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Mechanisms underlying mechanical overload-induced skeletal muscle hypertrophy have been extensively researched since the landmark report by Morpurgo (1897) of "work-induced hypertrophy" in dogs that were treadmill trained. Much of the preclinical rodent and human resistance training research to date supports that involved mechanisms include enhanced mammalian/mechanistic target of rapamycin complex 1 (mTORC1) signaling, an expansion in translational capacity through ribosome biogenesis, increased satellite cell abundance and myonuclear accretion, and postexercise elevations in muscle protein synthesis rates. However, several lines of past and emerging evidence suggest that additional mechanisms that feed into or are independent of these processes are also involved. This review first provides a historical account of how mechanistic research into skeletal muscle hypertrophy has progressed. A comprehensive list of mechanisms associated with skeletal muscle hypertrophy is then outlined, and areas of disagreement involving these mechanisms are presented. Finally, future research directions involving many of the discussed mechanisms are proposed.
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Músculo Esquelético , Transducción de Señal , Humanos , Animales , Perros , Músculo Esquelético/metabolismo , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Biosíntesis de Proteínas , Hipertrofia/metabolismo , Mamíferos/metabolismoRESUMEN
Older adults commonly end up on many medications. Deprescribing is an important part of individualizing care for older adults. It is an opportunity to discuss treatment options and revisit medications that may not have been reassessed in many years. A large evidence base exists in the field, suggesting that deprescribing is feasible and safe, though questions remain about the potential clinical benefits. Deprescribing research faces a myriad of challenges, such as identifying and employing the optimal outcome measures. Further, there is uncertainty about which deprescribing approaches are likely to be most effective and in what contexts. Evidence on barriers and facilitators to deprescribing has underscored how deprescribing in routine clinical practice can be complex and challenging. Thus, finding practical, sustainable ways to implement deprescribing is a priority for future research in the field.
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Deprescripciones , Humanos , Anciano , PolifarmaciaRESUMEN
Hepcidin, the iron-regulatory hormone, determines plasma iron concentrations and total body iron content. Hepcidin, secreted by hepatocytes, functions by controlling the activity of the cellular iron exporter ferroportin, which delivers iron to plasma from intestinal iron absorption and from iron stores. Hepcidin concentration in plasma is increased by iron loading and inflammation and is suppressed by erythropoietic stimulation and during pregnancy. Hepcidin deficiency causes iron overload in hemochromatosis and anemias with ineffective erythropoiesis. Hepcidin excess causes iron-restrictive anemias including anemia of inflammation. The development of hepcidin diagnostics and therapeutic agonists and antagonists should improve the treatment of iron disorders.
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Anemia , Hemocromatosis , Humanos , Hierro , Hepcidinas , InflamaciónRESUMEN
Brown adipose tissue (BAT) is correlated to cardiovascular health in rodents and humans, but the physiological role of BAT in the initial cardiac remodeling at the onset of stress is unknown. Activation of BAT via 48 h cold (16°C) in mice following transverse aortic constriction (TAC) reduced cardiac gene expression for LCFA uptake and oxidation in male mice and accelerated the onset of cardiac metabolic remodeling, with an early isoform shift of carnitine palmitoyltransferase 1 (CPT1) toward increased CPT1a, reduced entry of long chain fatty acid (LCFA) into oxidative metabolism (0.59 ± 0.02 vs. 0.72 ± 0.02 in RT TAC hearts, p < .05) and increased carbohydrate oxidation with altered glucose transporter content. BAT activation with TAC reduced early hypertrophic expression of ß-MHC by 61% versus RT-TAC and reduced pro-fibrotic TGF-ß1 and COL3α1 expression. While cardiac natriuretic peptide expression was yet to increase at only 3 days TAC, Nppa and Nppb expression were elevated in Cold TAC versus RT TAC hearts 2.7- and 2.4-fold, respectively. Eliminating BAT thermogenic activation with UCP1 KO mice eliminated differences between Cold TAC and RT TAC hearts, confirming effects of BAT activation rather than autonomous cardiac responses to cold. Female responses to BAT activation were blunted, with limited UCP1 changes with cold, partly due to already activated BAT in females at RT compared to thermoneutrality. These data reveal a previously unknown physiological mechanism of UCP1-dependent BAT activation in attenuating early cardiac hypertrophic and profibrotic signaling and accelerating remodeled metabolic activity in the heart at the onset of cardiac stress.
