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1.
Basic Res Cardiol ; 115(3): 31, 2020 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-32274570

RESUMO

From January 2020, coronavirus disease (COVID-19) originated in China has spread around the world. The disease is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The presence of myocarditis, cardiac arrest, and acute heart failure in COVID-19 patients suggests the existence of a relationship between SARS-CoV-2 infection and cardiac disease. The Notch signalling is a major regulator of cardiovascular function and it is also implicated in several biological processes mediating viral infections. In this report we discuss the possibility to target Notch signalling to prevent SARS-CoV-2 infection and interfere with the progression of COVID-19- associated heart and lungs disease.


Assuntos
Betacoronavirus/patogenicidade , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/fisiopatologia , Cardiopatias/tratamento farmacológico , Cardiopatias/etiologia , Pneumopatias/tratamento farmacológico , Pneumopatias/etiologia , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/fisiopatologia , Receptores Notch/antagonistas & inibidores , Proteína ADAM17/antagonistas & inibidores , Betacoronavirus/efeitos dos fármacos , China , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Progressão da Doença , Furina/metabolismo , Parada Cardíaca/etiologia , Parada Cardíaca/patologia , Cardiopatias/patologia , Cardiopatias/fisiopatologia , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/patologia , Humanos , Interleucina-6/imunologia , Pneumopatias/patologia , Pneumopatias/fisiopatologia , Miocardite/etiologia , Miocardite/patologia , Pandemias , Peptidil Dipeptidase A/deficiência , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Receptores Notch/metabolismo , Transdução de Sinais/efeitos dos fármacos
2.
Acta Cir Bras ; 35(2): e202000202, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32267288

RESUMO

PURPOSE: To investigate the effects of adalimumab pretreatment on the lipopolysaccharide-mediated myocardial injury. METHODS: Twenty-eight Wistar rats were randomized into four groups (n=7). Control (C) group animals were injected once a day with intraperitoneal (i.p) 0.9 % saline for two days. In the Adalimumab (Ada) group, adalimumab was injected at a dose of 10 mg/kg/ day (i.p) for two days. Lipopolysaccharide (Lps) group rats were injected with a dose of 5 mg/kg (i.p) lipopolysaccharide. Lipopolysaccharide + Adalimumab (Lps+Ada) group rats received adalimumab before the administration of lipopolysaccharide. The animals were sacrificed 24 h after the last injection and blood samples were obtained for determination of biochemical cardiac injury markers and circulating levels of TNF-α and interleukin-6 (IL-6). Hearts were harvested for histological examination. RESULTS: Endotoxin exposure resulted in significant increases in serum cardiac injury markers, serum cytokines and histological myocardial injury scores in the Lps group. The levels of circulating cytokines, cardiac injury markers and histological injury scores for myocardial necrosis, perivascular cell infiltration, and inflammation were significantly reduced in Lps+Ada as compared to Lps group (p<0.05). CONCLUSIONS: Adalimumab pretreatment reduces endotoxin-induced myocardial damage in rats. This beneficial effect is thought to be related to the reduction of cytokine release.


Assuntos
Adalimumab/administração & dosagem , Cardiopatias/tratamento farmacológico , Lipopolissacarídeos/administração & dosagem , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Animais , Modelos Animais de Doenças , Endotoxinas , Feminino , Cardiopatias/induzido quimicamente , Ratos , Ratos Wistar , Fator de Necrose Tumoral alfa/biossíntese
3.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 51(2): 207-212, 2020 Mar.
Artigo em Chinês | MEDLINE | ID: mdl-32220189

