly greater in cardiac-specific Drp1 heterozygous knockout than in control mice. CONCLUSIONS: Disruption of Drp1 induces mitochondrial elongation, inhibits mitochondrial autophagy, and causes mitochondrial dysfunction, thereby promoting cardiac dysfunction and increased susceptibility to ischemia/reperfusion.


Assuntos
Autofagia/fisiologia , Dinaminas/fisiologia , Metabolismo Energético/fisiologia , Mitocôndrias Cardíacas/metabolismo , Estresse Oxidativo/fisiologia , Animais , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Miócitos Cardíacos/fisiologia , Ratos , Ratos Wistar
5.
J Biol Chem ; 288(4): 2546-58, 2013 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-23229551

RESUMO

Cardiac hypertrophy is characterized by a generalized increase in gene expression that is commensurate with the increase in myocyte size and mass, on which is superimposed more robust changes in the expression of specialized genes. Both transcriptional and posttranscriptional mechanisms play fundamental roles in these processes; however, genome-wide characterization of the transcriptional changes has not been investigated. Our goal was to identify the extent and modes, RNA polymerase II (pol II) pausing versus recruitment, of transcriptional regulation underlying cardiac hypertrophy. We used anti-pol II and anti-histone H3K9-acetyl (H3K9ac) chromatin immunoprecipitation-deep sequencing to determine the extent of pol II recruitment and pausing, and the underlying epigenetic modifications, respectively, during cardiac growth. The data uniquely reveal two mutually exclusive modes of transcriptional regulation. One involves an incremental increase (30-50%) in the elongational activity of preassembled, promoter-paused, pol II, and encompasses ∼25% of expressed genes that are essential/housekeeping genes (e.g. RNA synthesis and splicing). Another involves a more robust activation via de novo pol II recruitment, encompassing ∼5% of specialized genes (e.g. contractile and extracellular matrix). Moreover, the latter subset has relatively shorter 3'-UTRs with fewer predicted targeting miRNA, whereas most miRNA targets fall in the former category, underscoring the significance of posttranscriptional regulation by miRNA. The results, for the first time, demonstrate that promoter-paused pol II plays a role in incrementally increasing housekeeping genes, proportionate to the increase in heart size. Additionally, the data distinguish between the roles of posttranscriptional versus transcriptional regulation of specific genes.


Assuntos
Cardiomegalia/metabolismo , Regulação da Expressão Gênica , Histonas/metabolismo , Miocárdio/metabolismo , Transcrição Gênica , Animais , Animais Recém-Nascidos , Imunoprecipitação da Cromatina , Estudo de Associação Genômica Ampla , Coração/fisiologia , Imunoprecipitação , Camundongos , Camundongos Endogâmicos C57BL , Regiões Promotoras Genéticas , RNA Polimerase II/metabolismo
6.
Circ Res ; 110(4): 638-50, 2012 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-22343558

RESUMO

Disturbances in gene expression as a result of perturbed transcription or posttranscriptional regulation is one of the main causes of cellular dysfunction that underlies different disease states. Approximately a decade ago, the discovery of microRNAs in mammalian cells has renewed our focus on posttranscriptional regulatory mechanisms during pathogenesis. These tiny posttranscriptional regulators are differentially expressed in almost every disease that has been studied to date and can modulate expression of a gene via specifically binding to its messenger RNA. Because of their capacity to simultaneously target multiple functionally related, genes, they are proving to be potentially powerful therapeutic agents/targets. In this review, we focus on the microRNAs that are differentially regulated in the more common cardiovascular pathologies, their targets, and potential function.


