RESUMEN
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
Heart failure (HF) remains the leading cause of morbidity and mortality in the developed world, highlighting the urgent need for novel, effective therapeutics. Recent studies support the proposition that improved myocardial energetics as a result of ketone body (KB) oxidation may account for the intriguing beneficial effects of sodium-glucose cotransporter-2 inhibitors in patients with HF. Similar small molecules, short-chain fatty acids (SCFAs) are now realized to be preferentially oxidized over KBs in failing hearts, contradicting the notion of KBs as a rescue "superfuel." In addition to KBs and SCFAs being alternative fuels, both exert a wide array of nonmetabolic functions, including molecular signaling and epigenetics and as effectors of inflammation and immunity, blood pressure regulation, and oxidative stress. In this review, the authors present a perspective supported by new evidence that the metabolic and unique nonmetabolic activities of KBs and SCFAs hold promise for treatment of patients with HF with reduced ejection fraction and those with HF with preserved ejection fraction.
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OPINION STATEMENT: Prostate cancer is the second leading cause of cancer death in men, and cardiovascular disease is the number one cause of death in patients with prostate cancer. Androgen deprivation therapy, the cornerstone of prostate cancer treatment, has been associated with adverse cardiovascular events. Emerging data supports decreased cardiovascular risk of gonadotropin releasing hormone (GnRH) antagonists compared to agonists. Ongoing clinical trials are assessing the relative safety of different modalities of androgen deprivation therapy. Racial disparities in cardiovascular outcomes in prostate cancer patients are starting to be explored. An intriguing inquiry connects androgen deprivation therapy with reduced risk of COVID-19 infection susceptibility and severity. Recognition of the cardiotoxicity of androgen deprivation therapy and aggressive risk factor modification are crucial for optimal patient care.
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Antineoplásicos Hormonales/efectos adversos , Enfermedades Cardiovasculares/epidemiología , Neoplasias de la Próstata/tratamiento farmacológico , Androstenos/uso terapéutico , Antineoplásicos Hormonales/uso terapéutico , COVID-19/epidemiología , COVID-19/patología , Cardiotoxicidad , Enfermedades Cardiovasculares/inducido químicamente , Enfermedades Cardiovasculares/etnología , Susceptibilidad a Enfermedades , Hormona Liberadora de Gonadotropina/agonistas , Hormona Liberadora de Gonadotropina/antagonistas & inhibidores , Disparidades en el Estado de Salud , Humanos , Masculino , Neoplasias de la Próstata/etnología , SARS-CoV-2RESUMEN
UNLABELLED: Calcific aortic valve disease (CAVD) is the most common cause of aortic stenosis. Matrix metalloproteinases (MMPs) are upregulated in CAVD and contribute to valvular remodeling and calcification. We investigated the feasibility and correlates of MMP-targeted molecular imaging for detection of valvular biology in CAVD. METHODS: Apolipoprotein E-deficient (apoE(-/-)) mice were fed a Western diet (WD) for 3, 6, and 9 mo (n = 108) to induce CAVD. Wild-type mice served as the control group (n = 24). The development of CAVD was tracked with CT, echocardiography, MMP-targeted small-animal SPECT imaging using (99m)Tc-RP805, and histologic analysis. RESULTS: Key features of CAVDleaflet thickening and valvular calcificationwere noted after 6 mo of WD and were more pronounced after 9 mo. These findings were associated with a significant reduction in aortic valve leaflet separation and a significant increase in transaortic valve flow velocity. On in vivo SPECT/CT images, MMP signal in the aortic valve area was significantly higher at 6 mo in WD mice than in control mice and decreased thereafter. The specificity of the signal was demonstrated by blocking, using an excess of nonlabeled precursor. Similar to MMP signal, MMP activity as determined by in situ zymography and valvular inflammation by CD68 staining were maximal at 6 mo. In vivo (99m)Tc-RP805 uptake correlated significantly with MMP activity (R(2) = 0.94, P < 0.05) and CD68 expression (R(2) = 0.98, P < 0.01) in CAVD. CONCLUSION: MMP-targeted imaging detected valvular inflammation and remodeling in a murine model of CAVD. If this ability is confirmed in humans, the technique may provide a tool for tracking the effect of emerging medical therapeutic interventions and for predicting outcome in CAVD.