RESUMO

Objective: To observe the changes of cardiac function in arthritic rats and the effect of triptolide on it. Methods: Forty rats were divided in random into normal control (NC) group, model control (MC) group, leflunomide (LEF) group and triptolide (TP) group. Except for the normal group, rats in the other three groups were injected with Freund's complete adjuvant to create arthritic inflammation in the right hind paws, and the interventional drug was administered on the 12th day after the inflammation. By treating for 30 d, the cardiac function of rats was detected by left ventricular catheterization. The expressions of superoxide dismutase (SOD), malondialdehyde (MDA), reacitve oxygen species (ROS), total antioxidation (T-AOC), interleukin-10 (IL-10) and tumor necrosis factor-α (TNF-α) in serum were measured by enzyme-linked immunosorbent assay. The expressions of keap-like protein 1 ( Keap1), muscular aponeurotic fibrosarcom ( maf) and nuclear factor-E2 related factor2 ( Nrf2) mRNAs in cardiac tissue were detected by real-time PCR. The expressions of Keap1, maf and Nrf2 proteins in heart tissues were detected by Western blot. Results: Comparing with the normal group, the heart rate (HR), heart index (HI), left ventricular systolic pressure (LVSP), and left ventricular end-diastolic pressure (LVEDP) of the model group were significantly increased, whereas the maximum change rate of ventricular pressure rise or decline (±dp/dtmax) was significantly decreased ( P<0.01). SOD, MDA, ROS, T-AOC, and TNF-α were all increased, and IL-10 was significantly decreased ( P<0.01). The mRNA and protein expressions of Keap1, maf and Nrf2 in heart tissues were increased ( P<0.01). Comparing with the model group, HR, HI, LVSP, and LVEDP in the triptolide group were significantly decreased, whereas the ±dp/dtmax was significantly increased ( P<0.01). SOD, MDA, T-AOC, ROS, TNF-α decreased while the IL-10 increased ( P<0.05, P<0.01). The expressions of Keap1, maf and Nrf2 mRNAs and proteins in the heart tissues of the triptolide group were decreased ( P<0.01). Conclusion: Triptolide could improve cardiac function in arthritic rats, and the mechanism may related to its ability of improving the anti-oxidationin cardiomyocytes, reducing oxidative stress damage, and inhibiting abnormal immune inflammatory response.


Assuntos
Artrite/complicações , Diterpenos/farmacologia , Cardiopatias/tratamento farmacológico , Coração/efeitos dos fármacos , Imunossupressores/farmacologia , Miócitos Cardíacos/efeitos dos fármacos , Fenantrenos/farmacologia , Animais , Compostos de Epóxi/farmacologia , Cardiopatias/complicações , Proteína 1 Associada a ECH Semelhante a Kelch , Miócitos Cardíacos/fisiologia , Fator 2 Relacionado a NF-E2 , Estresse Oxidativo/efeitos dos fármacos , Ratos
4.
Am J Physiol Heart Circ Physiol ; 318(4): H985-H993, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32167781

RESUMO

The roles of ACE-independent ANG II production via chymase and therapeutic potential of epoxyeicosatrienoic acids (EETs) in fructose-induced metabolic syndrome (MetS) in the adolescent population remain elusive. Thus we tested the hypothesis that a high-fructose diet (HFD) in young rats elicits chymase-dependent increases in ANG II production and oxidative stress, responses that are reversible by 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU), an inhibitor of soluble epoxide hydrolase (sEH) that metabolizes EETs. Three groups of weanling rats (21-day-old) were fed a normal diet, 60% HFD, and HFD with TPPU, respectively, for 30 days. HFD rats developed MetS, characterized by hyperglycemia, hyperinsulinemia, and hypertension and associated with decreases in cardiac output and stroke volume and loss of nitric oxide (NO) modulation of myocardial oxygen consumption; all impairments were normalized by TPPU that significantly elevated circulating 11,12-EET, a major cardiac EET isoform. In the presence of comparable cardiac angiotensin-converting enzyme (ACE) expression/activity among the three groups, HFD rats exhibited significantly greater chymase-dependent ANG II formation in hearts, as indicated by an augmented cardiac chymase content as a function of enhanced mast cell degranulation. The enhanced chymase-dependent ANG II production was paralleled with increases in ANG II type 1 receptor (AT1R) expression and NADPH oxidase (Nox)-induced superoxide, alterations that were significantly reversed by TPPU. Conversely, HFD-induced downregulation of cardiac ACE2, followed by a lower Ang-(1-7) level displayed in an TPPU-irreversible manner. In conclusion, HFD-driven adverse chymase/ANG II/Nox/superoxide signaling in young rats was prevented by inhibition of sEH via, at least in part, an EET-mediated stabilization of mast cells, highlighting chymase and sEH as therapeutic targets during treatment of MetS.NEW & NOTEWORTHY As the highest fructose consumers, the adolescent population is highly susceptible to the metabolic syndrome, where increases in mast cell chymase-dependent formation of ANG II, ensued by cardiometabolic dysfunction, are reversible in response to inhibition of soluble epoxide hydrolase (sEH). This study highlights chymase and sEH as therapeutic targets and unravels novel avenues for the development of optimal strategies for young patients with fructose-induced metabolic syndrome.