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Tejido Adiposo Pardo , Fibrosis , Proteína Desacopladora 1 , Animales , Tejido Adiposo Pardo/metabolismo , Ratones , Masculino , Proteína Desacopladora 1/metabolismo , Fibrosis/metabolismo , Carnitina O-Palmitoiltransferasa/metabolismo , Carnitina O-Palmitoiltransferasa/genética , Ratones Endogámicos C57BL , Cardiomegalia/metabolismo , Cardiomegalia/patología , Miocardio/metabolismo , Miocardio/patología , Estrés Fisiológico , Remodelación Ventricular/fisiología , Ratones Noqueados , FríoRESUMEN
Iron-sulfur (Fe-S) clusters (ISCs) are ubiquitous cofactors essential to numerous fundamental cellular processes. Assembly of ISCs and their insertion into apoproteins involves the function of complex cellular machineries that operate in parallel in the mitochondrial and cytosolic/nuclear compartments of mammalian cells. The spectrum of diseases caused by inherited defects in genes that encode the Fe-S assembly proteins has recently expanded to include multiple rare human diseases, which manifest distinctive combinations and severities of global and tissue-specific impairments. In this review, we provide an overview of our understanding of ISC biogenesis in mammalian cells, discuss recent work that has shed light on the molecular interactions that govern ISC assembly, and focus on human diseases caused by failures of the biogenesis pathway.
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Proteínas Hierro-Azufre/metabolismo , Citosol/metabolismo , ADN/metabolismo , Mitocondrias/metabolismo , ARN/metabolismoRESUMEN
The heart has the ability to detect and respond to changes in mechanical load through a process called mechanotransduction. In this study, we focused on investigating the role of the cardiac-specific N2B element within the spring region of titin, which has been proposed to function as a mechanosensor. To assess its significance, we conducted experiments using N2B knockout (KO) mice and wildtype (WT) mice, subjecting them to three different conditions: 1) cardiac pressure overload induced by transverse aortic constriction (TAC), 2) volume overload caused by aortocaval fistula (ACF), and 3) exercise-induced hypertrophy through swimming. Under conditions of pressure overload (TAC), both genotypes exhibited similar hypertrophic responses. In contrast, WT mice displayed robust left ventricular hypertrophy after one week of volume overload (ACF), while the KO mice failed to undergo hypertrophy and experienced a high mortality rate. Similarly, swim exercise-induced hypertrophy was significantly reduced in the KO mice. RNA-Seq analysis revealed an abnormal ß-adrenergic response to volume overload in the KO mice, as well as a diminished response to isoproterenol-induced hypertrophy. Because it is known that the N2B element interacts with the four-and-a-half LIM domains 1 and 2 (FHL1 and FHL2) proteins, both of which have been associated with mechanotransduction, we evaluated these proteins. Interestingly, while volume-overload resulted in FHL1 protein expression levels that were comparable between KO and WT mice, FHL2 protein levels were reduced by over 90% in the KO mice compared to WT. This suggests that in response to volume overload, FHL2 might act as a signaling mediator between the N2B element and downstream signaling pathways. Overall, our study highlights the importance of the N2B element in mechanosensing during volume overload, both in physiological and pathological settings.
