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1.
Cureus ; 16(1): e51916, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38333482

RESUMO

INTRODUCTION: The main feature of periodontitis is the development of periodontal pockets as a secondary consequence, which is mainly caused by an excessive immune response to the dental biofilm. The prime factor in the pathogenesis of periodontitis is an increase in oxidative stress. Numerous clinical studies have demonstrated that antioxidant supplementation can reduce endogenous antioxidant depletion and the oxidative damage that goes along with it. Hence, antioxidant therapy in the treatment of periodontal disease may prove to be a promising tool. OBJECTIVE: The objective of the study is to compare the efficiency of three different antioxidants as oral supplements. MATERIALS AND METHODS: Eighty patients with chronic periodontitis were randomly split into four groups. The control group received scaling and root planning (SRP), and the test group received oral supplements for 30 days with SRP. Pocket depth (PD), clinical attachment level (CAL), oral hygiene index-simplified (OHI-S), and sulcus bleeding index (SBI) were evaluated at baseline and 30 days. The analysis of the data was done with ANOVA, Kruskal-Wallis, and post hoc tests. The significance level was set at p<0.05 and p<0.001. RESULTS: All groups resulted in a statistically significant reduction in all parameters from baseline to one month. The treatment groups revealed a statistically significant reduction in PD and CAL (p<0.00) but no reduction in OHI-S and SBI (p>0.05) scores. A highly statistically significant reduction was observed in PD with green coffee bean extract when compared with other groups. CONCLUSION: Green coffee bean extract oral supplements may prove to be a promising appendage in therapeutic and prophylactic fashion, along with SRP, in the treatment of stage III grade B periodontitis patients.

2.
J Microsc Ultrastruct ; 11(1): 41-46, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37144169

RESUMO

Introduction: Dentinal hypersensitivity (DH) is a common chronic condition that affects a high proportion of the adult population and is one of the main reasons why patients seek dental opinion and treatment. Despite considerable success in reducing DH, unfortunately, most of the present methods can provide only temporary and unpredictable desensitization. Therefore, new treatment methods that are effective for long periods and at the same time do not have the complications are needed. Recently, two new desensitizing agents BioMin F and Propolis have been introduced for the treatment of DH. Aim: The aim of the study was to compare and evaluate the efficacy of BioMin F and Propolis containing toothpastes on dentinal tubule occlusion with and without the use of an adjunct 810 nm Diode Laser. Materials and Methods: Forty-five freshly extracted teeth were taken out of which thirty were sectioned into halves and divided into four test groups BioMin F, Propolis, BioMin F + Laser, and Propolis + Laser and control group. All the specimens were treated twice a day for 7 days and then evaluated under scanning electron microscope for partial and complete dentinal tubule occlusion. Results: A significantly higher number of completely occluded tubules were seen in BioMin F + laser group followed by Propolis + laser, Biomin F, and Propolis. Conclusion: Combination approach of desensitizing agent and laser provided a better result than the desensitizing agent alone and when compared individually Biomin F was more effective desensitizer as compared to Propolis.

3.
Res Sq ; 2023 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-38196615

RESUMO

Chronic kidney disease (CKD) is a global health epidemic that significantly increases mortality due to cardiovascular disease. Left ventricular hypertrophy (LVH) is an important mechanism of cardiac injury in CKD. High serum levels of fibroblast growth factor (FGF) 23 in patients with CKD may contribute mechanistically to the pathogenesis of LVH by activating FGF receptor (FGFR) 4 signaling in cardiac myocytes. Mitochondrial dysfunction and cardiac metabolic remodeling are early features of cardiac injury that predate development of hypertrophy, but these mechanisms of disease have been insufficiently studied in models of CKD. Wild-type mice with CKD induced by adenine diet developed LVH that was preceded by morphological changes in mitochondrial structure and evidence of cardiac mitochondrial and metabolic dysfunction. In bioengineered cardio-bundles and neonatal rat ventricular myocytes grown in vitro, FGF23-mediated activation of FGFR4 caused a mitochondrial pathology, characterized by increased bioenergetic stress and increased glycolysis, that preceded the development of cellular hypertrophy. The cardiac metabolic changes and associated mitochondrial alterations in mice with CKD were prevented by global or cardiac-specific deletion of FGFR4. These findings indicate that metabolic remodeling and eventually mitochondrial dysfunction are early cardiac complications of CKD that precede structural remodeling of the heart. Mechanistically, FGF23-mediated activation of FGFR4 causes mitochondrial dysfunction, suggesting that early pharmacologic inhibition of FGFR4 might serve as novel therapeutic intervention to prevent development of LVH and heart failure in patients with CKD.