Assuntos
Ácido 8,11,14-Eicosatrienoico/análogos & derivados , Angiotensina II/metabolismo , Quimases/metabolismo , Frutose/efeitos adversos , Cardiopatias/metabolismo , Síndrome Metabólica/complicações , Ácido 8,11,14-Eicosatrienoico/metabolismo , Animais , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Débito Cardíaco , Células Cultivadas , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Epóxido Hidrolases/antagonistas & inibidores , Coração/efeitos dos fármacos , Coração/fisiopatologia , Cardiopatias/tratamento farmacológico , Cardiopatias/etiologia , Frequência Cardíaca , Masculino , Síndrome Metabólica/etiologia , Miocárdio/metabolismo , Estresse Oxidativo , Compostos de Fenilureia/farmacologia , Compostos de Fenilureia/uso terapêutico , Piperidinas/farmacologia , Piperidinas/uso terapêutico , Ratos , Ratos Sprague-Dawley
5.
Am J Physiol Heart Circ Physiol ; 318(4): H883-H894, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32083974

RESUMO

Doxorubicin (Dox) is an effective chemotherapeutic for a variety of pediatric malignancies. Unfortunately, Dox administration often results in a cumulative dose-dependent cardiotoxicity that manifests with marked oxidative stress, leading to heart failure. Adjunct therapies are needed to mitigate Dox cardiotoxicity and enhance quality of life in pediatric patients with cancer. Angiotensin-(1-7) [Ang-(1-7)] is an endogenous hormone with cardioprotective properties. This study investigated whether adjunct Ang-(1-7) attenuates cardiotoxicity resulting from exposure to Dox in male and female juvenile rats. Dox significantly reduced body mass, and the addition of Ang-(1-7) had no effect. However, adjunct Ang-(1-7) prevented Dox-mediated diastolic dysfunction, including markers of decreased passive filling as measured by reduced early diastole mitral valve flow velocity peak (E) (P < 0.05) and early diastole mitral valve annulus peak velocity (e'; P < 0.001) and increased E/e' (P < 0.001), an echocardiographic measure of diastolic dysfunction. Since Dox treatment increases reactive oxygen species (ROS), the effect of Ang-(1-7) on oxidative by-products and enzymes that generate or reduce ROS was investigated. In hearts of male and female juvenile rats, Dox increased NADPH oxidase 4 (P < 0.05), a major cardiovascular NADPH oxidase isozyme that generates ROS, as well as 4-hydroxynonenal (P < 0.001) and malondialdehyde (P < 0.001), markers of lipid peroxidation; Ang-(1-7) prevented these effects of Dox. Cotreatment with Dox and Ang-(1-7) increased the antioxidant enzymes SOD1 (male: P < 0.05; female: P < 0.01) and catalase (P < 0.05), which likely contributed to reduced ROS. These results demonstrate that Ang-(1-7) prevents diastolic dysfunction in association with a reduction in ROS, suggesting that the heptapeptide hormone may serve as an effective adjuvant to improve Dox-induced cardiotoxicity.NEW & NOTEWORTHY Ang-(1-7) is a clinically safe peptide hormone with cardioprotective and antineoplastic properties that could be used as an adjuvant therapy to improve cancer treatment and mitigate the long-term cardiotoxicity associated with doxorubicin in pediatric patients with cancer.


Assuntos
Angiotensina I/uso terapêutico , Antineoplásicos/toxicidade , Antioxidantes/uso terapêutico , Doxorrubicina/toxicidade , Cardiopatias/tratamento farmacológico , Fragmentos de Peptídeos/uso terapêutico , Animais , Cardiotoxicidade , Catalase/metabolismo , Feminino , Cardiopatias/etiologia , Frequência Cardíaca , Masculino , Malondialdeído/metabolismo , Valva Mitral/fisiopatologia , Miocárdio/metabolismo , NADPH Oxidases/genética , NADPH Oxidases/metabolismo , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/metabolismo
6.
J Ethnopharmacol ; 246: 112210, 2020 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-31479707