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Conectina , Mecanotransducción Celular , Ratones Noqueados , Animales , Ratones , Conectina/metabolismo , Conectina/genética , Hipertrofia Ventricular Izquierda/metabolismo , Hipertrofia Ventricular Izquierda/fisiopatología , Hipertrofia Ventricular Izquierda/genética , Miocardio/metabolismo , Miocardio/patología , Masculino , Condicionamiento Físico Animal , Proteínas con Homeodominio LIM/metabolismo , Proteínas con Homeodominio LIM/genética , Modelos Animales de Enfermedad , Proteínas Musculares/metabolismo , Proteínas Musculares/genética , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Proteínas con Dominio LIM/metabolismo , Proteínas con Dominio LIM/genética , Proteínas Quinasas , Péptidos y Proteínas de Señalización IntracelularRESUMEN
Arrestin domain containing 2 and 3 (Arrdc2/3) are genes whose mRNA contents are decreased in young skeletal muscle following mechanical overload. Arrdc3 is linked to the regulation of signaling pathways in nonmuscle cells that could influence skeletal muscle size. Despite a similar amino acid sequence, Arrdc2 function remains undefined. The purpose of this study was to further explore the relationship of Arrdc2/Arrdc3 expression with changes in mechanical load in young and aged muscle and define the effect of Arrdc2/3 expression on C2C12 myotube diameter. In young and aged mice, mechanical load was decreased using hindlimb suspension whereas mechanical load was increased by reloading previously unloaded muscle or inducing high-force contractions. Arrdc2 and Arrdc3 mRNAs were overexpressed in C2C12 myotubes using adenoviruses. Myotube diameter was determined 48-h posttransfection, and RNA sequencing was performed on those samples. Arrdc2 and Arrdc3 mRNA content was higher in the unloaded muscle within 1 day of disuse and remained higher up through 10 days. The induction of Arrdc2 mRNA was more pronounced in aged muscle than young muscle in response to unloading. Reloading previously unloaded muscle of young and aged mice restored Arrdc2 and Arrdc3 levels to ambulatory levels. Increasing mechanical load beyond normal ambulatory levels lowered Arrdc2 mRNA, but not Arrdc3 mRNA, in young and aged muscle. Arrdc2 overexpression only was sufficient to lower myotube diameter in C2C12 cells in part by altering the transcriptome favoring muscle atrophy. These data are consistent with Arrdc2 contributing to disuse atrophy, particularly in aged muscle.NEW & NOTEWORTHY We establish Arrdc2 as a novel mechanosensitive gene highly induced in response to mechanical unloading, particularly in aged muscle. Arrdc2 induction in C2C12 myotubes is sufficient to produce thinner myotubes and a transcriptional landscape consistent with muscle atrophy and disuse.
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Arrestinas , Fibras Musculares Esqueléticas , Trastornos Musculares Atróficos , Animales , Ratones , Envejecimiento/genética , Arrestinas/genética , Arrestinas/metabolismo , Músculo Esquelético , Atrofia Muscular/genética , ARN Mensajero/genéticaRESUMEN
Age-related macular degeneration (AMD) is characterized by the degenerative senescence in the retinal pigment epithelium (RPE) and photoreceptors, which is accompanied by the accumulation of iron ions in the aging retina. However, current models of acute oxidative stress are still insufficient to simulate the gradual progression of AMD. To address this, we established chronic injury models by exposing the aRPE-19 cells, 661W cells, and mouse retina to iron ion overload over time. Investigations at the levels of cell biology and molecular biology were performed. It was demonstrated that long-term treatment of excessive iron ions induced senescence-like morphological changes, decreased cell proliferation, and impaired mitochondrial function, contributing to apoptosis. Activation of the mitogen-activated protein kinase (MAPK) pathway and the downstream molecules were confirmed both in the aRPE-19 and 661W cells. Furthermore, iron ion overload resulted in dry AMD-like lesions and decreased visual function in the mouse retina. These findings suggest that chronic exposure to overloading iron ions plays a significant role in the pathogenesis of retinopathy and provide a potential model for future studies on AMD.NEW & NOTEWORTHY To explore the possibility of constructing reliable research carriers on age-related macular degeneration (AMD), iron ion overload was applied to establish models in vitro and in vivo. Subsequent investigations into cellular physiology and molecular biology confirmed the presence of senescence in these models. Through this study, we hope to provide a better option of feasible methods for future researches into AMD.