4.
iScience ; 25(4): 104086, 2022 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-35378858

RESUMO

The complex and inaccessible space radiation environment poses an unresolved risk to astronaut cardiovascular health during long-term space exploration missions. To model this risk, healthy male c57BL/6 mice aged six months (corresponding to an astronaut of 34 years) were exposed to simplified galactic cosmic ray (GCR5-ion; 5-ion sim) irradiation at the NASA Space Radiation Laboratory (NSRL) at Brookhaven National Laboratories (BNL). Multi-modal cardiovascular functional assessments performed longitudinally and terminally revealed significant impairment in cardiac function in mice exposed to GCR5-ion compared to unirradiated controls, gamma irradiation, or single mono-energetic ions (56Fe or 16O). GCR5-ion-treated mice exhibited increased arterial elastance likely mediated by disruption of elastin fibers. This study suggests that a single exposure to GCR5-ion is associated with deterioration in cardiac structure and function that becomes apparent long after exposure, likely associated with increased morbidity and mortality. These findings represent important health considerations when preparing for successful space exploration.

5.
J Obstet Gynaecol India ; 71(3): 262-267, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34408345

RESUMO

BACKGROUND: Previous studies have suggested that chronic periodontal infection may be associate with preterm births and low birth weight. The present study was conducted to evaluate the levels of interleukin-17 (IL-17) in saliva samples of pregnant females as a possible marker in determining whether or not an association exists between chronic periodontitis and preterm labor. AIM: The aim of the study is to assess the relation between the periodontal health status and preterm low birth weight of the new born on the basis of salivary IL-17 levels. MATERIALS AND METHODS: This case-control study included a random sample of 40 female patients, aged 18 to 35 years, who were in their second trimester, assigned to two groups, Group 1 consisted of 20 pregnant females without periodontitis, Group 2 included 20 pregnant females with periodontitis. Saliva samples were obtained in the second trimester and postpartum. Saliva samples were measured by using ELISA for IL-17 levels. RESULTS: IL-17 levels in saliva were significantly higher in Group 2 than that of Group 1(p < 0.001). There was no significant difference found between the preterm and low birth weight cases and periodontitis. CONCLUSION: This study did not find any association between the periodontitis and preterm deliveries and low birth weight cases on the basis of IL-17 levels in saliva.

6.
J Card Fail ; 27(9): 942-948, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33965536

RESUMO

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) continues to increase in prevalence with a 50% mortality rate within 3 years of diagnosis, but lacking effective evidence-based therapies. Specific echocardiographic markers are not typically used to trigger alarm before acute HFpEF decompensation. The goal of this study was to retrospectively track changes in echocardiographic markers leading to the time of incident HFpEF hospitalization. METHODS AND RESULTS: In a single-center, retrospective analysis, patients with HFpEF admitted between 2007 and 2014 were identified using the International Classification of Diseases, 9th Revision with search refined using the European Society of Cardiology HFpEF guidelines. Using linear mixed effects models, changes in echocardiographic markers preceding acute HF decompensation owing to incident HFpEF were analyzed. We report on an incident HFpEF cohort of 242 patients, extending 18 years retrospectively, and including 675 echocardiograms analyzed from the overall sample at 14 distinct time intervals before acute decompensation. The regression models demonstrated 3 echocardiographic markers with statistically significant increases across multiple time intervals including, arterial elastance (P = .006), right atrial pressure estimate (P < .001), and right ventricular systolic pressure (P = .006). Other echocardiographic markers had individual time intervals with significant increases before acute decompensation, including (a) left atrial diameter, 8 to 10 years before HFpEF diagnosis, (b) left ventricular filling pressure 2 to 6 years before HFpEF diagnosis, (c) ventricular elastance 3 to 6 months before HFpEF diagnosis, and (d) ventricular elastance/arterial elastance as early as 10 to 20 years and as late as 3 to 6 months before HFpEF diagnosis. Furthermore, African Americans presented with incident HFpEF at an average younger age than White patients (65.6 ± 15.2 years vs. 76.7 years ± 11.7, P < .001). CONCLUSIONS: Noninvasive echocardiographic markers associated with incident HFpEF diagnosis showed long, mid, and acute range, significant changes as far back as 10 to 20 years and as close as 3 to 6 months before acute HFpEF decompensation. Including a diverse study cohort is critical to understanding the phenotypic differences of HFpEF. This hypothesis-generating study identified a novel approach to identifying trends in echocardiographic markers that may be used as a signal of impending incident HFpEF.


Assuntos
Insuficiência Cardíaca , Idoso , Idoso de 80 Anos ou mais , Ecocardiografia , Insuficiência Cardíaca/diagnóstico por imagem , Insuficiência Cardíaca/epidemiologia , Humanos , Pessoa de Meia-Idade , Estudos Retrospectivos , Volume Sistólico , Função Ventricular Esquerda
7.
Radiother Oncol ; 157: 155-162, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33545252

