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1.
Am J Cardiol ; 160: 96-98, 2021 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-34620488

RESUMO

Cardiac amyloidosis is often preceded by orthopedic manifestations such as carpal tunnel syndrome, and 10% of patients who underwent idiopathic carpal tunnel release surgery will have biopsy-confirmed amyloid deposits in the tenosynovial sheath. Trigger finger is also commonly reported in patients with amyloidosis and involves the same tendon sheath as carpal tunnel syndrome, but the prevalence of amyloid deposition is unclear. This prospective cross-sectional study enrolled 100 patients aged ≥50 years at the time of surgery for idiopathic trigger finger. Patients underwent release surgery, and a sample of the tenosynovium of the affected finger was excised, stained with Congo red, and subtyped with mass spectrometry if amyloid was demonstrated. Further cardiac evaluation was performed in patients with amyloid deposition. Of the 100 patients (mean age 65.5 ± 8.1 years) enrolled, only 2 demonstrated amyloid deposits on Congo red staining. One patient with previous proteinuric kidney disease had fibrinogen A α-chain amyloidosis, and the other patient had untyped amyloidosis. Neither patient had cardiac involvement. A total of 13 of the 100 patients underwent concomitant carpal tunnel release surgery, and 2 of these patients had amyloid deposits in the carpal tunnel with "false-negative" samples from the trigger finger tenosynovium. In conclusion, biopsy during trigger finger release surgery demonstrated a 2% yield for amyloidosis, which is significantly lower than the previously published yield of 10% during carpal tunnel release surgery. This observation has important implications for the development of diagnostic algorithms to screen patients for amyloidosis during orthopedic operations.


Assuntos
Amiloidose/diagnóstico , Cardiomiopatias/diagnóstico , Membrana Sinovial/patologia , Dedo em Gatilho/cirurgia , Idoso , Amiloidose/complicações , Amiloidose/metabolismo , Amiloidose/patologia , Cardiomiopatias/complicações , Cardiomiopatias/metabolismo , Cardiomiopatias/patologia , Síndrome do Túnel Carpal/etiologia , Síndrome do Túnel Carpal/metabolismo , Síndrome do Túnel Carpal/patologia , Síndrome do Túnel Carpal/cirurgia , Feminino , Fibrinogênio/metabolismo , Humanos , Masculino , Programas de Rastreamento , Espectrometria de Massas , Pessoa de Meia-Idade , Membrana Sinovial/metabolismo , Dedo em Gatilho/etiologia , Dedo em Gatilho/metabolismo , Dedo em Gatilho/patologia
2.
FASEB J ; 35(11): e21994, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34674311

RESUMO

Arrhythmogenic cardiomyopathy (ACM) caused by TMEM43 p.S358L is a fully penetrant heart disease that results in impaired cardiac function or fatal arrhythmia. However, the molecular mechanism of ACM caused by the TMEM43 variant has not yet been fully elucidated. In this study, we generated knock-in (KI) rats harboring a Tmem43 p.S358L mutation and established induced pluripotent stem cells (iPSCs) from patients based on the identification of TMEM43 p.S358L variant from a family with ACM. The Tmem43-S358L KI rats exhibited ventricular arrhythmia and fibrotic myocardial replacement in the subepicardium, which recapitulated the human ACM phenotype. The four-transmembrane protein TMEM43 with the p.S358L variant (TMEM43S358L ) was found to be modified by N-linked glycosylation in both KI rat cardiomyocytes and patient-specific iPSC-derived cardiomyocytes. TMEM43S358L glycosylation increased under the conditions of enhanced endoplasmic reticulum (ER) stress caused by pharmacological stimulation or age-dependent decline of the ER function. Intriguingly, the specific glycosylation of TMEM43S358L resulted from the altered membrane topology of TMEM43. Moreover, unlike TMEM43WT , which is mainly localized to the ER, TMEM43S358L accumulated at the nuclear envelope of cardiomyocytes with the increase in glycosylation. Finally, our comprehensive transcriptomic analysis demonstrated that the regional differences in gene expression patterns between the inner and outer layers observed in the wild type myocardium were partially diminished in the KI myocardium prior to exhibiting histological changes indicative of ACM. Altogether, these findings suggest that the aberrant accumulation of TMEM43S358L underlies the pathogenesis of ACM caused by TMEM43 p.S358L variant by affecting the transmural gene expression within the myocardium.


Assuntos
Cardiomiopatias , Proteínas de Membrana/fisiologia , Miocárdio/metabolismo , Adulto , Idoso , Animais , Cardiomiopatias/genética , Cardiomiopatias/metabolismo , Células Cultivadas , Feminino , Expressão Gênica , Humanos , Células-Tronco Pluripotentes Induzidas , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Mutação , Miócitos Cardíacos , Ratos
3.
Front Endocrinol (Lausanne) ; 12: 726967, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34484128