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Compound Danshen tablet, an herbal preparation consisting of salviae miltiorrhizae, notoginseng and borneolum, is extensively employed clinically to treat angina pectoris, coronary arteriosclerosis and significantly improve microcirculation. AIM OF THE STUDY: To reveal the potential underlying cardioprotective mechanism(s) in isoproterenol-induced myocardial injury in high-fat-diet fed mice. MATERIALS AND METHODS: Cardiac transcriptomics was analyzed by Illumina mRNA-Seq sequencing. The restored cardiovascular diseases (CVD)-related genes by Compound Danshen tablet were validated by quantitative real time polymerase chain reaction (qRT-PCR). Furthermore, Cardiac metabolomics were also performed using gas chromatography-mass spectrometry. RESULTS: From the transcriptomics study, we found the levels of 24 up-regulated and 44 down-regulated genes in the control compared to model groups. Among them, seven gene levels were restored by treatment of Compound Danshen tablet. Four CVD-related genes at the mRNA level (Sprr1a, Ppp1r3c, Bmp10 and Hspa1b) were validated successfully by qRT-PCR. From the metabolomics study, 37 differentially expressed metabolites were identified between the control and model groups. Among them, 21 metabolites were restored by treatment of Compound Danshen tablet. These altered metabolites are involved in glucose metabolism, fatty acid metabolism and amino acid metabolism. CONCLUSION: These genes and metabolites might provide clues for further molecular mechanistic study of Compound Danshen tablet.


Assuntos
Cardiotônicos/farmacologia , Cardiotônicos/uso terapêutico , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Cardiopatias/genética , Cardiopatias/metabolismo , Animais , Dieta Hiperlipídica , Perfilação da Expressão Gênica , Cardiopatias/induzido quimicamente , Cardiopatias/tratamento farmacológico , Isoproterenol , Masculino , Metabolômica , Camundongos Endogâmicos C57BL , Miocárdio/metabolismo , Comprimidos , Transcriptoma/efeitos dos fármacos
7.
Oxid Med Cell Longev ; 2019: 1243215, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31871537

RESUMO

Excessive fructose consumption induces oxidative stress and myocardial fibrosis. Antioxidant compound pterostilbene has cardioprotective effect in experimental animals. This study is aimed at investigating how fructose drove fibrotic responses via oxidative stress in cardiomyocytes and explored the attenuation mechanisms of pterostilbene. We observed fructose-induced myocardial hypertrophy and fibrosis with ROS overproduction in rats. Paired-like homeodomain 2 (Pitx2c) increase, microRNA-15b (miR-15b) low expression, and p53 phosphorylation (p-p53) upregulation, as well as activation of transforming growth factor-ß1 (TGF-ß1)/drosophila mothers against DPP homolog (Smads) signaling and connective tissue growth factor (CTGF) induction, were also detected in fructose-fed rat hearts and fructose-exposed rat myocardial cell line H9c2 cells. The results from p53 siRNA or TGF-ß1 siRNA transfection showed that TGF-ß1-induced upregulation of CTGF expression and p-p53 activated TGF-ß1/Smads signaling in fructose-exposed H9c2 cells. Of note, Pitx2c negatively modulated miR-15b expression via binding to the upstream of the miR-15b genetic loci by chromatin immunoprecipitation and transfection analysis with pEX1-Pitx2c plasmid and Pitx2c siRNA, respectively. In H9c2 cells pretreated with ROS scavenger N-acetylcysteine, or transfected with miR-15b mimic and inhibitor, fructose-induced cardiac ROS overload could drive Pitx2c-mediated miR-15b low expression, then cause p-p53-activated TGF-ß1/Smads signaling and CTGF induction in myocardial fibrosis. We also found that pterostilbene significantly improved myocardial hypertrophy and fibrosis in fructose-fed rats and fructose-exposed H9c2 cells. Pterostilbene reduced cardiac ROS to block Pitx2c-mediated miR-15b low expression and p-p53-dependent TGF-ß1/Smads signaling activation and CTGF induction in high fructose-induced myocardial fibrosis. These results firstly demonstrated that the ROS-driven Pitx2c/miR-15b pathway was required for p-p53-dependent TGF-ß1/Smads signaling activation in fructose-induced myocardial fibrosis. Pterostilbene protected against high fructose-induced myocardial fibrosis through the inhibition of Pitx2c/miR-15b pathway to suppress p-p53-activated TGF-ß1/Smads signaling, warranting the consideration of Pitx2c/miR-15b pathway as a therapeutic target in myocardial fibrosis.