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Modelos Animales de Enfermedad , Hierro , Degeneración Macular , Epitelio Pigmentado de la Retina , Animales , Humanos , Degeneración Macular/metabolismo , Degeneración Macular/patología , Degeneración Macular/genética , Epitelio Pigmentado de la Retina/metabolismo , Epitelio Pigmentado de la Retina/patología , Ratones , Hierro/metabolismo , Ratones Endogámicos C57BL , Apoptosis , Estrés Oxidativo , Línea Celular , Senescencia Celular , Sobrecarga de Hierro/metabolismo , Sobrecarga de Hierro/patología , Proliferación Celular , Retina/metabolismo , Retina/patología , Mitocondrias/metabolismo , Mitocondrias/patologíaRESUMEN
Pulmonary hypertension is a group of diseases characterized by elevated pulmonary artery pressure and pulmonary vascular resistance with significant morbidity and mortality. The most prevalent type is pulmonary hypertension secondary to left heart disease (PH-LHD). The available experimental models of PH-LHD use partial pulmonary clamping by technically nontrivial open chest surgery with lengthy recovery. We present a simple model in which reduction of the cross-sectional area of the ascending aorta is achieved not by external clamping, but by partial intravascular obstruction without opening the chest. In anesthetized rats, a blind polyethylene tubing was advanced from the right carotid artery to just above the aortic valve. The procedure is quick and easy to learn. Three weeks after the procedure, left heart pressure overload was confirmed by measuring left ventricular end diastolic pressure by puncture (1.3±0.2 vs. 0.4±0.3 mmHg in controls, mean±sd, P<0.0001). The presence of pulmonary hypertension was documented by measuring pulmonary artery pressure by catheterization (22.3±2.3 vs. 16.9±2.7 mmHg, P=0.0282) and by detecting right ventricular hypertrophy and increased muscularization of peripheral pulmonary vessels. Contributions of precapillary vascular segment and of vasoconstriction to the increased pulmonary vascular resistance were demonstrated, respectively, by arterial occlusion technique and by normalization of resistance by a vasodilator, sodium nitroprusside, in isolated lungs. These changes were comparable, but not additive, to those induced by an established pulmonary hypertension model, chronic hypoxic exposure. Intravascular partial aortic obstruction offers an easy model of pulmonary hypertension induced by left heart disease that has a vasoconstrictor and precapillary component.
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Having a multitude of choices can be advantageous, yet an abundance of options can be detrimental to the decision-making process. Based on existing research, the present study combined electroencephalogram and self-reported methodologies to investigate the neural mechanisms underlying the phenomenon of choice overload. Behavioural data suggested that an increase in the number of options led to negative evaluations and avoidance of choice tendencies, even in the absence of time pressure. Event-related potential results indicated that the large choice set interfered with the early visual process, as evidenced by the small P1 amplitude, and failed to attract more attentional resources in the early stage, as evidenced by the small amplitude of P2 and N2. However, the LPC amplitude was increased in the late stage, suggesting greater investment of attentional resources and higher emotional arousal. Multivariate pattern analysis revealed that the difference between small and large choice set began at around 120 ms, and the early and late stages were characterised by opposite activation patterns. This suggested that too many options interfered with early processing and necessitate continued processing at a later stage. In summary, both behavioural and event-related potential (ERP) results confirm the choice overload effect, and it was observed that individuals tend to subjectively exaggerate the choice overload effect.
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Conducta de Elección , Electroencefalografía , Potenciales Evocados , Humanos , Masculino , Electroencefalografía/métodos , Femenino , Conducta de Elección/fisiología , Potenciales Evocados/fisiología , Adulto Joven , Adulto , Atención/fisiología , Encéfalo/fisiologíaRESUMEN
Ferroptosis has been conceptualized as a novel cell death modality distinct from apoptosis, necroptosis, pyroptosis and autophagic cell death. The sensitivity of cellular ferroptosis is regulated at multiple layers, including polyunsaturated fatty acid metabolism, glutathione-GPX4 axis, iron homeostasis, mitochondria and other parallel pathways. In addition, microRNAs (miRNAs) have been implicated in modulating ferroptosis susceptibility through targeting different players involved in the execution or avoidance of ferroptosis. A growing body of evidence pinpoints the deregulation of miRNA-regulated ferroptosis as a critical factor in the development and progression of various pathophysiological conditions related to iron overload. The revelation of mechanisms of miRNA-dependent ferroptosis provides novel insights into the etiology of diseases and offers opportunities for therapeutic intervention. In this review, we discuss the interplay of emerging miRNA regulators and ferroptosis players under different pathological conditions, such as cancers, ischemia/reperfusion, neurodegenerative diseases, acute kidney injury and cardiomyopathy. We emphasize on the relevance of miRNA-regulated ferroptosis to disease progression and the targetability for therapeutic interventions.