RESUMO

BACKGROUND AND PURPOSE: Late cardiac toxicity is a major side effect of radiation therapy (RT) for breast cancer. We developed and characterized a mouse model of radiation-induced heart disease that mimics the dose, fractionation, and beam arrangement of left breast and chest wall RT. MATERIAL AND METHODS: Female wild-type (C57BL6/J) and atherosclerosis-prone apolipoprotein E-deficient (ApoE-/-) mice (on a C57BL/6J background) on regular chow were treated with 2 Gy × 25 fractions of partial-heart irradiation via opposed tangential beams to the left chest wall. The changes in myocardial perfusion and cardiac function of C57BL/6J mice were examined by single-photon emission computed tomography (SPECT) and echocardiography, respectively. In addition to SPECT and echocardiography, the formation of calcified plaques and changes in cardiac function of ApoE-/- mice were examined by dual-energy microCT (DE-CT) and pressure-volume (PV) loop analysis, respectively. The development of myocardial fibrosis was examined by histopathology. RESULTS: Compared to unirradiated controls, irradiated C57BL/6J mice showed no significant changes by SPECT or echocardiography up to 18 months after 2 Gy × 25 partial-heart irradiation even though irradiated mice exhibited a modest increase in myocardial fibrosis. For ApoE-/- mice, 2 Gy × 25 partial-heart irradiation did not cause significant changes by SPECT, DE-CT, or echocardiography. However, PV loop analysis revealed a significant decrease in load-dependent systolic and diastolic function measures including cardiac output, dV/dtmax and dV/dt min 12 months after RT. CONCLUSIONS: Following clinically relevant doses of partial-heart irradiation in C57BL/6J and ApoE-/- mice, assessment with noninvasive imaging modalities such as echocardiography, SPECT, and DE-CT yielded no evidence of decreased myocardial perfusion and cardiac dysfunction related to RT. However, invasive hemodynamic assessment with PV loop analysis indicated subtle, but significant, changes in cardiac function of irradiated ApoE-/- mice. PV loop analysis may be useful for future preclinical studies of radiation-induced heart disease, especially if subtle changes in cardiac function are expected.


Assuntos
Coração , Tomografia Computadorizada de Emissão de Fóton Único , Animais , Fracionamento da Dose de Radiação , Ecocardiografia , Feminino , Coração/diagnóstico por imagem , Camundongos , Camundongos Endogâmicos C57BL
8.
J Appl Physiol (1985) ; 130(3): 853-864, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33411638

RESUMO

Rheumatoid arthritis (RA) is a systemic inflammatory arthritis impacting primarily joints and cardiac and skeletal muscle. RA's distinct impact on cardiac and skeletal muscle tissue is suggested by studies showing that new RA pharmacologic agents strongly improve joint inflammation, but have little impact on RA-associated mortality, cardiovascular disease, and sarcopenia. Thus, the objective is to understand the distinct effects of RA on cardiac and skeletal muscle, and to therapeutically target these tissues through endurance-based exercise as a way to improve RA mortality and morbidity. We utilize the well-characterized RA mouse model, the K/BxN mouse, to investigate cardiac and skeletal muscle pathologies, including the use of wheel-running exercise to mitigate these pathologies. Strikingly, we found that K/BxN mice, like patients with RA, also exhibit both cardiac and skeletal muscle myopathies that were correlated with circulating IL-6 levels. Three months of wheel-running exercise significantly improved K/BxN joint swelling and reduced systemic IL-6 concentrations. Importantly, there were morphological, gene expression, and functional improvements in both the skeletal muscle and cardiac myopathies with exercise. The K/BxN mouse model of RA recapitulated important RA clinical comorbidities, including altered joint, cardiac and skeletal muscle function. These morphological, molecular, and functional alterations were mitigated with regular exercise, thus suggesting exercise as a potential therapeutic intervention to lessen disease activity in the joint and the peripheral tissues, including the heart and skeletal muscle.NEW & NOTEWORTHY RA, even when controlled, is associated with skeletal muscle weakness and greater risk of cardiovascular disease (CVD). Using exercise as a therapeutic against, the progression of RA is often avoided due to fear of worsening RA pathology. We introduce the K/BxN mouse as an RA model to study both myocardial and skeletal muscle dysfunction. We show that endurance exercise can improve joint, cardiac, and skeletal muscle function in K/BxN mice, suggesting exercise may be beneficial for patients with RA.


Assuntos
Artrite Reumatoide , Músculo Esquelético , Animais , Modelos Animais de Doenças , Terapia por Exercício , Coração , Humanos , Camundongos
9.
Hypertension ; 77(2): 393-404, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33390039