Assuntos
Fibrose/tratamento farmacológico , Fibrose/metabolismo , Frutose/toxicidade , Cardiopatias/tratamento farmacológico , Cardiopatias/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Estilbenos/uso terapêutico , Animais , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos
8.
Proc Jpn Acad Ser B Phys Biol Sci ; 95(8): 459-467, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31611501

RESUMO

Ghrelin, a growth hormone-releasing peptide first discovered in rat stomach in 1999, is a ligand for the growth hormone secretagogue receptor. It participates in the regulation of diverse processes, including energy balance and body weight maintenance, and appears to be beneficial for the treatment of cardiovascular diseases. In animal models of chronic heart failure, ghrelin improves cardiac function and remodeling; these findings have been recapitulated in human patients. In other animal models, ghrelin effectively diminishes pulmonary hypertension. Moreover, ghrelin administration early after myocardial infarction decreased the frequency of fatal arrhythmia and improved survival rate. In ghrelin-deficient mice, endogenous ghrelin protects against fatal arrhythmia and promotes remodeling after myocardial infarction. Although the mechanisms underlying the effects of ghrelin on the cardiovascular system have not been fully elucidated, its beneficial effects appear to be mediated through regulation of the autonomic nervous system. Ghrelin is a promising therapeutic agent for cardiac diseases.


Assuntos
Sistema Cardiovascular/metabolismo , Grelina/metabolismo , Sequência de Aminoácidos , Animais , Sistema Nervoso Autônomo/metabolismo , Sistema Nervoso Autônomo/fisiologia , Sistema Cardiovascular/efeitos dos fármacos , Sistema Cardiovascular/fisiopatologia , Grelina/química , Grelina/farmacologia , Grelina/uso terapêutico , Cardiopatias/tratamento farmacológico , Cardiopatias/fisiopatologia , Humanos , Receptores de Grelina/metabolismo
9.
J Invasive Cardiol ; 31(9): E277, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31478897

RESUMO

TAVI complications may occur in the peri- and postprocedural periods. A 79-year-old woman with known severe degenerative calcified aortic stenosis underwent transfemoral TAVI; prior to groin closure, she became hypotensive. Prosthetic valve thrombosis was confirmed with transesophageal echocardiography and computed tomography aortogram, which showed thrombus on the immobile non-coronary cusp leaflet.


Assuntos
Estenose da Valva Aórtica/cirurgia , Valva Aórtica/patologia , Calcinose/cirurgia , Complicações Pós-Operatórias/diagnóstico , Trombose/diagnóstico , Substituição da Valva Aórtica Transcateter/efeitos adversos , Idoso , Anticoagulantes/uso terapêutico , Valva Aórtica/cirurgia , Estenose da Valva Aórtica/diagnóstico , Calcinose/diagnóstico , Ecocardiografia Transesofagiana , Feminino , Cardiopatias/diagnóstico , Cardiopatias/tratamento farmacológico , Humanos , Tomografia Computadorizada Multidetectores , Complicações Pós-Operatórias/tratamento farmacológico , Desenho de Prótese , Falha de Prótese , Trombose/tratamento farmacológico
11.
Int J Mol Med ; 44(4): 1255-1266, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31432099

RESUMO

The primary mechanism underlying sepsis­induced cardiac dysfunction is loss of endothelial barrier function. Neuregulin­1 (NRG­1) exerts its functions on multiple targets. The present study aimed to identify the protective effects of NRG­1 in myocardial cells, including endothelial, anti­inflammatory and anti­apoptotic effects. Subsequent to lipopolysaccharide (LPS)­induced sepsis, rats were administered with either a vehicle or recombinant human NRG­1 (rhNRG­1; 10 µg/kg/day) for one or two days. H9c2 cardiomyoblasts were subjected to LPS (10 µg/ml) treatment for 12 and 24 h with or without rhNRG­1 (1 µg/ml). Survival rates were recorded at 48 h following sepsis induction. The hemodynamic method was performed to evaluate cardiac function, and myocardial morphology was observed. Von Willebrand Factor levels were detected using an immunofluorescence assay. Serum levels of tumor necrosis factor α, interleukin­6, intercellular cell adhesion molecule­1 and vascular endothelial growth factor were detected using an enzyme­linked immunosorbent assay; the reductase method was performed to detect serum nitric oxide levels. Apoptosis rates were determined using terminal deoxynucleotidyl transferase dUTP nick end labeling staining. Ras homolog family member A (RhoA) and Rho­associated protein kinase 1 (ROCK1) protein levels were assessed using western blotting. Transmission electron microscopy was used to observe endothelial cells and myocardial ultrastructure changes. Results revealed that NRG­1­treated rats displayed less myocardial damage compared with sham rats. NRG­1 administration strengthened the barrier function of the vasculature, reduced the secretion of endothelial­associated biomarkers and exerted anti­inflammatory and anti­apoptotic effects. In addition, NRG­1 inhibited RhoA and ROCK1 signaling. The results revealed that NRG­1 improves cardiac function, increases the survival rate of septic rats and exerts protective effects via multiple targets throughout the body. The present results contribute to the development of a novel approach to reverse damage to myocardial and endothelial cells during sepsis.