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Lesión Renal Aguda , Ferroptosis , Sobrecarga de Hierro , MicroARNs , Humanos , Apoptosis , Ferroptosis/genética , Sobrecarga de Hierro/genética , MicroARNs/genéticaRESUMEN
Iron overload from repeated transfusions has a negative impact on cardiac function, and iron chelation therapy may help prevent cardiac dysfunction in transfusion-dependent patients with myelodysplastic syndromes (MDS). TELESTO (NCT00940602) was a prospective, placebo-controlled, randomised study to evaluate the iron chelator deferasirox in patients with low- or intermediate-1-risk MDS and iron overload. Echocardiographic parameters were collected at screening and during treatment. Patients receiving deferasirox experienced a significant decrease in the composite risk of hospitalisation for congestive heart failure (CHF) or worsening of cardiac function (HR = 0.23; 95% CI: 0.05, 0.99; nominal p = 0.0322) versus placebo. No significant differences between the arms were found in left ventricular ejection fraction, ventricular diameter and mass or pulmonary artery pressure. The absolute number of events was low, but the enrolled patients were younger than average for patients with MDS, with no serious cardiac comorbidities and a modest cardiovascular risk profile. These results support the effectiveness of deferasirox in preventing cardiac damage caused by iron overload in this patient population. Identification of patients developing CHF is challenging due to the lack of distinctive echocardiographic features. The treatment of iron overload may be important to prevent cardiac dysfunction in these patients, even those with moderate CHF risk.
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Deferasirox , Quelantes del Hierro , Sobrecarga de Hierro , Síndromes Mielodisplásicos , Humanos , Deferasirox/uso terapéutico , Síndromes Mielodisplásicos/terapia , Síndromes Mielodisplásicos/tratamiento farmacológico , Síndromes Mielodisplásicos/complicaciones , Masculino , Femenino , Quelantes del Hierro/uso terapéutico , Persona de Mediana Edad , Anciano , Sobrecarga de Hierro/etiología , Sobrecarga de Hierro/tratamiento farmacológico , Estudios Prospectivos , Benzoatos/uso terapéutico , Benzoatos/efectos adversos , Insuficiencia Cardíaca/etiología , Reacción a la Transfusión/etiología , Ecocardiografía , Adulto , Anciano de 80 o más Años , Triazoles/uso terapéutico , Triazoles/efectos adversos , Transfusión SanguíneaRESUMEN
Optimal targets for red blood cell exchange (RCE) are not well defined in the chronic management of sickle cell disease. We analysed transfusion requirements and iron-related outcomes in 101 patients on chronic RCE with a post-procedure haematocrit (Ht) targeted at 34%, which is higher than typically used. A majority were of HbSS/HbSß0 genotype (n = 72) and enrolled for neurological complications (n = 53). Fifty patients had a positive Ht balance with RCE (>2% mean increase from pre-procedure level), while 43 patients maintained a neutral balance. The first group required fewer red blood cell units/year (65 vs. 80, p < 0.001), but a significant proportion were iron overloaded based on R2* with liver MRI (32% vs. none performed) and prescription of iron chelation (52% vs. 0%, p < 0.001, after a median of 19 months). The second group was more likely to receive iron supplementation (6% vs. 56%, p < 0.001). Chronic automated RCE with a post-procedure Ht targeted at 34% is not iron-neutral, and personalized Ht goals may be more appropriate in certain settings. This higher target should be compared with a lower Ht strategy in individuals with similar baseline red cell volumes to assess iron homeostasis and blood product requirements.
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We compared serum anti-Mullerian hormone (AMH) levels in women with sickle cell disease (SCD) (n = 152) to those of Black comparison women (n = 128) between the ages of 20 and 45 years and evaluated the impact of hydroxyurea (HU) and iron overload on ovarian reserve in those with SCD. SCD treatment was abstracted from medical records. Linear regression models were fit to examine the relationship between log(AMH) and SCD, adjusting for age. The analysis was repeated to account for HU use (current, previous, never) and iron overload (ferritin ≥1000 ng/mL vs. <1000 ng/mL). AMH estimates among women with SCD were lower than those among comparison women (2.23, 95% confidence interval [CI] 1.80-2.76 vs. 4.12, 95% CI 3.11-5.45, respectively). Women with SCD who were currently using HU had 63% lower (95% CI 43-76) AMH values than comparison women; those with SCD with prior or no HU use also had lower AMH estimates than comparison women, but the difference was less pronounced. There were no differences in predicted AMH values among women with SCD for those with and without iron overload. Women with SCD and low AMH may have a shorter reproductive window and may benefit from referral to a reproductive specialist.