RESUMO

Activation of AT1 (type 1 Ang) receptors stimulates cardiomyocyte hypertrophy in vitro. Accordingly, it has been suggested that regression of cardiac hypertrophy associated with renin-Ang system blockade is due to inhibition of cellular actions of Ang II in the heart, above and beyond their effects to reduce pressure overload. We generated 2 distinct mouse lines with cell-specific deletion of AT1A receptors, from cardiomyocytes. In the first line (C-SMKO), elimination of AT1A receptors was achieved using a heterologous Cre recombinase transgene under control of the Sm22 promoter, which expresses in cells of smooth muscle lineage including cardiomyocytes and vascular smooth muscle cells of conduit but not resistance vessels. The second line (R-SMKO) utilized a Cre transgene knocked-in to the Sm22 locus, which drives expression in cardiac myocytes and vascular smooth muscle cells in both conduit and resistance arteries. Thus, although both groups lack AT1 receptors in the cardiomyocytes, they are distinguished by presence (C-SMKO) or absence (R-SMKO) of peripheral vascular responses to Ang II. Similar to wild-types, chronic Ang II infusion caused hypertension and cardiac hypertrophy in C-SMKO mice, whereas both hypertension and cardiac hypertrophy were reduced in R-SMKOs. Thus, despite the absence of AT1A receptors in cardiomyocytes, C-SMKOs develop robust cardiac hypertrophy. By contrast, R-SMKOs developed identical levels of hypertrophy in response to pressure overload-induced by transverse aortic banding. Our findings suggest that direct activation of AT1 receptors in cardiac myocytes has minimal influence on cardiac hypertrophy induced by renin-Ang system activation or pressure overload.


Assuntos
Angiotensina II/farmacologia , Cardiomegalia/genética , Hipertensão/genética , Miócitos Cardíacos/metabolismo , Receptor Tipo 1 de Angiotensina/genética , Sistema Renina-Angiotensina/efeitos dos fármacos , Animais , Cardiomegalia/induzido quimicamente , Cardiomegalia/metabolismo , Hipertensão/induzido quimicamente , Hipertensão/metabolismo , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Miocárdio/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Resistência Vascular/efeitos dos fármacos
10.
Circ Res ; 127(8): 1094-1108, 2020 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-32660330

RESUMO

RATIONALE: Circumstantial evidence links the development of heart failure to posttranslational modifications of mitochondrial proteins, including lysine acetylation (Kac). Nonetheless, direct evidence that Kac compromises mitochondrial performance remains sparse. OBJECTIVE: This study sought to explore the premise that mitochondrial Kac contributes to heart failure by disrupting oxidative metabolism. METHODS AND RESULTS: A DKO (dual knockout) mouse line with deficiencies in CrAT (carnitine acetyltransferase) and Sirt3 (sirtuin 3)-enzymes that oppose Kac by buffering the acetyl group pool and catalyzing lysine deacetylation, respectively-was developed to model extreme mitochondrial Kac in cardiac muscle, as confirmed by quantitative acetyl-proteomics. The resulting impact on mitochondrial bioenergetics was evaluated using a respiratory diagnostics platform that permits comprehensive assessment of mitochondrial function and energy transduction. Susceptibility of DKO mice to heart failure was investigated using transaortic constriction as a model of cardiac pressure overload. The mitochondrial acetyl-lysine landscape of DKO hearts was elevated well beyond that observed in response to pressure overload or Sirt3 deficiency alone. Relative changes in the abundance of specific acetylated lysine peptides measured in DKO versus Sirt3 KO hearts were strongly correlated. A proteomics comparison across multiple settings of hyperacetylation revealed ≈86% overlap between the populations of Kac peptides affected by the DKO manipulation as compared with experimental heart failure. Despite the severity of cardiac Kac in DKO mice relative to other conditions, deep phenotyping of mitochondrial function revealed a surprisingly normal bioenergetics profile. Thus, of the >120 mitochondrial energy fluxes evaluated, including substrate-specific dehydrogenase activities, respiratory responses, redox charge, mitochondrial membrane potential, and electron leak, we found minimal evidence of oxidative insufficiencies. Similarly, DKO hearts were not more vulnerable to dysfunction caused by transaortic constriction-induced pressure overload. CONCLUSIONS: The findings challenge the premise that hyperacetylation per se threatens metabolic resilience in the myocardium by causing broad-ranging disruption to mitochondrial oxidative machinery.


Assuntos
Insuficiência Cardíaca/metabolismo , Mitocôndrias Cardíacas/metabolismo , Proteínas Mitocondriais/metabolismo , Miócitos Cardíacos/metabolismo , Proteoma , Acetilação , Animais , Carnitina O-Acetiltransferase/deficiência , Carnitina O-Acetiltransferase/genética , Modelos Animais de Doenças , Metabolismo Energético , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/fisiopatologia , Lisina , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Estresse Oxidativo , Processamento de Proteína Pós-Traducional , Proteômica , Sirtuína 3/deficiência , Sirtuína 3/genética
11.
J Assoc Physicians India ; 68(4): 39-42, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32610845