Assuntos
Cardiopatias/genética , MicroRNAs/metabolismo , Animais , Predisposição Genética para Doença , Cardiopatias/patologia , Cardiopatias/fisiopatologia , Humanos , Fenótipo , Interferência de RNA
7.
Circ Res ; 111(5): 642-56, 2012 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-22904043

RESUMO

The silencer information regulator (Sir) family of proteins has attracted much attention during the past decade due to its prominent role in metabolic homeostasis in mammals. The Sir1-4 proteins were first discovered in yeast as nicotinamide adenine dinucleotide (NAD(+))-dependent deacetylases, which through a gene silencing effect promoted longevity. The subsequent discovery of a homologous sirtuin (Sirt) family of proteins in the mammalian systems soon led to the realization that these molecules have beneficial effects in metabolism- and aging-related diseases. Through their concerted functions in the central nervous system, liver, pancreas, skeletal muscle, and adipose tissue, they regulate the body's metabolism. Sirt1, -6, and -7 exert their functions, predominantly, through a direct effect on nuclear transcription of genes involved in metabolism, whereas Sirt3-5 reside in the mitochondrial matrix and regulate various enzymes involved in the tricarboxylic acid and urea cycles, oxidative phosphorylation, as well as reactive oxygen species production. An interesting aspect of the functionality of sirtuin involves their regulation by the circadian rhythm, which affects their function via cyclically regulating systemic NAD(+) availability, further establishing the link of these proteins to metabolism. In this review, we will discuss the relation of sirtuins to NAD(+) metabolism, their mechanism of function, and their role in metabolism and mitochondrial functions. In addition, we will describe their effects in the cardiovascular and central nervous systems.


Assuntos
Fenômenos Fisiológicos Cardiovasculares , Metabolismo Energético/fisiologia , NAD/fisiologia , Fenômenos Fisiológicos do Sistema Nervoso , Sirtuínas/fisiologia , Animais , Humanos
8.
Antimicrob Resist Infect Control ; 13(1): 104, 2024 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-39294829

RESUMO

BACKGROUND: The rise of antimicrobial resistance, which is partially attributed to the overuse and/or misuse of antibiotics in health care, is one of the world's largest public health challenges. The distribution of antibiotics in absence of a prescription in pharmacies is a significant contributor to the growing global public health crisis of antibiotic resistance. A pharmacist's clinical and lawful knowledge of antibiotic provide has an impact on the proper way to dispense medication. There are few novel studies assessing pharmacists comprehension and experience in prescribing antibiotics in low- and middle-income countries, including those in the Arabian region. OBJECTIVES: (I) assess pharmacy team members Knowledge about antibiotics as reported by individuals themselves and their behavior in dispensing antimicrobial without a prescription and (ii) find potential influences on this behavior. SETTING: Pharmacists were chosen from various regions in Algeria, Bahrain, Egypt, Iraq, Jordan, Kuwait, Lebanon, Libya, Morocco, Oman, Palestine, Qatar, Saudi Arabia, Somalia, Sudan, Syria, Tunisia, the United Arab Emirates, and Yemen, based on their convenience and ease of access. METHODS: A descriptive cross-sectional assessment among a random sample (n = 2833) of community pharmacists was conducted Utilizing a structured, validated, and questionnaire that underwent pilot testing, a comprehensive survey with four distinct sections covering biography, knowledge, practice, and attitude domains was employed. THE MAIN OUTCOME: Measures were knowledge, attitude, and practice toward dispensing antibiotics without prescription. RESULTS: Of the 3100 pharmacists reached, 2833 completed and return the questionnaires (response rate 91.3%). Most of the respondents were male (57.4%). Aged between 19 and 31 years old (76.2%). Most of them held a B.Sc. Degree (78.5%). Worked as staff pharmacists (73.2%). During the survey, it was discovered that there were gaps in their knowledge regarding antibiotic usage. A total of 45.7% of the respondents were unaware that antibiotics can be used as prophylaxis, while 33.3% did not recognize the consequences of making incorrect antibiotic choices. Regarding their practice patterns, 53.8% of the pharmacists admitted that they did not consistently adhere to guidelines when dispensing antibiotics. In terms of attitudes toward antibiotic usage, 36.8% disagreed with the guidelines of not supply antibiotics without a prescription, suggesting some variation in opinions among pharmacists on this matter. Additionally, a significant percentage (75%) believed that community pharmacists had qualifications to prescribe antibiotics for infections. CONCLUSION: The recent survey has shed light on the differences among pharmacists in regard to dispensing antibiotics without prescriptions and their understanding of resistance. The findings are concerning, indicating a deficient in of knowledge as regards the use of antibiotics. It is crucial to implement regulations and enhance education efforts to tackle the growing problem of resistance. Collaboration between healthcare professionals and awareness campaigns is essential in addressing this issue.