RESUMO

In March 2020, the WHO declared coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a global pandemic. Obesity was soon identified as a risk factor for poor prognosis, with an increased risk of intensive care admissions and mechanical ventilation, but also of adverse cardiovascular events. Obesity is associated with adipose tissue, chronic low-grade inflammation, and immune dysregulation with hypertrophy and hyperplasia of adipocytes and overexpression of pro-inflammatory cytokines. However, to implement appropriate therapeutic strategies, exact mechanisms must be clarified. The role of white visceral adipose tissue, increased in individuals with obesity, seems important, as a viral reservoir for SARS-CoV-2 via angiotensin-converting enzyme 2 (ACE2) receptors. After infection of host cells, the activation of pro-inflammatory cytokines creates a setting conducive to the "cytokine storm" and macrophage activation syndrome associated with progression to acute respiratory distress syndrome. In obesity, systemic viral spread, entry, and prolonged viral shedding in already inflamed adipose tissue may spur immune responses and subsequent amplification of a cytokine cascade, causing worse outcomes. More precisely, visceral adipose tissue, more than subcutaneous fat, could predict intensive care admission; and lower density of epicardial adipose tissue (EAT) could be associated with worse outcome. EAT, an ectopic adipose tissue that surrounds the myocardium, could fuel COVID-19-induced cardiac injury and myocarditis, and extensive pneumopathy, by strong expression of inflammatory mediators that could diffuse paracrinally through the vascular wall. The purpose of this review is to ascertain what mechanisms may be involved in unfavorable prognosis among COVID-19 patients with obesity, especially cardiovascular events, emphasizing the harmful role of excess ectopic adipose tissue, particularly EAT.


Assuntos
COVID-19/metabolismo , Cardiomiopatias/metabolismo , Gordura Intra-Abdominal/metabolismo , Obesidade/metabolismo , Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Enzima de Conversão de Angiotensina 2/metabolismo , COVID-19/complicações , COVID-19/imunologia , Cardiomiopatias/imunologia , Cardiomiopatias/patologia , Cardiopatias/imunologia , Cardiopatias/metabolismo , Cardiopatias/patologia , Humanos , Inflamação , Gordura Intra-Abdominal/patologia , Obesidade/complicações , Obesidade/imunologia , Obesidade/patologia , Pericárdio , Prognóstico , SARS-CoV-2/metabolismo , Serina Endopeptidases/metabolismo
4.
Int J Mol Sci ; 22(17)2021 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-34502534

RESUMO

Rare pediatric non-compaction and restrictive cardiomyopathy are usually associated with a rapid and severe disease progression. While the non-compaction phenotype is characterized by structural defects and is correlated with systolic dysfunction, the restrictive phenotype exhibits diastolic dysfunction. The molecular mechanisms are poorly understood. Target genes encode among others, the cardiac troponin subunits forming the main regulatory protein complex of the thin filament for muscle contraction. Here, we compare the molecular effects of two infantile de novo point mutations in TNNC1 (p.cTnC-G34S) and TNNI3 (p.cTnI-D127Y) leading to severe non-compaction and restrictive phenotypes, respectively. We used skinned cardiomyocytes, skinned fibers, and reconstituted thin filaments to measure the impact of the mutations on contractile function. We investigated the interaction of these troponin variants with actin and their inter-subunit interactions, as well as the structural integrity of reconstituted thin filaments. Both mutations exhibited similar functional and structural impairments, though the patients developed different phenotypes. Furthermore, the protein quality control system was affected, as shown for TnC-G34S using patient's myocardial tissue samples. The two troponin targeting agents levosimendan and green tea extract (-)-epigallocatechin-3-gallate (EGCg) stabilized the structural integrity of reconstituted thin filaments and ameliorated contractile function in vitro in some, but not all, aspects to a similar degree for both mutations.


Assuntos
Cardiomiopatias/genética , Mutação de Sentido Incorreto , Miofibrilas/metabolismo , Troponina I/genética , Adenosina Trifosfatases/metabolismo , Adulto , Cálcio/metabolismo , Cardiomiopatias/metabolismo , Cardiomiopatias/patologia , Catequina/análogos & derivados , Catequina/farmacologia , Humanos , Lactente , Masculino , Microscopia Eletrônica de Transmissão , Miofibrilas/efeitos dos fármacos , Miofibrilas/ultraestrutura , Sarcômeros/efeitos dos fármacos , Sarcômeros/metabolismo , Índice de Gravidade de Doença , Simendana/farmacologia , Tropomiosina/metabolismo , Troponina I/metabolismo
5.
Int J Mol Sci ; 22(17)2021 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-34502355

RESUMO

As part of our ongoing studies on the potential pathophysiological role of serine/threonine phosphatases (PP) in the mammalian heart, we have generated transgenic mice with cardiac muscle cell-specific overexpression of PP2Acα (PP2A) and PP5 (PP5). For further studies we crossbred PP2A and PP5 mice to obtain PP2AxPP5 double transgenic mice (PP2AxPP5, DT) and compared them with littermate wild-type mice (WT) serving as a control. The mortality of DT mice was greatly enhanced vs. other genotypes. Cardiac fibrosis was noted histologically and mRNA levels of collagen 1α, collagen 3α and fibronectin 1 were augmented in DT. DT and PP2A mice exhibited an increase in relative heart weight. The ejection fraction (EF) was reduced in PP2A and DT but while the EF of PP2A was nearly normalized after ß-adrenergic stimulation by isoproterenol, it was almost unchanged in DT. Moreover, left atrial preparations from DT were less sensitive to isoproterenol treatment both under normoxic conditions and after hypoxia. In addition, levels of the hypertrophy markers atrial natriuretic peptide and B-type natriuretic peptide as well as the inflammation markers interleukin 6 and nuclear factor kappa B were increased in DT. PP2A enzyme activity was enhanced in PP2A vs. WT but similar to DT. This was accompanied by a reduced phosphorylation state of phospholamban at serine-16. Fittingly, the relaxation times in left atria from DT were prolonged. In summary, cardiac co-overexpression of PP2A and PP5 were detrimental to animal survival and cardiac function, and the mechanism may involve dephosphorylation of important regulatory proteins but also fibrosis and inflammation.