RESUMO

BACKGROUND: Cardiovascular diseases, especially coronary artery disease, are epidemic in India. However there is paucity of data regarding coronary artery disease in high altitude. This study was conducted to determine the importance of asymptomatic ECG abnormalities in high altitude with relevance to coronary artery disease. METHOD: A total of 54 subjects were included in the study. All of them underwent acclimatization before ascent to high altitude. Subjects were selected if they were detected to have ECG abnormality in high altitude. Various parameters such as height, weight, BMI, and multiple laboratory parameters were also recorded. RESULTS: Out of 54 subjects, mean age was 40.6 yrs. Mean BMI was 24.28 Kg/ m2. Most common ECG abnormality was T wave inversion in inferiorly directed frontal plane leads seen in 16 (29.6%) subjects followed by T wave inversion in both inferiorly directed frontal plane leads and precordial leads noted in 13 (24%) subjects. Next most common ECG abnormality was T wave inversion in the precordial leads seen in 10 (18.5%) subjects. Only three subjects turned out to be positive for inducible ischemia. Coronary angiography however showed normal coronaries in all the three subjects. CONCLUSIONS: Our study suggests that majority of ECG abnormalities in high altitude are transient/ benign in nature and do not suggest an increased risk of cardiovascular disease whether evaluated by Framingham Risk Score or structural/ functional evaluation by 2D Echocardiography/ Treadmill Test.


Assuntos
Altitude , Eletrocardiografia , Adulto , Arritmias Cardíacas , Angiografia Coronária , Humanos , Índia
12.
Cell ; 181(6): 1364-1379.e14, 2020 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-32470395

RESUMO

Small molecule neurotensin receptor 1 (NTSR1) agonists have been pursued for more than 40 years as potential therapeutics for psychiatric disorders, including drug addiction. Clinical development of NTSR1 agonists has, however, been precluded by their severe side effects. NTSR1, a G protein-coupled receptor (GPCR), signals through the canonical activation of G proteins and engages ß-arrestins to mediate distinct cellular signaling events. Here, we characterize the allosteric NTSR1 modulator SBI-553. This small molecule not only acts as a ß-arrestin-biased agonist but also extends profound ß-arrestin bias to the endogenous ligand by selectively antagonizing G protein signaling. SBI-553 shows efficacy in animal models of psychostimulant abuse, including cocaine self-administration, without the side effects characteristic of balanced NTSR1 agonism. These findings indicate that NTSR1 G protein and ß-arrestin activation produce discrete and separable physiological effects, thus providing a strategy to develop safer GPCR-targeting therapeutics with more directed pharmacological action.


Assuntos
Comportamento Aditivo/metabolismo , Receptores de Neurotensina/metabolismo , beta-Arrestinas/metabolismo , Regulação Alostérica/efeitos dos fármacos , Regulação Alostérica/fisiologia , Animais , Comportamento Aditivo/tratamento farmacológico , Linhagem Celular , Feminino , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Animais , Receptores Acoplados a Proteínas G/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Bibliotecas de Moléculas Pequenas/farmacologia
13.
Biomaterials ; 236: 119824, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32028169

RESUMO

In response to heart injury, inflammation, or mechanical overload, quiescent cardiac fibroblasts (CFs) can become activated myofibroblasts leading to pathological matrix remodeling and decline in cardiac function. Specific targeting of fibroblasts may thus enable new therapeutic strategies to delay or reverse the progression of heart failure and cardiac fibrosis. However, it remains unknown if all CFs are equally responsive to specific pathological insults and if there exist sub-populations of resident fibroblasts in the heart that have distinctive pathogenic phenotypes. Here, we show that in response to transverse aortic constriction (TAC)-induced heart failure, previously uncharacterized Thy1neg (Thy1-/MEFSK4+/CD45-/CD31-) fraction of mouse ventricular fibroblasts became more abundant and attained a more activated, pro-fibrotic myofibroblast phenotype compared to Thy1Pos fraction. In a tissue-engineered 3D co-culture model of healthy cardiomyocytes and freshly isolated CFs, Thy1neg CFs from TAC hearts significantly decreased cardiomyocyte contractile function and calcium transient amplitude, and increased extracellular collagen deposition yielding a profibrotic heart tissue phenotype. In vivo, mice with global knockout of Thy1 developed more severe cardiac dysfunction and fibrosis in response to TAC-induced heart failure than wild-type mice. Taken together, our studies identify cardiac myofibroblasts lacking Thy1 as a pathogenic CF fraction in cardiac fibrosis and suggest important roles of Thy1 in pathophysiology of heart failure.


Assuntos
Insuficiência Cardíaca , Animais , Fibroblastos/patologia , Fibrose , Ventrículos do Coração/patologia , Camundongos , Camundongos Endogâmicos C57BL , Miocárdio/patologia , Miócitos Cardíacos , Miofibroblastos , Remodelação Ventricular
14.
Am J Physiol Heart Circ Physiol ; 318(3): H566-H580, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31977249