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Anemia de Células Falciformes , Hormona Antimülleriana , Hidroxiurea , Reserva Ovárica , Humanos , Femenino , Anemia de Células Falciformes/tratamiento farmacológico , Anemia de Células Falciformes/sangre , Anemia de Células Falciformes/complicaciones , Adulto , Hormona Antimülleriana/sangre , Hidroxiurea/uso terapéutico , Persona de Mediana Edad , Sobrecarga de Hierro/etiología , Sobrecarga de Hierro/tratamiento farmacológico , Sobrecarga de Hierro/sangre , Adulto Joven , Negro o AfroamericanoRESUMEN
Pyruvate kinase (PK) deficiency, a rare, congenital haemolytic anaemia caused by mutations in the PKLR gene, is associated with many clinical manifestations, but the full disease burden has yet to be characterised. The Peak Registry (NCT03481738) is an observational, longitudinal registry of adult and paediatric patients with PK deficiency. Here, we described comorbidities and complications in these patients by age at most recent visit and PKLR genotype. As of 13 May 2022, 241 patients were included in the analysis. In total, 48.3% had undergone splenectomy and 50.5% had received chelation therapy. History of iron overload (before enrolment/during follow-up) was common (52.5%), even in never-transfused patients (20.7%). Neonatal complications and symptoms included jaundice, splenomegaly and hepatomegaly, with treatment interventions required in 41.5%. Among adults, osteopenia/osteoporosis occurred in 19.0% and pulmonary hypertension in 6.7%, with median onset ages of 37, 33 and 22 years, respectively. Biliary events and bone health problems were common across PKLR genotypes. Among 11 patients who had thromboembolic events, eight had undergone prior splenectomy. Patients with PK deficiency may have many complications, which can occur early in and throughout life. Awareness of their high disease burden may help clinicians better provide appropriate monitoring and management of these patients.
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Anemia Hemolítica Congénita no Esferocítica , Piruvato Quinasa , Errores Innatos del Metabolismo del Piruvato , Sistema de Registros , Humanos , Piruvato Quinasa/deficiencia , Piruvato Quinasa/genética , Masculino , Femenino , Adulto , Niño , Anemia Hemolítica Congénita no Esferocítica/genética , Anemia Hemolítica Congénita no Esferocítica/epidemiología , Errores Innatos del Metabolismo del Piruvato/genética , Errores Innatos del Metabolismo del Piruvato/epidemiología , Adolescente , Preescolar , Lactante , Comorbilidad , Persona de Mediana Edad , Esplenectomía , Adulto Joven , Hipertensión Pulmonar/etiología , Hipertensión Pulmonar/genética , Hipertensión Pulmonar/epidemiología , Sobrecarga de Hierro/etiología , Sobrecarga de Hierro/epidemiología , Enfermedades Óseas Metabólicas/etiología , Enfermedades Óseas Metabólicas/epidemiología , Recién NacidoRESUMEN
Cardiac fibroblasts play a pivotal role in maintaining heart homeostasis by depositing extracellular matrix (ECM) to provide structural support for the myocardium, vasculature, and neuronal network and by contributing to essential physiological processes. In response to injury such as myocardial infarction or pressure overload, fibroblasts become activated, leading to increased ECM production that can ultimately drive left ventricular remodeling and progress to heart failure. Recently, the AJP-Heart and Circulatory Physiology issued a call for papers on cardiac fibroblasts that yielded articles with topics spanning fibroblast physiology, technical considerations, signaling pathways, and interactions with other cell types. This mini-review summarizes those articles and places the new findings in the context of what is currently known for cardiac fibroblasts and what future directions remain.