Assuntos
Glicoproteínas/metabolismo , Proteína Fosfatase 2C/metabolismo , Sístole/fisiologia , Animais , Cardiomiopatias/metabolismo , Fibrose/metabolismo , Cardiopatias/metabolismo , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Contração Miocárdica/fisiologia , Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Fosforilação , Inibidores de Serino Proteinase/metabolismo , Sístole/genética
6.
Sci Rep ; 11(1): 17495, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34471171

RESUMO

Uremic cardiomyopathy is characterized by diastolic dysfunction (DD), left ventricular hypertrophy (LVH), and fibrosis. Angiotensin-II plays a major role in the development of uremic cardiomyopathy via nitro-oxidative and inflammatory mechanisms. In heart failure, the beta-3 adrenergic receptor (ß3-AR) is up-regulated and coupled to endothelial nitric oxide synthase (eNOS)-mediated pathways, exerting antiremodeling effects. We aimed to compare the antiremodeling effects of the angiotensin-II receptor blocker losartan and the ß3-AR agonist mirabegron in uremic cardiomyopathy. Chronic kidney disease (CKD) was induced by 5/6th nephrectomy in male Wistar rats. Five weeks later, rats were randomized into four groups: (1) sham-operated, (2) CKD, (3) losartan-treated (10 mg/kg/day) CKD, and (4) mirabegron-treated (10 mg/kg/day) CKD groups. At week 13, echocardiographic, histologic, laboratory, qRT-PCR, and Western blot measurements proved the development of uremic cardiomyopathy with DD, LVH, fibrosis, inflammation, and reduced eNOS levels, which were significantly ameliorated by losartan. However, mirabegron showed a tendency to decrease DD and fibrosis; but eNOS expression remained reduced. In uremic cardiomyopathy, ß3-AR, sarcoplasmic reticulum ATPase (SERCA), and phospholamban levels did not change irrespective of treatments. Mirabegron reduced the angiotensin-II receptor 1 expression in uremic cardiomyopathy that might explain its mild antiremodeling effects despite the unchanged expression of the ß3-AR.


Assuntos
Acetanilidas/farmacologia , Cardiomiopatias/tratamento farmacológico , Losartan/farmacologia , Óxido Nítrico Sintase Tipo III/metabolismo , Insuficiência Renal Crônica/complicações , Tiazóis/farmacologia , Uremia/tratamento farmacológico , Agonistas de Receptores Adrenérgicos beta 3/farmacologia , Animais , Anti-Hipertensivos/farmacologia , Cardiomiopatias/etiologia , Cardiomiopatias/metabolismo , Cardiomiopatias/patologia , Masculino , Nefrectomia/efeitos adversos , Óxido Nítrico Sintase Tipo III/genética , Ratos , Ratos Wistar , Uremia/etiologia , Uremia/metabolismo , Uremia/patologia
7.
Mayo Clin Proc ; 96(8): 2185-2191, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34353472

RESUMO

Whether diagnostic timing in transthyretin (TTR) cardiac amyloidosis (CA) predisposes patients to worse outcomes is unresolved. We aimed to describe the long-term association of diagnostic timing (time from first onset of symptoms consistent with CA leading to medical contact to definitive diagnosis) with mortality in patients with wild-type TTR-CA (ATTRwt-CA). Overall, we reviewed the medical records of 160 patients seen at a tertiary care amyloidosis unit from January 1, 2016, to January 1, 2020 (median [interquartile range] follow-up, 21 [10 to 34] months), and compared them by survival. Median diagnostic timing was 4 (2 to 12) months and was longer in nonsurvivors (9 [3 to 15] vs 3 [1 to 7] months; P<.001). Patients diagnosed 6 or more months after symptom onset had higher mortality, with a median survival of 30 months (95% CI, 22 to 37 months). On Cox multivariable analysis, timing was independently associated with all-cause mortality (hazard ratio per month increase, 1.049 [95% CI, 1.017 to 1.083]) together with age at diagnosis, disease stage, New York Heart Association class, and coronary artery disease. In conclusion, diagnostic timing of ATTRwt-CA is associated with mortality. Timely diagnosis is warranted whenever "red flags" are present.