RESUMO

Tandem pore domain acid-sensitive K+ (TASK) channels are present in cardiac tissue; however, their contribution to cardiac pathophysiology is not well understood. Here, we investigate the role of TASK-1 and TASK-3 in the pathogenesis of cardiac dysfunction using both human tissue and mouse models of genetic TASK channel loss of function. Compared with normal human cardiac tissue, TASK-1 gene expression is reduced in association with either cardiac hypertrophy alone or combined cardiac hypertrophy and heart failure. In a pressure overload cardiomyopathy model, TASK-1 global knockout (TASK-1 KO) mice have both reduced cardiac hypertrophy and preserved cardiac function compared with wild-type mice. In contrast to the TASK-1 KO mouse pressure overload response, TASK-3 global knockout (TASK-3 KO) mice develop cardiac hypertrophy and a delayed onset of cardiac dysfunction compared with wild-type mice. The cardioprotective effects observed in TASK-1 KO mice are associated with pressure overload-induced augmentation of AKT phosphorylation and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) expression, with consequent augmentation of cardiac energetics and fatty acid oxidation. The protective effects of TASK-1 loss of function are associated with an enhancement of physiologic hypertrophic signaling and preserved metabolic functions. These findings may provide a rationale for TASK-1 channel inhibition in the treatment of cardiac dysfunction.NEW & NOTEWORTHY The role of tandem pore domain acid-sensitive K+ (TASK) channels in cardiac function is not well understood. This study demonstrates that TASK channel gene expression is associated with the onset of human cardiac hypertrophy and heart failure. TASK-1 and TASK-3 strongly affect the development of pressure overload cardiomyopathies in genetic models of TASK-1 and TASK-3 loss of function. The effects of TASK-1 loss of function were associated with enhanced AKT phosphorylation and expression of peroxisome proliferator-activated receptor-γ coactivator-1 (PGC-1) transcription factor. These data suggest that TASK channels influence the development of cardiac hypertrophy and dysfunction in response to injury.


Assuntos
Cardiomegalia/metabolismo , Cardiomiopatias/metabolismo , Miocárdio/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Canais de Potássio de Domínios Poros em Tandem/metabolismo , Canais de Potássio/metabolismo , Remodelação Ventricular/fisiologia , Animais , Cardiomegalia/genética , Cardiomiopatias/genética , Humanos , Camundongos , Camundongos Knockout , Miócitos Cardíacos/metabolismo , Proteínas do Tecido Nervoso/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Fosforilação , Canais de Potássio/genética , Canais de Potássio de Domínios Poros em Tandem/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo
15.
Mol Genet Metab ; 129(2): 73-79, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31645300

RESUMO

Pompe disease is caused by the deficiency of lysosomal acid α-glucosidase (GAA) leading to progressive myopathy. Enzyme replacement therapy (ERT) with recombinant human (rh) GAA has limitations, including inefficient uptake of rhGAA in skeletal muscle linked to low cation-independent mannose-6-phosphate receptor (CI-MPR) expression. PURPOSE: To test the hypothesis that antihypertensive agents causing muscle hypertrophy by increasing insulin-like growth factor 1 expression can increase CI-MPR-mediated uptake of recombinant enzyme with therapeutic effects in skeletal muscle. METHODS: Three such agents were evaluated in mice with Pompe disease (carvedilol, losartan, and propranolol), either with or without concurrent ERT. RESULTS: Carvedilol, a selective ß-blocker, increased muscle strength but reduced biochemical correction from ERT. Administration of drugs alone had minimal effect, with the exception of losartan that increased glycogen storage and mortality either by itself or in combination with ERT. CONCLUSION: The ß-blocker carvedilol had beneficial effects during ERT in mice with Pompe disease, in comparison with propranolol or losartan. Caution is warranted when prescribing antihypertensive drugs in Pompe disease.


Assuntos
Anti-Hipertensivos/uso terapêutico , Terapia de Reposição de Enzimas , Doença de Depósito de Glicogênio Tipo II/tratamento farmacológico , Músculo Esquelético/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Quimioterapia Combinada , Feminino , Fator de Crescimento Insulin-Like I/genética , Masculino , Camundongos , Camundongos Knockout , Músculo Esquelético/patologia , alfa-Glucosidases/genética
16.
Am J Kidney Dis ; 75(5): 713-724, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31732231

RESUMO

RATIONALE & OBJECTIVE: Pulmonary hypertension (PH) contributes to cardiovascular disease and mortality in patients with chronic kidney disease (CKD), but the pathophysiology is mostly unknown. This study sought to estimate the prevalence and consequences of PH subtypes in the setting of CKD. STUDY DESIGN: Observational retrospective cohort study. SETTING & PARTICIPANTS: We examined 12,618 patients with a right heart catheterization in the Duke Databank for Cardiovascular Disease from January 1, 2000, to December 31, 2014. EXPOSURES: Baseline kidney function stratified by CKD glomerular filtration rate category and PH subtype. OUTCOMES: All-cause mortality. ANALYTICAL APPROACH: Multivariable Cox proportional hazards analysis. RESULTS: In this cohort, 73.4% of patients with CKD had PH, compared with 56.9% of patients without CKD. Isolated postcapillary PH (39.0%) and combined pre- and postcapillary PH (38.3%) were the most common PH subtypes in CKD. Conversely, precapillary PH was the most common subtype in the non-CKD cohort (35.9%). The relationships between mean pulmonary artery pressure, pulmonary capillary wedge pressure, and right atrial pressure with mortality were similar in both the CKD and non-CKD cohorts. Compared with those without PH, precapillary PH conferred the highest mortality risk among patients without CKD (HR, 2.27; 95% CI, 2.00-2.57). By contrast, in those with CKD, combined pre- and postcapillary PH was associated with the highest risk for mortality in CKD in adjusted analyses (compared with no PH, HRs of 1.89 [95% CI, 1.57-2.28], 1.87 [95% CI, 1.52-2.31], 2.13 [95% CI, 1.52-2.97], and 1.63 [95% CI, 1.12-2.36] for glomerular filtration rate categories G3a, G3b, G4, and G5/G5D). LIMITATIONS: The cohort referred for right heart catheterization may not be generalizable to the general population. Serum creatinine data in the 6 months preceding catheterization may not reflect true baseline CKD. Observational design precludes assumptions of causality. CONCLUSIONS: In patients with CKD referred for right heart catheterization, PH is common and associated with poor survival. Combined pre- and postcapillary PH was common and portended the worst survival for patients with CKD.