Assuntos
Antibacterianos , Conhecimentos, Atitudes e Prática em Saúde , Farmacêuticos , Estudos Transversais , Humanos , Antibacterianos/uso terapêutico , Feminino , Masculino , Adulto , Inquéritos e Questionários , Farmácias , Oriente Médio , Pessoa de Meia-Idade , Padrões de Prática dos Farmacêuticos , Adulto Jovem
9.
Circ Res ; 108(3): 305-13, 2011 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-21183740

RESUMO

RATIONALE: Thioredoxin (Trx)1 inhibits pathological cardiac hypertrophy. MicroRNAs (miRNAs) are small noncoding RNAs that downregulate posttranscriptional expression of target molecules. OBJECTIVES: We investigated the role of miRNAs in mediating the antihypertrophic effect of Trx1 on angiotensin II (Ang II)-induced cardiac hypertrophy. METHODS AND RESULTS: Microarray analyses of mature rodent microRNAs and quantitative RT-PCR/Northern blot analyses showed that Trx1 upregulates members of the let-7 family, including miR-98, in the heart and the cardiomyocytes therein. Adenovirus-mediated expression of miR-98 in cardiomyocytes reduced cell size both at baseline and in response to Ang II. Knockdown of miR-98, and of other members of the let-7 family, augmented Ang II-induced cardiac hypertrophy, and attenuated Trx1-mediated inhibition of Ang II-induced cardiac hypertrophy, suggesting that endogenous miR-98/let-7 mediates the antihypertrophic effect of Trx1. Cyclin D2 is one of the predicted targets of miR-98. Ang II significantly upregulated cyclin D2, which in turn plays an essential role in mediating Ang II-induced cardiac hypertrophy, whereas overexpression of Trx1 inhibited Ang II-induced upregulation of cyclin D2. miR-98 decreased both expression of cyclin D2 and the activity of a cyclin D2 3'UTR luciferase reporter, suggesting that both Trx1 and miR-98 negatively regulate cyclin D2. Overexpression of cyclin D2 attenuated the suppression of Ang II-induced cardiac hypertrophy by miR-98, suggesting that the antihypertrophic actions of miR-98 are mediated in part by downregulation of cyclin D2. CONCLUSIONS: These results suggest that Trx1 upregulates expression of the let-7 family, including miR-98, which in turn inhibits cardiac hypertrophy, in part through downregulation of cyclin D2.


Assuntos
Angiotensina II/fisiologia , Cardiomegalia/fisiopatologia , MicroRNAs/fisiologia , Tiorredoxinas/fisiologia , Regulação para Cima/fisiologia , Adenoviridae/genética , Angiotensina II/farmacologia , Animais , Células Cultivadas , Ciclina D2/fisiologia , Modelos Animais de Doenças , Camundongos , Camundongos Transgênicos , MicroRNAs/genética , Miócitos Cardíacos/citologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Ratos , Ratos Wistar , Transdução de Sinais/fisiologia , Tiorredoxinas/genética
10.
J Clin Invest ; 133(22)2023 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-37669116