Assuntos
Neuropatias Amiloides Familiares/diagnóstico , Cardiomiopatias/metabolismo , Diagnóstico Precoce , Idoso , Idoso de 80 Anos ou mais , Cardiomiopatias/diagnóstico , Diagnóstico Diferencial , Eletrocardiografia , Feminino , Humanos , Masculino , Microscopia Imunoeletrônica , Cintilografia
8.
Nat Commun ; 12(1): 5180, 2021 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-34462437

RESUMO

Heart failure (HF) is a major cause of morbidity and mortality worldwide, highlighting an urgent need for novel treatment options, despite recent improvements. Aberrant Ca2+ handling is a key feature of HF pathophysiology. Restoring the Ca2+ regulating machinery is an attractive therapeutic strategy supported by genetic and pharmacological proof of concept studies. Here, we study antisense oligonucleotides (ASOs) as a therapeutic modality, interfering with the PLN/SERCA2a interaction by targeting Pln mRNA for downregulation in the heart of murine HF models. Mice harboring the PLN R14del pathogenic variant recapitulate the human dilated cardiomyopathy (DCM) phenotype; subcutaneous administration of PLN-ASO prevents PLN protein aggregation, cardiac dysfunction, and leads to a 3-fold increase in survival rate. In another genetic DCM mouse model, unrelated to PLN (Cspr3/Mlp-/-), PLN-ASO also reverses the HF phenotype. Finally, in rats with myocardial infarction, PLN-ASO treatment prevents progression of left ventricular dilatation and improves left ventricular contractility. Thus, our data establish that antisense inhibition of PLN is an effective strategy in preclinical models of genetic cardiomyopathy as well as ischemia driven HF.


Assuntos
Proteínas de Ligação ao Cálcio/genética , Cardiomiopatias/genética , Cardiomiopatias/terapia , Terapia Genética , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/terapia , Oligonucleotídeos Antissenso/genética , Animais , Cálcio/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Cardiomiopatias/metabolismo , Feminino , Insuficiência Cardíaca/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/metabolismo , Oligonucleotídeos Antissenso/metabolismo , Ratos , Ratos Endogâmicos Lew
9.
Int J Mol Sci ; 22(16)2021 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-34445659

RESUMO

Despite major progress in treating skeletal muscle disease associated with dystrophinopathies, cardiomyopathy is emerging as a major cause of death in people carrying dystrophin gene mutations that remain without a targeted cure even with new treatment directions and advances in modelling abilities. The reasons for the stunted progress in ameliorating dystrophin-associated cardiomyopathy (DAC) can be explained by the difficulties in detecting pathophysiological mechanisms which can also be efficiently targeted within the heart in the widest patient population. New perspectives are clearly required to effectively address the unanswered questions concerning the identification of authentic and effectual readouts of DAC occurrence and severity. A potential way forward to achieve further therapy breakthroughs lies in combining multiomic analysis with advanced preclinical precision models. This review presents the fundamental discoveries made using relevant models of DAC and how omics approaches have been incorporated to date.


Assuntos
Cardiomiopatias/patologia , Biologia Computacional/métodos , Distrofina/deficiência , Genoma , Proteoma/análise , Transcriptoma , Animais , Cardiomiopatias/etiologia , Cardiomiopatias/metabolismo , Humanos
10.
Oxid Med Cell Longev ; 2021: 2989974, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34457111

RESUMO

In the present study, we used lipopolysaccharide- (LPS-) stimulated H9C2 cardiomyocytes to investigate whether irisin treatment attenuates septic cardiomyopathy via Fundc1-related mitophagy. Fundc1 levels and mitophagy were significantly reduced in LPS-stimulated H9C2 cardiomyocytes but were significantly increased by irisin treatment. Irisin significantly increased ATP production and the activities of mitochondrial complexes I and III in the LPS-stimulated cardiomyocytes. Irisin also improved glucose metabolism and significantly reduced LPS-induced levels of reactive oxygen species by increasing the activities of antioxidant enzymes, glutathione peroxidase (GPX), and superoxide dismutase (SOD), as well as levels of reduced glutathione (GSH). TUNEL assays showed that irisin significantly reduced LPS-stimulated cardiomyocyte apoptosis by suppressing the activation of caspase-3 and caspase-9. However, the beneficial effects of irisin on oxidative stress, mitochondrial metabolism, and viability of LPS-stimulated H9C2 cardiomyocytes were abolished by silencing Fundc1. These results demonstrate that irisin abrogates mitochondrial dysfunction, oxidative stress, and apoptosis through Fundc1-related mitophagy in LPS-stimulated H9C2 cardiomyocytes. This suggests irisin is a potentially useful treatment for septic cardiomyopathy, though further investigations are necessary to confirm our findings.


Assuntos
Apoptose , Cardiomiopatias/patologia , Fibronectinas/metabolismo , Proteínas de Membrana/metabolismo , Mitocôndrias/patologia , Proteínas Mitocondriais/metabolismo , Miócitos Cardíacos/patologia , Estresse Oxidativo , Sepse/patologia , Animais , Cardiomiopatias/etiologia , Cardiomiopatias/metabolismo , Células Cultivadas , Fibronectinas/genética , Proteínas de Membrana/genética , Mitocôndrias/metabolismo , Proteínas Mitocondriais/genética , Mitofagia , Miócitos Cardíacos/metabolismo , Ratos , Sepse/etiologia , Sepse/metabolismo
11.
Redox Biol ; 46: 102038, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34416478