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Cardiac hypertrophy is a common feature in several cardiomyopathies. We previously reported that loss of ADAM15 (disintegrin and metalloproteinase 15) worsened cardiac hypertrophy and dilated cardiomyopathy following cardiac pressure overload. Here, we investigated the impact of ADAM15 loss in female mice following cardiac pressure overload induced by transverse aortic constriction (TAC). Female Adam15-/- mice developed the same degree of cardiac hypertrophy, dilation, and dysfunction as the parallel female wild-type (WT) mice at 6 wk post-TAC. To determine if this is due to the protective effects of estrogen, which could mask the negative impact of Adam15 loss, WT and Adam15-/- mice underwent ovariectomy (OVx) 2 wk before TAC. Cardiac structure and function analyses were performed at 6 wk post-TAC. OVx similarly impacted females of both genotypes post-TAC. Calcineurin (Cn) activity was increased post-OVx-TAC, and more in Adam15-/- mice; however, this increase was not reflected in the total-to-phospho-NFAT levels. Integrin-α7 expression, which was upstream of Cn activation in male Adam15-/- -TAC mice, remained unchanged in female mice. However, activation of the mitogen-activated protein kinases (ERK, JNK, P38) was greater in Adam15-/--OVx-TAC than in WT-OVx-TAC mice. In addition, ADAM15 protein levels were significantly increased post-TAC in male but not in female WT mice. Myocardial fibrosis was comparable in non-OVx WT-TAC and Adam15-/- -TAC mice. OVx increased the perivascular fibrosis more in Adam15-/- compared with WT mice post-TAC. Our data demonstrate that loss of ovarian hormones did not fully replicate the male phenotype in the female Adam15-/- mice post-TAC. As ADAM15 levels were increased in males but not in females post-TAC, it is plausible that ADAM15 does not play a prominent role in post-TAC events in female mice. Our findings highlight the significance of factors other than sex hormones in mediating cardiomyopathies in females, which require a more thorough understanding.NEW & NOTEWORTHY Loss of ADAM15 in female mice, unlike the male mice, does not worsen the cardiomyopathy following cardiac pressure overload. Ovariectomy does not worsen the post-TAC cardiomyopathy in female Adam15-/- mice compared with female WT mice. Lack of deleterious impact of Adam15 deficiency in female mice is not because of the protective effects of ovarian hormones but could be due to a less prominent role of ADAM15 in cardiac response to post-TAC remodeling in female mice.
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Proteínas ADAM , Proteínas de la Membrana , Ratones Noqueados , Ovariectomía , Animales , Femenino , Proteínas ADAM/genética , Proteínas ADAM/metabolismo , Proteínas ADAM/deficiencia , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Masculino , Ratones Endogámicos C57BL , Calcineurina/metabolismo , Calcineurina/genética , Modelos Animales de Enfermedad , Ratones , Remodelación Ventricular , Factores de Transcripción NFATC/metabolismo , Factores de Transcripción NFATC/genética , Miocardio/metabolismo , Miocardio/patología , Fibrosis , Cardiomiopatías/fisiopatología , Cardiomiopatías/metabolismo , Cardiomiopatías/genética , Cardiomiopatías/etiología , Cardiomiopatías/patología , Factores Sexuales , Transducción de Señal , Función Ventricular Izquierda , Hipertrofia Ventricular Izquierda/fisiopatología , Hipertrofia Ventricular Izquierda/metabolismo , Hipertrofia Ventricular Izquierda/genética , Hipertrofia Ventricular Izquierda/patología , Hipertrofia Ventricular Izquierda/etiologíaRESUMEN
Approximately 50% of Americans have hypertension, which significantly increases the risk of heart failure. In response to increased peripheral resistance in hypertension, intensified mechanical stretch in the myocardium induces cardiomyocyte hypertrophy and fibroblast activation to withstand increased pressure overload. This changes the structure and function of the heart, leading to pathological cardiac remodeling and eventual progression to heart failure. In the presence of hypertensive stimuli, cardiac fibroblasts activate and differentiate to myofibroblast phenotype capable of enhanced extracellular matrix secretion in coordination with other cell types, mainly cardiomyocytes. Both systemic and local renin-angiotensin-aldosterone system activation lead to increased angiotensin II stimulation of fibroblasts. Angiotensin II directly activates fibrotic signaling such as transforming growth factor ß/SMAD and mitogen-activated protein kinase (MAPK) signaling to produce extracellular matrix comprised of collagens and matricellular proteins. With the advent of single-cell RNA sequencing techniques, heterogeneity in fibroblast populations has been identified in the left ventricle in models of hypertension and pressure overload. The various clusters of fibroblasts reveal a range of phenotypes and activation states. Select antihypertensive therapies have been shown to be effective in limiting fibrosis, with some having direct actions on cardiac fibroblasts. The present review focuses on the fibroblast-specific changes that occur in response to hypertension and pressure overload, the knowledge gained from single-cell analyses, and the effect of antihypertensive therapies. Understanding the dynamics of hypertensive fibroblast populations and their similarities and differences by sex is crucial for the advent of new targets and personalized medicine.