RESUMO

Identification of branched-chain amino acid (BCAA) oxidation enzymes in the nucleus led us to predict that they are a source of the propionyl-CoA that is utilized for histone propionylation and, thereby, regulate gene expression. To investigate the effects of BCAAs on the development of cardiac hypertrophy and failure, we applied pressure overload on the heart in mice maintained on a diet with standard levels of BCAAs (BCAA control) versus a BCAA-free diet. The former was associated with an increase in histone H3K23-propionyl (H3K23Pr) at the promoters of upregulated genes (e.g., cell signaling and extracellular matrix genes) and a decrease at the promoters of downregulated genes (e.g., electron transfer complex [ETC I-V] and metabolic genes). Intriguingly, the BCAA-free diet tempered the increases in promoter H3K23Pr, thus reducing collagen gene expression and fibrosis during cardiac hypertrophy. Conversely, the BCAA-free diet inhibited the reductions in promoter H3K23Pr and abolished the downregulation of ETC I-V subunits, enhanced mitochondrial respiration, and curbed the progression of cardiac hypertrophy. Thus, lowering the intake of BCAAs reduced pressure overload-induced changes in histone propionylation-dependent gene expression in the heart, which retarded the development of cardiomyopathy.


Assuntos
Aminoácidos de Cadeia Ramificada , Histonas , Camundongos , Animais , Histonas/genética , Aminoácidos de Cadeia Ramificada/metabolismo , Coração , Dieta , Cardiomegalia/genética
11.
Cell Signal ; 111: 110886, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37690661

RESUMO

Glucocorticoids through activation of the Glucocorticoid receptor (GR) play an essential role in cellular homeostasis during physiological variations and in response to stress. Our genomic GR binding and transcriptome data from Dexamethasone (Dex) treated cardiomyocytes showed an early differential regulation of mostly transcription factors, followed by sequential change in genes involved in downstream functional pathways. We examined the role of Krüppel-like factor 9 (Klf9), an early direct target of GR in cardiomyocytes. Klf9-ChIPseq identified 2150 genes that showed an increase in Klf9 binding in response to Dex. Transcriptome analysis of Dex treated cardiomyocytes with or without knockdown of Klf9 revealed differential regulation of 1777 genes, of which a reversal in expression is seen in 1640 genes with knockdown of Klf9 compared to Dex. Conversely, only 137 (∼8%) genes show further dysregulation in expression with siKLf9, as seen with Dex treated cardiomyocytes. Functional annotation identified genes of metabolic pathways on the top of differentially expressed genes, including those involved in glycolysis and oxidative phosphorylation. Knockdown of Klf9 in cardiomyocytes inhibited Dex induced increase in glycolytic function and mitochondrial spare respiratory capacity, as measured by glycolysis and mito stress tests, respectively. Thus, we conclude that cyclic, diurnal GR activation, through Klf9 -dependent feedforward signaling plays a central role in maintaining cellular homeostasis through metabolic adaptations in cardiomyocytes.


Assuntos
Miócitos Cardíacos , Receptores de Glucocorticoides , Receptores de Glucocorticoides/genética , Receptores de Glucocorticoides/metabolismo , Miócitos Cardíacos/metabolismo , Fatores de Transcrição Kruppel-Like/metabolismo , Fatores de Transcrição/metabolismo , Transdução de Sinais
12.
Life Sci ; 334: 122257, 2023 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-37949207

RESUMO

Mitochondria play a vital role in the nervous system, as they are responsible for generating energy in the form of ATP and regulating cellular processes such as calcium (Ca2+) signaling and apoptosis. However, mitochondrial dysfunction can lead to oxidative stress (OS), inflammation, and cell death, which have been implicated in the pathogenesis of various neurological disorders. In this article, we review the main functions of mitochondria in the nervous system and explore the mechanisms related to mitochondrial dysfunction. We discuss the role of mitochondrial dysfunction in the development and progression of some neurological disorders including Parkinson's disease (PD), multiple sclerosis (MS), Alzheimer's disease (AD), depression, and epilepsy. Finally, we provide an overview of various current treatment strategies that target mitochondrial dysfunction, including pharmacological treatments, phototherapy, gene therapy, and mitotherapy. This review emphasizes the importance of understanding the role of mitochondria in the nervous system and highlights the potential for mitochondrial-targeted therapies in the treatment of neurological disorders. Furthermore, it highlights some limitations and challenges encountered by the current therapeutic strategies and puts them in future perspective.