Assuntos
Hipertensão Pulmonar/classificação , Insuficiência Renal Crônica/epidemiologia , Idoso , Cateterismo Cardíaco , Causas de Morte , Comorbidade , Feminino , Hemodinâmica , Humanos , Hipertensão Pulmonar/complicações , Hipertensão Pulmonar/epidemiologia , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Mortalidade , Prevalência , Modelos de Riscos Proporcionais , Estudos Retrospectivos
17.
J Biol Chem ; 294(7): 2500-2518, 2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30538132

RESUMO

Reversible ubiquitination of G protein-coupled receptors regulates their trafficking and signaling; whether deubiquitinases regulate myocardial ß1-adrenergic receptors (ß1ARs) is unknown. We report that ubiquitin-specific protease 20 (USP20) deubiquitinates and attenuates lysosomal trafficking of the ß1AR. ß1AR-induced phosphorylation of USP20 Ser-333 by protein kinase A-α (PKAα) was required for optimal USP20-mediated regulation of ß1AR lysosomal trafficking. Both phosphomimetic (S333D) and phosphorylation-impaired (S333A) USP20 possess intrinsic deubiquitinase activity equivalent to WT activity. However, unlike USP20 WT and S333D, the S333A mutant associated poorly with the ß1AR and failed to deubiquitinate the ß1AR. USP20-KO mice showed normal baseline systolic function but impaired ß1AR-induced contractility and relaxation. Dobutamine stimulation did not increase cAMP in USP20-KO left ventricles (LVs), whereas NKH477-induced adenylyl cyclase activity was equivalent to WT. The USP20 homolog USP33, which shares redundant roles with USP20, had no effect on ß1AR ubiquitination, but USP33 was up-regulated in USP20-KO hearts suggesting compensatory regulation. Myocardial ß1AR expression in USP20-KO was drastically reduced, whereas ß2AR expression was maintained as determined by radioligand binding in LV sarcolemmal membranes. Phospho-USP20 was significantly increased in LVs of wildtype (WT) mice after a 1-week catecholamine infusion and a 2-week chronic pressure overload induced by transverse aortic constriction (TAC). Phospho-USP20 was undetectable in ß1AR KO mice subjected to TAC, suggesting a role for USP20 phosphorylation in cardiac response to pressure overload. We conclude that USP20 regulates ß1AR signaling in vitro and in vivo Additionally, ß1AR-induced USP20 phosphorylation may serve as a feed-forward mechanism to stabilize ß1AR expression and signaling during pathological insults to the myocardium.


Assuntos
Endopeptidases/biossíntese , Regulação Enzimológica da Expressão Gênica , Ativação do Canal Iônico , Miocárdio/metabolismo , Receptores Adrenérgicos beta 1/metabolismo , Substituição de Aminoácidos , Animais , Endopeptidases/genética , Ventrículos do Coração , Camundongos , Camundongos Knockout , Mutação de Sentido Incorreto , Fosforilação , Receptores Adrenérgicos beta 1/genética , Ubiquitina Tiolesterase , Ubiquitinação
18.
J Clin Invest ; 128(11): 4843-4855, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30153110

RESUMO

Cardiac two-pore domain potassium channels (K2P) exist in organisms from Drosophila to humans; however, their role in cardiac function is not known. We identified a K2P gene, CG8713 (sandman), in a Drosophila genetic screen and show that sandman is critical to cardiac function. Mice lacking an ortholog of sandman, TWIK-related potassium channel (TREK-1, also known Kcnk2), exhibit exaggerated pressure overload-induced concentric hypertrophy and alterations in fetal gene expression, yet retain preserved systolic and diastolic cardiac function. While cardiomyocyte-specific deletion of TREK-1 in response to in vivo pressure overload resulted in cardiac dysfunction, TREK-1 deletion in fibroblasts prevented deterioration in cardiac function. The absence of pressure overload-induced dysfunction in TREK-1-KO mice was associated with diminished cardiac fibrosis and reduced activation of JNK in cardiomyocytes and fibroblasts. These findings indicate a central role for cardiac fibroblast TREK-1 in the pathogenesis of pressure overload-induced cardiac dysfunction and serve as a conceptual basis for its inhibition as a potential therapy.