Assuntos
Cardiotônicos/farmacologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Cardiopatias/etiologia , Cardiopatias/fisiopatologia , Neuregulina-1/farmacologia , Sepse/complicações , Animais , Apoptose/efeitos dos fármacos , Biomarcadores , Permeabilidade Capilar/efeitos dos fármacos , Citocinas/metabolismo , Cardiopatias/tratamento farmacológico , Cardiopatias/mortalidade , Testes de Função Cardíaca , Humanos , Mediadores da Inflamação , Miocárdio/metabolismo , Miocárdio/patologia , Miocárdio/ultraestrutura , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/ultraestrutura , Estresse Oxidativo/efeitos dos fármacos , Ligação Proteica , Ratos , Espécies Reativas de Oxigênio/metabolismo , Proteínas Recombinantes/farmacologia
12.
Integr Cancer Ther ; 18: 1534735419862351, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31282195

RESUMO

Background: This study evaluated the cardioprotective effect of Ajwa nano-preparation against doxorubicin-associated cardiotoxicity. Methods: Twenty-four male Wistar rats (200-250 g) were divided into 3 groups. One group was given the nanopreparation containing both Ajwa fruit and pit in a dose of 1.4 g/kg orally 1 hour before doxorubicin infusion (Dates-DOX group). Another group was given the vehicle for 1 hour before doxorubicin infusion (DOX group). The third group received the vehicle but no DOX infusion (time control). Cardiac hemodynamics, blood pressure, cardiac contractility, and conductivity were recorded before and after 45 minutes of infusion of doxorubicin (15 mg/kg, slow intravenous over 45 minutes). Blood samples were collected before and after doxorubicin infusion. Heart tissue samples were collected and snap frozen until assay of reduced glutathione. Results: Rats pre-administered Ajwa nanopreparation were protected from doxorubicin-associated systolic and diastolic dysfunction based on the significant elevation in the rate of rise in left ventricular pressure (dp/dtmax) and (dp/dtmin) compared with the DOX group. In addition, it prevented the doxorubicin-associated ischemia based on the significant shortening in QT interval, JT interval, and Tpeak-Tend interval versus the DOX group. There was no effect on atrial conductivity (PR interval and P duration). Ajwa pretreatment increased the antioxidant capacity of cardiac tissue, as evidenced by increasing the cardiac content of reduced glutathione compared with the untreated doxorubicin group. Conclusion: Ajwa nanopreparation protects from doxorubicin-associated cardiotoxicity through alleviating cardiac ischemia and increasing cardiac antioxidant capacity.


Assuntos
Antioxidantes/metabolismo , Doxorrubicina/efeitos adversos , Cardiopatias/induzido quimicamente , Cardiopatias/tratamento farmacológico , Coração/efeitos dos fármacos , Nanopartículas/administração & dosagem , Preparações de Plantas/farmacologia , Animais , Antibióticos Antineoplásicos/efeitos adversos , Cardiotoxicidade/tratamento farmacológico , Cardiotoxicidade/metabolismo , Frutas/química , Glutationa/metabolismo , Cardiopatias/metabolismo , Masculino , Estresse Oxidativo/efeitos dos fármacos , Phoeniceae/química , Ratos , Ratos Wistar
13.
Turk Kardiyol Dern Ars ; 47(5): 391-398, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31311898