Assuntos
Doença de Alzheimer , Doenças Neurodegenerativas , Doença de Parkinson , Humanos , Doenças Neurodegenerativas/metabolismo , Mitocôndrias/metabolismo , Estresse Oxidativo , Doença de Alzheimer/tratamento farmacológico , Doença de Parkinson/metabolismo
13.
J Clin Invest ; 132(6)2022 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-35133975

RESUMO

The heart utilizes multiple adaptive mechanisms to maintain pump function. Compensatory cardiac hypertrophy reduces wall stress and oxygen consumption, thereby protecting the heart against acute blood pressure elevation. The nuclear effector of the Hippo pathway, Yes-associated protein 1 (YAP), is activated and mediates compensatory cardiac hypertrophy in response to acute pressure overload (PO). In this study, YAP promoted glycolysis by upregulating glucose transporter 1 (GLUT1), which in turn caused accumulation of intermediates and metabolites of the glycolytic, auxiliary, and anaplerotic pathways during acute PO. Cardiac hypertrophy was inhibited and heart failure was exacerbated in mice with YAP haploinsufficiency in the presence of acute PO. However, normalization of GLUT1 rescued the detrimental phenotype. PO induced the accumulation of glycolytic metabolites, including l-serine, l-aspartate, and malate, in a YAP-dependent manner, thereby promoting cardiac hypertrophy. YAP upregulated the GLUT1 gene through interaction with TEA domain family member 1 (TEAD1) and HIF-1α in cardiomyocytes. Thus, YAP induces compensatory cardiac hypertrophy through activation of the Warburg effect.


Assuntos
Cardiomegalia , Miócitos Cardíacos , Proteínas de Sinalização YAP/metabolismo , Animais , Cardiomegalia/genética , Cardiomegalia/metabolismo , Ciclo do Ácido Cítrico , Transportador de Glucose Tipo 1/genética , Glicólise , Camundongos , Miócitos Cardíacos/metabolismo
14.
J Biol Chem ; 285(26): 20281-90, 2010 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-20404348

RESUMO

MicroRNA-21 (miR-21) is highly up-regulated during hypertrophic and cancerous cell growth. In contrast, we found that it declines in cardiac myocytes upon exposure to hypoxia. Thus, the objective was to explore its role during hypoxia. We show that miR-21 not only regulates phosphatase and tensin homologue deleted on chromosome 10 (PTEN), but also targets Fas ligand (FasL). During prolonged hypoxia, down-regulation of miR-21 proved necessary and sufficient for enhancing expression of both proteins. We demonstrate here for the first time that miR-21 is positively regulated via an AKT-dependent pathway, which is depressed during prolonged hypoxia. Accordingly, hypoxia-induced down-regulation of miR-21 and up-regulation of FasL and PTEN were reversed by activated AKT and reproduced by a dominant negative mutant, wortmannin, or PTEN. Moreover, the antiapoptotic function of AKT partly required miR-21, which was sufficient for inhibition of caspase-8 activity and mitochondrial damage. In consensus, overexpression of miR-21 in a transgenic mouse heart resulted in suppression of ischemia-induced up-regulation of PTEN and FasL expression, an increase in phospho-AKT, a smaller infarct size, and ameliorated heart failure. Thus, we have identified a unique aspect of the function of AKT by which it inhibits apoptosis through miR-21-dependent suppression of FasL.