Assuntos
Cardiomegalia/metabolismo , Fibroblastos/metabolismo , Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Canais de Potássio de Domínios Poros em Tandem/metabolismo , Animais , Cardiomegalia/genética , Cardiomegalia/patologia , Drosophila melanogaster , Fibroblastos/patologia , Fibrose , Humanos , Camundongos , Camundongos Knockout , Miocárdio/patologia , Miócitos Cardíacos/patologia , Canais de Potássio de Domínios Poros em Tandem/genética , Domínios Proteicos
19.
J Biol Chem ; 293(27): 10630-10645, 2018 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-29769314

RESUMO

Mitochondrial Sirtuin 5 (SIRT5) is an NAD+-dependent demalonylase, desuccinylase, and deglutarylase that controls several metabolic pathways. A number of recent studies point to SIRT5 desuccinylase activity being important in maintaining cardiac function and metabolism under stress. Previously, we described a phenotype of increased mortality in whole-body SIRT5KO mice exposed to chronic pressure overload compared with their littermate WT controls. To determine whether the survival phenotype we reported was due to a cardiac-intrinsic or cardiac-extrinsic effect of SIRT5, we developed a tamoxifen-inducible, heart-specific SIRT5 knockout (SIRT5KO) mouse model. Using our new animal model, we discovered that postnatal cardiac ablation of Sirt5 resulted in persistent accumulation of protein succinylation up to 30 weeks after SIRT5 depletion. Succinyl proteomics revealed that succinylation increased on proteins of oxidative metabolism between 15 and 31 weeks after ablation. Heart-specific SIRT5KO mice were exposed to chronic pressure overload to induce cardiac hypertrophy. We found that, in contrast to whole-body SIRT5KO mice, there was no difference in survival between heart-specific SIRT5KO mice and their littermate controls. Overall, the data presented here suggest that survival of SIRT5KO mice may be dictated by a multitissue or prenatal effect of SIRT5.


Assuntos
Cardiomegalia/mortalidade , Coração/fisiopatologia , Pressão/efeitos adversos , Processamento de Proteína Pós-Traducional , Sirtuínas/fisiologia , Ácido Succínico/metabolismo , Animais , Cardiomegalia/etiologia , Cardiomegalia/metabolismo , Cardiomegalia/patologia , Feminino , Regulação da Expressão Gênica , Masculino , Redes e Vias Metabólicas , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteômica , Análise de Sobrevida
20.
Synapse ; 72(1)2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28941296

RESUMO

The "brain-gut" peptide ghrelin, which mediates food-seeking behaviors, is recognized as a very strong endogenous modulator of dopamine (DA) signaling. Ghrelin binds the G protein-coupled receptor GHSR1a, and administration of ghrelin increases the rewarding properties of psychostimulants while ghrelin receptor antagonists decrease them. In addition, the GHSR1a signals through ßarrestin-2 to regulate actin/stress fiber rearrangement, suggesting ßarrestin-2 participation in the regulation of actin-mediated synaptic plasticity for addictive substances like cocaine. The effects of ghrelin receptor ligands on reward strongly suggest that modulation of ghrelin signaling could provide an effective strategy to ameliorate undesirable behaviors arising from addiction. To investigate this possibility, we tested the effects of ghrelin receptor antagonism in a cocaine behavioral sensitization paradigm using DA neuron-specific ßarrestin-2 KO mice. Our results show that these mice sensitize to cocaine as well as wild-type littermates. The ßarrestin-2 KO mice, however, no longer respond to the locomotor attenuating effects of the GHSR1a antagonist YIL781. The data presented here suggest that the separate stages of addictive behavior differ in their requirements for ßarrestin-2 and show that pharmacological inhibition of ßarrestin-2 function through GHSR1a antagonism is not equivalent to the loss of ßarrestin-2 function achieved by genetic ablation. These data support targeting GHSR1a signaling in addiction therapy but indicate that using signaling biased compounds that modulate ßarrestin-2 activity differentially from G protein activity may be required.


Assuntos
Transtornos Relacionados ao Uso de Cocaína/metabolismo , Cocaína/farmacologia , Inibidores da Captação de Dopamina/farmacologia , Atividade Motora/efeitos dos fármacos , Receptores de Grelina/antagonistas & inibidores , beta-Arrestina 2/metabolismo , Animais , Linhagem Celular Tumoral , Fármacos do Sistema Nervoso Central , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/metabolismo , Feminino , Grelina/metabolismo , Células HEK293 , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Atividade Motora/fisiologia , Piperidinas/farmacologia , Quinazolinonas/farmacologia , Receptores de Grelina/metabolismo , beta-Arrestina 2/genética
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