RESUMO

Due to the high redox activity of the mitochondrion, this organelle can suffer oxidative stress. To manage energy demands while minimizing redox stress, mitochondrial homeostasis is maintained by the dynamic processes of mitochondrial biogenesis, mitochondrial network dynamics (fusion/fission), and mitochondrial clearance by mitophagy. Friedreich's ataxia (FA) is a mitochondrial disease resulting in a fatal hypertrophic cardiomyopathy due to the deficiency of the mitochondrial protein, frataxin. Our previous studies identified defective mitochondrial iron metabolism and oxidative stress potentiating cardiac pathology in FA. However, how these factors alter mitochondrial homeostasis remains uncharacterized in FA cardiomyopathy. This investigation examined the muscle creatine kinase conditional frataxin knockout mouse, which closely mimics FA cardiomyopathy, to dissect the mechanisms of dysfunctional mitochondrial homeostasis. Dysfunction of key mitochondrial homeostatic mechanisms were elucidated in the knockout hearts relative to wild-type littermates, namely: (1) mitochondrial proliferation with condensed cristae; (2) impaired NAD+ metabolism due to perturbations in Sirt1 activity and NAD+ salvage; (3) increased mitochondrial biogenesis, fusion and fission; and (4) mitochondrial accumulation of Pink1/Parkin with increased autophagic/mitophagic flux. Immunohistochemistry of FA patients' heart confirmed significantly enhanced expression of markers of mitochondrial biogenesis, fusion/fission and autophagy. These novel findings demonstrate cardiac frataxin-deficiency results in significant changes to metabolic mechanisms critical for mitochondrial homeostasis. This mechanistic dissection provides critical insight, offering the potential for maintaining mitochondrial homeostasis in FA and potentially other cardio-degenerative diseases by implementing innovative treatments targeting mitochondrial homeostasis and NAD+ metabolism.


Assuntos
Cardiomiopatias , Ataxia de Friedreich , Doenças Mitocondriais , Animais , Cardiomiopatias/metabolismo , Ataxia de Friedreich/genética , Ataxia de Friedreich/metabolismo , Homeostase , Humanos , Ferro/metabolismo , Camundongos , Mitocôndrias/metabolismo , Doenças Mitocondriais/metabolismo , NAD/metabolismo , Oxirredução
12.
Elife ; 102021 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-34402430

RESUMO

Maternal loss of imprinting (LOI) at the H19/IGF2 locus results in biallelic IGF2 and reduced H19 expression and is associated with Beckwith--Wiedemann syndrome (BWS). We use mouse models for LOI to understand the relative importance of Igf2 and H19 mis-expression in BWS phenotypes. Here we focus on cardiovascular phenotypes and show that neonatal cardiomegaly is exclusively dependent on increased Igf2. Circulating IGF2 binds cardiomyocyte receptors to hyperactivate mTOR signaling, resulting in cellular hyperplasia and hypertrophy. These Igf2-dependent phenotypes are transient: cardiac size returns to normal once Igf2 expression is suppressed postnatally. However, reduced H19 expression is sufficient to cause progressive heart pathologies including fibrosis and reduced ventricular function. In the heart, H19 expression is primarily in endothelial cells (ECs) and regulates EC differentiation both in vivo and in vitro. Finally, we establish novel mouse models to show that cardiac phenotypes depend on H19 lncRNA interactions with Mirlet7 microRNAs.


Assuntos
Sistema Cardiovascular/metabolismo , Sistema Cardiovascular/patologia , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Animais , Síndrome de Beckwith-Wiedemann/genética , Síndrome de Beckwith-Wiedemann/metabolismo , Cardiomiopatias/metabolismo , Cardiomiopatias/patologia , Diferenciação Celular , Modelos Animais de Doenças , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Fator de Crescimento Insulin-Like II/genética , Fator de Crescimento Insulin-Like II/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/metabolismo , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Fenótipo , Transdução de Sinais
13.
Artigo em Inglês | MEDLINE | ID: mdl-34300048

RESUMO

Due to the need for continuous work, the heart uses up to 8% of the total energy expenditure. Due to the relatively low adenosine triphosphate (ATP) storage capacity, the heart's work is dependent on its production. This is possible due to the metabolic flexibility of the heart, which allows it to use numerous substrates as a source of energy. Under normal conditions, a healthy heart obtains approximately 95% of its ATP by oxidative phosphorylation in the mitochondria. The primary source of energy is fatty acid oxidation, the rest of the energy comes from the oxidation of pyruvate. A failed heart is characterised by a disturbance in these proportions, with the contribution of individual components as a source of energy depending on the aetiology and stage of heart failure. A unique form of cardiac dysfunction is sepsis-induced cardiomyopathy, characterised by a significant reduction in energy production and impairment of cardiac oxidation of both fatty acids and glucose. Metabolic disorders appear to contribute to the pathogenesis of cardiac dysfunction and therefore are a promising target for future therapies. However, as many aspects of the metabolism of the failing heart remain unexplained, this issue requires further research.


Assuntos
Cardiomiopatias , Insuficiência Cardíaca , Sepse , Trifosfato de Adenosina , Cardiomiopatias/etiologia , Cardiomiopatias/metabolismo , Metabolismo Energético , Ácidos Graxos/metabolismo , Glucose/metabolismo , Coração , Insuficiência Cardíaca/etiologia , Humanos , Miocárdio/metabolismo , Oxirredução
14.
Int J Mol Sci ; 22(14)2021 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-34298968

RESUMO

Mitochondrial dysfunction is considered the major contributor to skeletal muscle wasting in different conditions. Genetically determined neuromuscular disorders occur as a result of mutations in the structural proteins of striated muscle cells and therefore are often combined with cardiac phenotype, which most often manifests as a cardiomyopathy. The specific roles played by mitochondria and mitochondrial energetic metabolism in skeletal muscle under muscle-wasting conditions in cardiomyopathies have not yet been investigated in detail, and this aspect of genetic muscle diseases remains poorly characterized. This review will highlight dysregulation of mitochondrial representation and bioenergetics in specific skeletal muscle disorders caused by mutations that disrupt the structural and functional integrity of muscle cells.