Assuntos
Apoptose , Proteína Ligante Fas/metabolismo , MicroRNAs/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Regiões 3' não Traduzidas/genética , Animais , Animais Recém-Nascidos , Western Blotting , Hipóxia Celular , Linhagem Celular Tumoral , Células Cultivadas , Proteína Ligante Fas/genética , Humanos , Imuno-Histoquímica , Camundongos , Camundongos Transgênicos , MicroRNAs/genética , Traumatismo por Reperfusão Miocárdica/genética , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Miócitos Cardíacos/citologia , Miócitos Cardíacos/metabolismo , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas c-akt/genética , Interferência de RNA , Ratos , Ratos Sprague-Dawley
15.
Curr Opin Cardiol ; 26(3): 181-9, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21464712

RESUMO

PURPOSE OF REVIEW: Reprogramming of gene expression underlies the mechanisms involved in cardiac pathogenesis. MicroRNAs (miRNAs) are unique posttranscriptional regulators of gene expression whose function in cardiac development and disease has recently begun to unravel. In addition, they are potentially highly effective therapeutic tools. In this review, we will summarize the recent advancements in the field. RECENT FINDINGS: The cardiac-enriched miRNAs, including miR-1, miR-133, and miR-208, as well as the ubiquitous miR-23a and miR-199b, play major roles in the development of cardiac hypertrophy. On the other hand, miR-21, miR-199a, miR-210, and miR-494 have been proven critical for the myocytes' adaptation and survival during hypoxia/ischemia. Using depletion or replacement strategies against some of these miRNAs has proven very effective in preventing or even reversing some disorders. These findings and more will be detailed in this review. SUMMARY: In general, the discovery of miRNAs has uncovered a new dimension of gene regulation that provides us with unique mechanistic insights into cardiac diseases, in addition to which they can be utilized for new diagnostics and therapeutic strategies.


Assuntos
Cardiomegalia/genética , Sistema Cardiovascular , Expressão Gênica/genética , Insuficiência Cardíaca/genética , MicroRNAs , Cardiomegalia/diagnóstico , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/genética , Insuficiência Cardíaca/diagnóstico , Humanos , Células Musculares , Isquemia Miocárdica/genética
16.
Circ Res ; 104(7): 879-86, 2009 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-19265035

RESUMO

MicroRNAs are posttranscriptional gene regulators that are differentially expressed during various diseases and have been implicated in the underlying pathogenesis. We report here that miR-199a is acutely downregulated in cardiac myocytes on a decline in oxygen tension. This reduction is required for the rapid upregulation of its target, hypoxia-inducible factor (Hif)-1alpha. Replenishing miR-199a during hypoxia inhibits Hif-1alpha expression and its stabilization of p53 and, thus, reduces apoptosis. On the other hand, knockdown of miR-199a during normoxia results in the upregulation of Hif-1alpha and Sirtuin (Sirt)1 and reproduces hypoxia preconditioning. Sirt1 is also a direct target of miR-199a and is responsible for downregulating prolyl hydroxylase 2, required for stabilization of Hif-1alpha. Thus, we conclude that miR-199a is a master regulator of a hypoxia-triggered pathway and can be exploited for preconditioning cells against hypoxic damage. In addition, the data demonstrate a functional link between 2 key molecules that regulate hypoxia preconditioning and longevity.


Assuntos
Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Precondicionamento Isquêmico Miocárdico , MicroRNAs/metabolismo , Isquemia Miocárdica/terapia , Miócitos Cardíacos/metabolismo , Oxigênio/metabolismo , Traumatismo por Reperfusão/prevenção & controle , Sirtuínas/metabolismo , Animais , Animais Recém-Nascidos , Apoptose/genética , Hipóxia Celular , Células Cultivadas , Modelos Animais de Doenças , Regulação para Baixo , Técnicas de Silenciamento de Genes , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Prolina Dioxigenases do Fator Induzível por Hipóxia , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Mitocôndrias Cardíacas/metabolismo , Isquemia Miocárdica/genética , Isquemia Miocárdica/metabolismo , Miócitos Cardíacos/patologia , Pró-Colágeno-Prolina Dioxigenase/metabolismo , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/metabolismo , Sirtuína 1 , Sirtuínas/genética , Suínos , Transdução Genética
17.
Circ Res ; 104(4): 514-21, 2009 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-19131648