RESUMO

OBJECTIVE: The aim of this study is to assess the prevalence of polypharmacy, inappropriate drug use, and drug-drug interactions (DDIs) in elderly patients presenting at outpatient cardiology clinics in Turkey. METHODS: The EPIC (Epidemiology of Polypharmacy and Potential Drug-Drug Interactions in Elderly Cardiac Outpatients) study will be an observational, real-world, multicenter study conducted to evaluate DDIs and polypharmacy in elderly cardiac outpatients. All consecutive patients (aged ≥65 years) admitted to outpatient cardiology clinics between July 30, 2018 and July 30, 2019 who provide written, informed consent will be enrolled. A total of approximately 5000 patients are to be enrolled in this non-interventional study. All of the data will be collected at one point in time and current clinical practice will be evaluated (ClinicalTrials.gov NCT03370523). RESULTS: Patient demographics, comorbid disease characteristics, laboratory test results, and details of medication use will be collected using self-reports and medical records. The severity of comorbid disease will be recorded and scored according to Charlson Comorbidity Index (CCI) and patients will be divided into 3 groups: mild, those with a CCI score of 1-2; moderate, those with a CCI score of 3-4; and severe, those with a CCI score of ≥5. Polypharmacy will be defined as the use of 5 or more medications at one time. DDIs will be determined using the Lexicomp Online drug interaction screening tool and potentially inappropriate medications will be defined based on the 2015 update of the Beers Criteria for Potentially Inappropriate Medication Use in Older Adults. Severe drug interactions will be defined as those in category D or X. CONCLUSION: EPIC will be the first large-scale study in Turkey to evaluate polypharmacy, potentially inappropriate medications, and DDIs in elderly cardiac outpatients in a real-world clinical setting.


Assuntos
Fármacos Cardiovasculares , Ensaios Clínicos como Assunto , Interações Medicamentosas , Polimedicação , Projetos de Pesquisa , Idoso , Idoso de 80 Anos ou mais , Assistência Ambulatorial , Fármacos Cardiovasculares/efeitos adversos , Fármacos Cardiovasculares/farmacologia , Fármacos Cardiovasculares/uso terapêutico , Cardiopatias/tratamento farmacológico , Humanos , Lista de Medicamentos Potencialmente Inapropriados
14.
G Ital Cardiol (Rome) ; 20(6): 374-383, 2019 Jun.
Artigo em Italiano | MEDLINE | ID: mdl-31184324

RESUMO

Atrial fibrillation (AF) is the most frequent sustained cardiac arrhythmia, and its prevalence is increasing, partly due to the progressive aging of the population. AF predisposes to thrombus formation in the atria and the atrial appendage through a complex interaction among local, systemic and hemodynamic factors, significantly increasing the risk for cerebral and systemic thromboembolic events. These complications have a major impact in terms of morbidity and mortality, and numerous therapeutic strategies have been proposed to reduce such risk. Systemic anticoagulation is the main strategy in the prevention of atrial and left atrial appendage thrombosis, and the advent of non-vitamin K antagonist oral anticoagulants (NOACs) has been a significant step forward, especially for safety, compared to warfarin. While prevention of atrial appendage thrombosis with NOACs has been widely explored, their role in the resolution of thrombi is less clear. The use of NOACs in this setting is largely unexplored, and some studies are underway to clarify their effectiveness. The objective of this paper is to review the literature on atrial and left atrial appendage thrombosis, describing pathophysiological mechanisms and current treatment strategies using NOACs.


Assuntos
Anticoagulantes/administração & dosagem , Apêndice Atrial , Fibrilação Atrial/complicações , Átrios do Coração , Cardiopatias/tratamento farmacológico , Cardiopatias/etiologia , Trombose/tratamento farmacológico , Trombose/etiologia , Administração Oral , Fibrilação Atrial/fisiopatologia , Humanos
15.
Int J Mol Med ; 44(2): 549-558, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31198980

RESUMO

Hydrogen sulfide (H2S) has antifibrotic activity in the kidneys, heart, lungs, and other organs. The present study investigated the protective activity of exogenous H2S against myocardial fibrosis in a rat model of diabetes. Animals were assigned to normal control, diabetes mellitus (DM), DM + sodium hydrosulfide (NaHS; DM + NaHS) and NaHS groups. Fasting blood glucose (FBG), cardiac function and hydroxyproline were monitored. Heart histomorphology and ultrastructure were additionally evaluated. Wnt1­inducible signaling pathway protein (WISP)­1 protein expression in the myocardium was determined by immunohistochemical staining. Matrix metalloprotease (MMP)­2, tissue inhibitor of metalloproteinase (TIMP)­2, collagens, and canonical Wnt and transforming growth factor (TGF)­ß1/SMAD family member 3 (Smad3) pathway­related proteins were assessed by western blotting. Cardiac function was decreased, and myocardial injury, hypertrophy and fibrosis were increased in the diabetes model rats. MMP­2 expression was decreased, and the expressions of WISP­1, TIMP­2, collagens, and canonical Wnt and TGF­ß1/Smad3 pathway­related proteins were increased in the myocardia of the diabetes model rats. The present results indicated that the canonical Wnt pathway promoted diabetic myocardial fibrosis by upregulating the TGF­ß1/Smad3 pathway. Except for FBG, exogenous H2S ameliorated the changes in diabetes­associated indices in rats in the DM + NaHS group. The results are consistent with H2S protection of streptozotocin­induced myocardial fibrosis in the diabetes model rats by downregulation of the canonical Wnt and TGF­ß1/Smad3 pathway and decreased myocardial collagen deposition.