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Estenosis de la Válvula Aórtica/diagnóstico por imagen , Estenosis de la Válvula Aórtica/diagnóstico , Válvula Aórtica/diagnóstico por imagen , Válvula Aórtica/patología , Calcinosis/diagnóstico por imagen , Calcinosis/diagnóstico , Cardiopatías Congénitas/diagnóstico , Enfermedades de las Válvulas Cardíacas/diagnóstico , Metaloproteinasas de la Matriz/metabolismo , Imagen Molecular , Imagen Multimodal , Animales , Válvula Aórtica/enzimología , Estenosis de la Válvula Aórtica/patología , Apolipoproteínas E/genética , Enfermedad de la Válvula Aórtica Bicúspide , Calcinosis/patología , Dieta Alta en Grasa , Ecocardiografía , Cardiopatías Congénitas/diagnóstico por imagen , Cardiopatías Congénitas/enzimología , Enfermedades de las Válvulas Cardíacas/diagnóstico por imagen , Enfermedades de las Válvulas Cardíacas/enzimología , Humanos , Ratones , Ratones Transgénicos , Tecnecio/química , Tomografía Computarizada de Emisión de Fotón Único , Tomografía Computarizada por Rayos XRESUMEN
Type I collagen is the most abundant protein in the human body. Its excessive synthesis results in fibrosis of various organs. Fibrosis is a major medical problem without an existing cure. Excessive synthesis of type I collagen in fibrosis is primarily due to stabilization of collagen mRNAs. We recently reported that intermediate filaments composed of vimentin regulate collagen synthesis by stabilizing collagen mRNAs. Vimentin is a primary target of Withaferin-A (WF-A). Therefore, we hypothesized that WF-A may reduce type I collagen production by disrupting vimentin filaments and decreasing the stability of collagen mRNAs. This study is to determine if WF-A exhibits anti-fibrotic properties in vitro and in vivo and to elucidate the molecular mechanisms of its action. In lung, skin and heart fibroblasts WF-A disrupted vimentin filaments at concentrations of 0.5-1.5 µM and reduced 3 fold the half-lives of collagen α1(I) and α2(I) mRNAs and protein expression. In addition, WF-A inhibited TGF-ß1 induced phosphorylation of TGF-ß1 receptor I, Smad3 phosphorylation and transcription of collagen genes. WF-A also inhibited in vitro activation of primary hepatic stellate cells and decreased their type I collagen expression. In mice, administration of 4 mg/kg WF-A daily for 2 weeks reduced isoproterenol-induced myocardial fibrosis by 50%. Our findings provide strong evidence that Withaferin-A could act as an anti-fibrotic compound against fibroproliferative diseases, including, but not limited to, cardiac interstitial fibrosis.
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Colágeno Tipo I/genética , Fibrosis Endomiocárdica/genética , Witanólidos/farmacología , Animales , Línea Celular , Colágeno Tipo I/metabolismo , Fibrosis Endomiocárdica/inducido químicamente , Fibrosis Endomiocárdica/tratamiento farmacológico , Fibrosis Endomiocárdica/patología , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Técnicas de Inactivación de Genes , Células Estrelladas Hepáticas/efectos de los fármacos , Células Estrelladas Hepáticas/metabolismo , Humanos , Isoproterenol/efectos adversos , Masculino , Ratones , Fosforilación/efectos de los fármacos , Regiones Promotoras Genéticas , Proteolisis/efectos de los fármacos , Estabilidad del ARN/efectos de los fármacos , ARN Mensajero/genética , ARN Mensajero/metabolismo , Proteína smad3/metabolismo , Factor de Crecimiento Transformador beta1/farmacología , Vimentina/genética , Vimentina/metabolismo , Witanólidos/administración & dosificación , Witanólidos/toxicidadRESUMEN
The stem-loop in the 5' untranslated region (UTR) of collagen α1(I) and α2(I) mRNAs (5'SL) is the key element regulating their stability and translation. Stabilization of collagen mRNAs is the predominant mechanism for high collagen expression in fibrosis. LARP6 binds the 5'SL of α1(I) and α2(I) mRNAs with high affinity. Here, we report that vimentin filaments associate with collagen mRNAs in a 5'SL- and LARP6-dependent manner and stabilize collagen mRNAs. LARP6 interacts with vimentin filaments through its La domain and colocalizes with the filaments in vivo. Knockdown of LARP6 by small interfering RNA (siRNA) or mutation of the 5'SL abrogates the interaction of collagen mRNAs with vimentin filaments. Vimentin knockout fibroblasts produce reduced amounts of type I collagen due to decreased stability of collagen α1(I) and α2(I) mRNAs. Disruption of vimentin filaments using a drug or by expression of dominant-negative desmin reduces type I collagen expression, primarily due to decreased stability of collagen mRNAs. RNA fluorescence in situ hybridization (FISH) experiments show that collagen α1(I) and α2(I) mRNAs are associated with vimentin filaments in vivo. Thus, vimentin filaments may play a role in the development of tissue fibrosis by stabilizing collagen mRNAs. This finding will serve as a rationale for targeting vimentin in the development of novel antifibrotic therapies.