RESUMO

MicroRNAs are small endogenous noncoding RNAs that regulate protein expression by hybridization to imprecise complementary sequences of target mRNAs. Changes in abundance of muscle-specific microRNA, miR-1, have been implicated in cardiac disease, including arrhythmia and heart failure. However, the specific molecular targets and cellular mechanisms involved in the action of miR-1 in the heart are only beginning to emerge. In this study we investigated the effects of increased expression of miR-1 on excitation-contraction coupling and Ca(2+) cycling in rat ventricular myocytes using methods of electrophysiology, Ca(2+) imaging and quantitative immunoblotting. Adenoviral-mediated overexpression of miR-1 in myocytes resulted in a marked increase in the amplitude of the inward Ca(2+) current, flattening of Ca(2+) transients voltage dependence, and enhanced frequency of spontaneous Ca(2+) sparks while reducing the sarcoplasmic reticulum Ca(2+) content as compared with control. In the presence of isoproterenol, rhythmically paced, miR-1-overexpressing myocytes exhibited spontaneous arrhythmogenic oscillations of intracellular Ca(2+), events that occurred rarely in control myocytes under the same conditions. The effects of miR-1 were completely reversed by the CaMKII inhibitor KN93. Although phosphorylation of phospholamban was not altered, miR-1 overexpression increased phosphorylation of the ryanodine receptor (RyR2) at S2814 (Ca(2+)/calmodulin-dependent protein kinase) but not at S2808 (protein kinase A). Overexpression of miR-1 was accompanied by a selective decrease in expression of the protein phosphatase PP2A regulatory subunit B56alpha involved in PP2A targeting to specialized subcellular domains. We conclude that miR-1 enhances cardiac excitation-contraction coupling by selectively increasing phosphorylation of the L-type and RyR2 channels via disrupting localization of PP2A activity to these channels.


Assuntos
Arritmias Cardíacas/enzimologia , Sinalização do Cálcio , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , MicroRNAs/metabolismo , Contração Miocárdica , Miócitos Cardíacos/enzimologia , Proteína Fosfatase 2/metabolismo , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Adenoviridae/genética , Agonistas Adrenérgicos beta/farmacologia , Animais , Arritmias Cardíacas/genética , Arritmias Cardíacas/fisiopatologia , Benzilaminas/farmacologia , Canais de Cálcio Tipo L/metabolismo , Sinalização do Cálcio/efeitos dos fármacos , Sinalização do Cálcio/genética , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/antagonistas & inibidores , Células Cultivadas , Vetores Genéticos , Isoproterenol/farmacologia , Potenciais da Membrana , Camundongos , Contração Miocárdica/efeitos dos fármacos , Contração Miocárdica/genética , Miócitos Cardíacos/efeitos dos fármacos , Fosforilação , Inibidores de Proteínas Quinases/farmacologia , Ratos , Retículo Sarcoplasmático/metabolismo , Sulfonamidas/farmacologia , Fatores de Tempo , Transdução Genética
18.
Nat Med ; 8(11): 1310-7, 2002 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-12368904

RESUMO

Hypertrophic growth is a risk factor for mortality in heart diseases. Mechanisms are lacking for this global increase in RNA and protein per cell, which underlies hypertrophy. Hypertrophic signals cause phosphorylation of the RNA polymerase II C-terminal domain, required for transcript elongation. RNA polymerase II kinases include cyclin-dependent kinases-7 (Cdk7) and Cdk9, components of two basal transcription factors. We report activation of Cdk7 and -9 in hypertrophy triggered by signaling proteins (Galphaq, calcineurin) or chronic mechanical stress. Only Cdk9 was activated by acute load or, in culture, by endothelin. A preferential role for Cdk9 was shown in RNA polymerase II phosphorylation and growth induced by endothelin, using pharmacological and dominant-negative inhibitors. All four hypertrophic signals dissociated 7SK small nuclear RNA, an endogenous inhibitor, from cyclin T-Cdk9. Cdk9 was limiting for cardiac growth, shown by suppressing its inhibitor (7SK) in culture and preventing downregulation of its activator (cyclin T1) in mouse myocardium.Note: In the AOP version of this article, the numbering of the author affiliations was incorrect. This has now been fixed, and the affiliations appear correctly online and in print.