Assuntos
Cardiomiopatias/genética , Coração/fisiopatologia , Mitocôndrias Musculares/metabolismo , Músculo Esquelético/metabolismo , Doenças Neuromusculares/genética , Animais , Cardiomiopatias/metabolismo , Cardiomiopatias/patologia , Modelos Animais de Doenças , Metabolismo Energético , Humanos , Camundongos , Mitocôndrias Cardíacas/metabolismo , Proteínas Musculares/deficiência , Proteínas Musculares/genética , Proteínas Musculares/fisiologia , Músculo Esquelético/ultraestrutura , Atrofia Muscular/metabolismo , Distrofias Musculares/genética , Distrofias Musculares/metabolismo , Distrofias Musculares/patologia , Distrofia Muscular Animal/genética , Distrofia Muscular Animal/metabolismo , Distrofia Muscular Animal/patologia , Doenças Neuromusculares/metabolismo , Doenças Neuromusculares/patologia , Fenótipo
15.
Cell Death Dis ; 12(7): 688, 2021 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-34244467

RESUMO

The insulin-like growth factor 1 receptor (IGF-1R) signaling in cardiomyocytes is implicated in physiological hypertrophy and myocardial aging. Although fibroblasts account for a small amount of the heart, they are activated when the heart is damaged to promote cardiac remodeling. However, the role of IGF-1R signaling in cardiac fibroblasts is still unknown. In this study, we investigated the roles of IGF-1 signaling during agonist-induced cardiac fibrosis and evaluated the molecular mechanisms in cultured cardiac fibroblasts. Using an experimental model of cardiac fibrosis with angiotensin II/phenylephrine (AngII/PE) infusion, we found severe interstitial fibrosis in the AngII/PE infused myofibroblast-specific IGF-1R knockout mice compared to the wild-type mice. In contrast, low-dose IGF-1 infusion markedly attenuated AngII-induced cardiac fibrosis by inhibiting fibroblast proliferation and differentiation. Mechanistically, we demonstrated that IGF-1-attenuated AngII-induced cardiac fibrosis through the Akt pathway and through suppression of rho-associated coiled-coil containing kinases (ROCK)2-mediated α-smooth muscle actin (αSMA) expression. Our study highlights a novel function of the IGF-1/IGF-1R signaling in agonist-induced cardiac fibrosis. We propose that low-dose IGF-1 may be an efficacious therapeutic avenue against cardiac fibrosis.


Assuntos
Actinas/metabolismo , Cardiomiopatias/prevenção & controle , Fibroblastos/efeitos dos fármacos , Fator de Crescimento Insulin-Like I/administração & dosagem , Miócitos Cardíacos/efeitos dos fármacos , Angiotensina II , Animais , Cardiomiopatias/induzido quimicamente , Cardiomiopatias/metabolismo , Cardiomiopatias/patologia , Proliferação de Células , Células Cultivadas , Modelos Animais de Doenças , Fibroblastos/metabolismo , Fibroblastos/patologia , Fibrose , Infusões Intravenosas , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Fenilefrina , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Receptor IGF Tipo 1/genética , Receptor IGF Tipo 1/metabolismo , Transdução de Sinais , Quinases Associadas a rho/metabolismo
16.
Biomolecules ; 11(6)2021 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-34204299

RESUMO

Alzheimer's disease (AD), the most common cause of dementia in the elderly, is a neurodegenerative disorder associated with neurovascular dysfunction and cognitive decline. While the deposition of amyloid ß peptide (Aß) and the formation of neurofibrillary tangles (NFTs) are the pathological hallmarks of AD-affected brains, the majority of cases exhibits a combination of comorbidities that ultimately lead to multi-organ failure. Of particular interest, it can be demonstrated that Aß pathology is present in the hearts of patients with AD, while the formation of NFT in the auditory system can be detected much earlier than the onset of symptoms. Progressive hearing impairment may beget social isolation and accelerate cognitive decline and increase the risk of developing dementia. The current review discusses the concept of a brain-ear-heart axis by which Aß and NFT inhibition could be achieved through targeted supplementation of neurotrophic factors to the cochlea and the brain. Such amyloid inhibition might also indirectly affect amyloid accumulation in the heart, thus reducing the risk of developing AD-associated amyloid cardiomyopathy and cardiovascular disease.


Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Amiloidose , Encéfalo/metabolismo , Cardiomiopatias , Cóclea/metabolismo , Perda Auditiva , Miocárdio/metabolismo , Polissacarídeos , Idoso , Doença de Alzheimer/metabolismo , Doença de Alzheimer/terapia , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Amiloidose/metabolismo , Amiloidose/terapia , Cardiomiopatias/metabolismo , Cardiomiopatias/terapia , Feminino , Perda Auditiva/metabolismo , Perda Auditiva/terapia , Humanos , Masculino , Polissacarídeos/antagonistas & inibidores , Polissacarídeos/metabolismo
17.
Int J Mol Sci ; 22(13)2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34281156