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Insuficiencia Cardíaca , Hipertensión , Humanos , Antihipertensivos/farmacología , Angiotensina II/farmacología , Miocardio/metabolismo , Hipertensión/metabolismo , Fibroblastos/metabolismo , FibrosisRESUMEN
Pressure overload-induced hypertrophy compromises cardiac stretch-induced compliance (SIC) after acute volume overload (AVO). We hypothesized that SIC could be enhanced by physiological hypertrophy induced by pregnancy's chronic volume overload. This study evaluated SIC-cardiac adaptation in pregnant women with or without cardiovascular risk (CVR) factors. Thirty-seven women (1st trimester, 1stT) and a separate group of 31 (3rd trimester, 3rdT) women [healthy or with CVR factors (obesity and/or hypertension and/or with gestational diabetes)] underwent echocardiography determination of left ventricular end-diastolic volume (LVEDV) and E/e' before (T0), immediately after (T1), and 15 min after (T2; SIC) AVO induced by passive leg elevation. Blood samples for NT-proBNP quantification were collected before and after the AVO. Acute leg elevation significantly increased inferior vena cava diameter and stroke volume from T0 to T1 in both 1stT and 3rdT, confirming AVO. LVEDV and E/e' also increased immediately after AVO (T1) in both 1stT and 3rdT. SIC adaptation (T2, 15 min after AVO) significantly decreased E/e' in both trimesters, with additional expansion of LVEDV only in the 1stT. NT-pro-BNP increased slightly after AVO but only in the 1stT. CVR factors, but not parity or age, significantly impacted SIC cardiac adaptation. A distinct functional response to SIC was observed between 1stT and 3rdT, which was influenced by CVR factors. The LV of 3rdT pregnant women was hypertrophied, showing a structural limitation to dilate with AVO, whereas the lower LV filling pressure values suggest increased diastolic compliance.NEW & NOTEWORTHY The sudden increase of volume overload triggers an acute myocardial stretch characterized by an immediate rise in contractility by the Frank-Starling mechanism, followed by a progressive increase known as the slow force response. The present study is the first to characterize echocardiographically the stretch-induced compliance (SIC) mechanism in the context of physiological hypertrophy induced by pregnancy. A distinct functional adaptation to SIC was observed between first and third trimesters, which was influenced by cardiovascular risk factors.
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Adaptación Fisiológica , Factores de Riesgo de Enfermedad Cardiaca , Humanos , Femenino , Embarazo , Adulto , Función Ventricular Izquierda , Cardiomegalia/fisiopatología , Cardiomegalia/diagnóstico por imagen , Cardiomegalia/etiología , Péptido Natriurético Encefálico/sangre , Fragmentos de Péptidos/sangre , Complicaciones Cardiovasculares del Embarazo/fisiopatología , Complicaciones Cardiovasculares del Embarazo/diagnóstico por imagen , Complicaciones Cardiovasculares del Embarazo/sangre , Volumen Sistólico , Tercer Trimestre del Embarazo , Diabetes Gestacional/fisiopatología , Adaptabilidad , Primer Trimestre del Embarazo , Obesidad/fisiopatología , Obesidad/complicaciones , Factores de RiesgoRESUMEN
Piezo1 channels are activated by mechanical stress and play a significant role in cardiac hypertrophy and fibrosis. However, the molecular mechanisms underlying Piezo1 activation on the cell membrane following pressure overload remain unclear. Caveolae are known to mitigate mechanical forces and regulate Piezo1 function. Therefore, this study aimed to investigate the interaction between caveolae and Piezo1 in the development of pressure overload-induced cardiac remodeling. We observed reduced colocalization between Piezo1 and Caveolin-3 in hypertrophic cardiomyocytes following abdominal aortic constriction and Angiotensin-II treatment, accompanied by increased Piezo1 function and expression. Furthermore, enhanced Piezo1 function was also noted upon caveolae disruption using methyl-beta-cyclodextrin (mßCD). Thus, our findings suggested that pressure overload led to Piezo1 translocation from caveolae, thereby augmenting its function and expression, which may contribute to cardiac remodeling.