Assuntos
Cardiomegalia/metabolismo , Quinases Ciclina-Dependentes/metabolismo , Ciclinas/metabolismo , Animais , Sequência de Bases , Linhagem Celular , Células Cultivadas , Ciclina T , Quinase 9 Dependente de Ciclina , DNA , Humanos , Camundongos , Dados de Sequência Molecular , RNA/metabolismo , Ratos , Ratos Sprague-Dawley
19.
Pediatr Cardiol ; 32(3): 311-6, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21243487

RESUMO

MicroRNAs (miRNAs) are involved in almost every aspect of a mammalian cell's functionality, from stem cell differentiation to aging and pathogenesis; however, their role in immediate cell signaling is less defined. This has been recently demonstrated by the rapid increase or decrease of miR-21's abundance within minutes of activation or inhibition of the v-akt murine thymoma viral oncogene homolog 1 (AKT) pathway, respectively, which mediates its regulation of Fas ligand and phosphatase and tensin homologue deleted on chromosome 10 expression, among other targets. Conversely, AKT induces rapid downregulation of miR-199a-5p to effect upregulation of hypoxia-inducible factor 1α and sirtuin 1. This suggests that posttranscriptional mechanisms regulate miRNAs' processing and/or stability to induce the rapid fluctuation in their levels. In support, a growing number of studies are showing specific posttranscriptional regulation of miRNAs. The data potentially explain how AKT, and plausibly other signaling pathways, can specifically and promptly modulate a gene's translation while circumventing the need for transcription during transient signaling events.


Assuntos
Hipóxia/metabolismo , MicroRNAs/metabolismo , Transdução de Sinais , Regulação da Expressão Gênica , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Proteínas Proto-Oncogênicas c-akt , Sirtuína 1/genética , Sirtuína 1/metabolismo
20.
Mol Metab ; 53: 101249, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-33989779

RESUMO

OBJECTIVE: We previously reported that ß-oxidation enzymes are present in the nucleus in close proximity to transcriptionally active promoters. Thus, we hypothesized that the fatty acid intermediate, butyryl-CoA, is the substrate for histone butyrylation and its abundance is regulated by acyl-CoA dehydrogenase short chain (ACADS). The objective of this study was to determine the genomic distribution of H3K9-butyryl (H3K9Bu) and its regulation by dietary fat, stress, and ACADS and its impact on gene expression. METHODS AND RESULTS: Using genome-wide chromatin immunoprecipitation-sequencing (ChIP-Seq), we show that H3K9Bu is abundant at all transcriptionally active promoters, where, paradoxically, it is most enriched in mice fed a fat-free vs high-fat diet. Deletion of fatty acid synthetase (FASN) abolished H3K9Bu in cells maintained in a glucose-rich but not fatty acid-rich medium, signifying that fatty acid synthesis from carbohydrates substitutes for dietary fat as a source of butyryl-CoA. A high-fat diet induced an increase in ACADS expression that accompanied the decrease in H3K9Bu. Conversely, the deletion of ACADS increased H3K9Bu in human cells and mouse hearts and reversed high-fat- and stress-induced reduction in promoter-H3K9Bu, whose abundance coincided with diminished stress-regulated gene expression as revealed by RNA sequencing. In contrast, H3K9-acetyl (H3K9Ac) abundance was minimally impacted by diet. CONCLUSION: Promoter H3K9 butyrylation is a major histone modification that is negatively regulated by high fat and stress in an ACADS-dependent fashion and moderates stress-regulated gene expression.


Assuntos
Acil-CoA Desidrogenases/metabolismo , Gorduras na Dieta/metabolismo , Histonas/metabolismo , Estresse Fisiológico , Acetilação , Animais , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL
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