RESUMO

Cardiotoxicity is associated with the long-term clinical application of doxorubicin (DOX) in cancer patients. Mesenchymal stem cell-derived small extracellular vesicles (MSC-sEVs) including exosomes have been suggested for the treatment of various diseases, including ischemic diseases. However, the effects and functional mechanism of MSC-sEVs in DOX-induced cardiomyopathy have not been clarified. Here, MSC-sEVs were isolated from murine embryonic mesenchymal progenitor cell (C3H/10T1/2) culture media, using ultrafiltration. H9c2 cardiac myoblast cells were pretreated with MSC-sEVs and then exposed to DOX. For in vivo studies, male C57BL/6 mice were administered MSC-sEVs intravenously, prior to a single dose of DOX (15 mg/kg, intraperitoneal). The mice were sacrificed 14 days after DOX treatment. The results showed that MSC-sEVs protected cardiomyocytes from DOX-induced cell death. H9c2 cells treated with DOX showed downregulation of both phosphorylated Akt and survivin, whereas the treatment of MSC-sEVs recovered expression, indicating their anti-apoptotic effects. Three microRNAs (miRNAs) (miR 199a-3p, miR 424-5p, and miR 21-5p) in MSC-sEVs regulated the Akt-Sp1/p53 signaling pathway in cardiomyocytes. Among them, miR 199a-3p was involved in regulating survivin expression, which correlated with the anti-apoptotic effects of MSC-sEVs. In in vivo studies, the echocardiographic results showed that the group treated with MSC-sEVs recovered from DOX-induced cardiomyopathy, showing improvement of both the left ventricle fraction and ejection fraction. MSC-sEVs treatment also increased both survivin and B-cell lymphoma 2 expression in heart tissue compared to the DOX group. Our results demonstrate that MSC-sEVs have protective effects against DOX-induced cardiomyopathy by upregulating survivin expression, which is mediated by the regulation of Akt activation by miRNAs in MSC-sEVs. Thus, MSC-sEVs may be a novel therapy for the prevention of DOX-induced cardiomyopathy.


Assuntos
Cardiomiopatias/metabolismo , Vesículas Extracelulares/metabolismo , Células-Tronco Mesenquimais/metabolismo , Animais , Apoptose/efeitos dos fármacos , Cardiomiopatias/prevenção & controle , Cardiotoxicidade/metabolismo , Doxorrubicina/efeitos adversos , Doxorrubicina/farmacologia , Exossomos/metabolismo , Vesículas Extracelulares/fisiologia , Masculino , Células-Tronco Mesenquimais/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/fisiologia , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Transdução de Sinais/efeitos dos fármacos , Fator de Transcrição Sp1/genética , Fator de Transcrição Sp1/metabolismo , Survivina/genética , Survivina/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
18.
Molecules ; 26(12)2021 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-34207886

RESUMO

Interleukin-1ß (IL-1ß), a product of the NLRP3 inflammasome, modulates cardiac contractility and diastolic function. We proposed that OLT1177® (dapansutrile), a novel NLRP3 inhibitor, could preserve contractile reserve and diastolic function after myocardial infarction (MI). We used an experimental murine model of severe ischemic cardiomyopathy through the ligation of the left coronary artery without reperfusion, and after 7 days randomly assigned mice showing large anterior MI (>4 akinetic segments), increased left ventricular (LV) dimensions ([LVEDD] > 4.4 mm), and reduced function (LV ejection fraction < 40%) to a diet that was enriched with OLT1177® admixed with the chow in the diet at 3.75 g/kg (Group 1 [n = 10]) or 7.5 g/kg (Group 2 [n = 9]), or a standard diet as the no-treatment control group (Group 3 [n = 10]) for 9 weeks. We measured the cardiac function and contractile reserve with an isoproterenol challenge, and the diastolic function with cardiac catheterization at 10 weeks following the MI surgery. When compared with the control (Group 3), the mice treated with OLT1177 (Group 1 and 2) showed significantly greater preservation of their contractile reserve (the percent increase in the left ventricular ejection fraction [LVEF] after the isoproterenol challenge was +33 ± 11% and +40 ± 6% vs. +9 ± 7% in the standard diet; p < 0.05 and p < 0.005 for Group 1 and 2, respectively) and of diastolic function measured as the lower left ventricular end-diastolic pressure (3.2 ± 0.5 mmHg or 4.5 ± 0.5 mmHg vs. 10.0 ± 1.6 mmHg; p < 0.005 and p < 0.009 respectively). No differences were noted between the resting LVEF of the MI groups. These effects were independent of the effects on the ventricular remodeling after MI. NLRP3 inflammasome inhibition with OLT1177® can preserve ß-adrenergic responsiveness and prevent left ventricular diastolic dysfunction in a large non-reperfused anterior MI mouse model. OLT1177® could therefore be used to prevent the development of heart failure in patients with ischemic cardiomyopathy.


Assuntos
Infarto Miocárdico de Parede Anterior/tratamento farmacológico , Cardiomiopatias/tratamento farmacológico , Isquemia Miocárdica/tratamento farmacológico , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Nitrilas/farmacologia , Animais , Infarto Miocárdico de Parede Anterior/metabolismo , Infarto Miocárdico de Parede Anterior/patologia , Anti-Inflamatórios/farmacologia , Cardiomiopatias/metabolismo , Cardiomiopatias/patologia , Diástole , Modelos Animais de Doenças , Inflamassomos/antagonistas & inibidores , Masculino , Camundongos , Camundongos Endogâmicos ICR , Contração Miocárdica , Isquemia Miocárdica/metabolismo , Isquemia Miocárdica/patologia
19.
FASEB J ; 35(8): e21761, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34245616

RESUMO

Uremic cardiomyopathy is a common complication in chronic kidney disease (CKD) patients, accounting for a high mortality rate. Several mechanisms have been proposed to link CKD and cardiac alterations; however, the early cardiac modifications that occur in CKD that may trigger cardiac remodeling and dysfunction remain largely unexplored. Here, in a mouse model of CKD induced by 5/6 nephrectomy, we first analyzed the early transcriptional and inflammatory changes that occur in the heart. Five days after 5/6 nephrectomy, RNA-sequencing showed the upregulation of 54 genes in the cardiac tissue of CKD mice and the enrichment of biological processes related to immune system processes. Increased cardiac infiltration of T-CD4+ lymphocytes, myeloid cells, and macrophages during early CKD was observed. Next, since CC chemokine ligand-8 (CCL8) was one of the most upregulated genes in the heart of mice with early CKD, we investigated the effect of acute and transient CCL8 inhibition on uremic cardiomyopathy severity. An increase in CCL8 protein levels was confirmed in the heart of early CKD mice. CCL8 inhibition attenuated the early infiltration of T-CD4+ lymphocytes and macrophages to the cardiac tissue, leading to a protection against chronic cardiac fibrotic remodeling, inflammation and cardiac dysfunction induced by CKD. Altogether, our data show the occurrence of transcriptional and inflammatory changes in the heart during the early phases of CKD and identify CCL8 as a key contributor to the early cardiac inflammatory state that triggers further cardiac remodeling and dysfunction in uremic cardiomyopathy.


Assuntos
Cardiomiopatias/metabolismo , Quimiocina CCL8/biossíntese , Miocárdio/metabolismo , Insuficiência Renal Crônica/metabolismo , Regulação para Cima , Uremia/metabolismo , Animais , Cardiomiopatias/patologia , Inflamação/metabolismo , Inflamação/patologia , Masculino , Camundongos , Miocárdio/patologia , Insuficiência Renal Crônica/patologia , Uremia/patologia
20.
Am J Physiol Cell Physiol ; 321(3): C519-C534, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34319827

RESUMO

Mitochondria are recognized as signaling organelles, because under stress, mitochondria can trigger various signaling pathways to coordinate the cell's response. The specific pathway(s) engaged by mitochondria in response to mitochondrial energy defects in vivo and in high-energy tissues like the heart are not fully understood. Here, we investigated cardiac pathways activated in response to mitochondrial energy dysfunction by studying mice with cardiomyocyte-specific loss of the mitochondrial phosphate carrier (SLC25A3), an established model that develops cardiomyopathy as a result of defective mitochondrial ATP synthesis. Mitochondrial energy dysfunction induced a striking pattern of acylome remodeling, with significantly increased posttranslational acetylation and malonylation. Mass spectrometry-based proteomics further revealed that energy dysfunction-induced remodeling of the acetylome and malonylome preferentially impacts mitochondrial proteins. Acetylation and malonylation modified a highly interconnected interactome of mitochondrial proteins, and both modifications were present on the enzyme isocitrate dehydrogenase 2 (IDH2). Intriguingly, IDH2 activity was enhanced in SLC25A3-deleted mitochondria, and further study of IDH2 sites targeted by both acetylation and malonylation revealed that these modifications can have site-specific and distinct functional effects. Finally, we uncovered a novel cross talk between the two modifications, whereby mitochondrial energy dysfunction-induced acetylation of sirtuin 5 (SIRT5), inhibited its function. Because SIRT5 is a mitochondrial deacylase with demalonylase activity, this finding suggests that acetylation can modulate the malonylome. Together, our results position acylations as an arm of the mitochondrial response to energy dysfunction and suggest a mechanism by which focal disruption to the energy production machinery can have an expanded impact on global mitochondrial function.


Assuntos
Cardiomiopatias/genética , Proteínas de Transporte de Cátions/genética , Isocitrato Desidrogenase/genética , Mitocôndrias Cardíacas/metabolismo , Proteínas Mitocondriais/genética , Miócitos Cardíacos/metabolismo , Proteínas de Transporte de Fosfato/genética , Processamento de Proteína Pós-Traducional , Proteínas Carreadoras de Solutos/genética , Acetilação , Animais , Transporte Biológico , Cardiomiopatias/metabolismo , Cardiomiopatias/patologia , Proteínas de Transporte de Cátions/deficiência , Metabolismo Energético , Feminino , Redes Reguladoras de Genes , Isocitrato Desidrogenase/metabolismo , Masculino , Malonatos/metabolismo , Camundongos , Camundongos Knockout , Mitocôndrias Cardíacas/genética , Mitocôndrias Cardíacas/patologia , Proteínas Mitocondriais/deficiência , Modelos Moleculares , Miocárdio/metabolismo , Miocárdio/patologia , Miócitos Cardíacos/patologia , Proteínas de Transporte de Fosfato/deficiência , Fosfatos , Conformação Proteica , Mapeamento de Interação de Proteínas , Transdução de Sinais , Sirtuínas/genética , Sirtuínas/metabolismo , Proteínas Carreadoras de Solutos/deficiência
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