Assuntos
Diabetes Mellitus Experimental/complicações , Cardiopatias/tratamento farmacológico , Coração/efeitos dos fármacos , Sulfeto de Hidrogênio/uso terapêutico , Miocárdio/patologia , Via de Sinalização Wnt/efeitos dos fármacos , Animais , Colágeno/análise , Colágeno/metabolismo , Fibrose , Cardiopatias/metabolismo , Cardiopatias/patologia , Masculino , Miocárdio/metabolismo , Ratos Sprague-Dawley
16.
Nat Rev Cardiol ; 16(10): 612-622, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31186538

RESUMO

G protein-coupled receptors (GPCRs) are critical cellular sensors that mediate numerous physiological processes. In the heart, multiple GPCRs are expressed on various cell types, where they coordinate to regulate cardiac function by modulating critical processes such as contractility and blood flow. Under pathological settings, these receptors undergo aberrant changes in expression levels, localization and capacity to couple to downstream signalling pathways. Conventional therapies for heart failure work by targeting GPCRs, such as ß-adrenergic receptor and angiotensin II receptor antagonists. Although these treatments have improved patient survival, heart failure remains one of the leading causes of mortality worldwide. GPCR kinases (GRKs) are responsible for GPCR phosphorylation and, therefore, desensitization and downregulation of GPCRs. In this Review, we discuss the GPCR signalling pathways and the GRKs involved in the pathophysiology of heart disease. Given that increased expression and activity of GRK2 and GRK5 contribute to the loss of contractile reserve in the stressed and failing heart, inhibition of overactive GRKs has been proposed as a novel therapeutic approach to treat heart failure.


Assuntos
Quinases de Receptores Acoplados a Proteína G/antagonistas & inibidores , Quinases de Receptores Acoplados a Proteína G/metabolismo , Cardiopatias/tratamento farmacológico , Cardiopatias/fisiopatologia , Antagonistas Adrenérgicos beta/uso terapêutico , Animais , Catecolaminas/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/genética , Quinase 2 de Receptor Acoplado a Proteína G/antagonistas & inibidores , Quinase 2 de Receptor Acoplado a Proteína G/metabolismo , Quinase 5 de Receptor Acoplado a Proteína G/antagonistas & inibidores , Quinase 5 de Receptor Acoplado a Proteína G/metabolismo , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/fisiopatologia , Humanos , Contração Muscular , Miócitos Cardíacos , Fragmentos de Peptídeos/genética , Receptores Adrenérgicos/metabolismo , Proteínas Recombinantes/genética , Transdução de Sinais/genética , beta-Arrestinas/metabolismo
18.
Life Sci ; 232: 116526, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31170418

RESUMO

Tumors and heart disease are two of the leading causes of human death. With the development of anti-cancer therapy, the survival rate of cancer patients has been significantly improved. But at the same time, the incidence of cardiovascular adverse events caused by cancer treatment has also been considerably increased, such as arrhythmia, left ventricular (LV) systolic and diastolic dysfunction, and even heart failure (HF), etc., which seriously affects the quality of life of cancer patients. More importantly, the occurrence of adverse events may lead to the adjustment or the cessation of anti-cancer treatment, which affects the survival rate of patients. Understanding the mechanism of cardiotoxicity (CTX) induced by antineoplastic drugs is the basis of adequate protection of the heart without impairing the efficacy of antineoplastic therapy. Based on current research, a large amount of evidence has shown that oxidative stress (OS) plays an essential role in CTX induced by antineoplastic drugs and participates in its toxic reaction directly and indirectly. Here, we will review the mechanism of action of OS in cardiac toxicity of antineoplastic drugs, to provide new ideas for researchers, and provide further guidance for clinical prevention and treatment of cardiac toxicity of anti-tumor drugs in the future.


Assuntos
Antineoplásicos/metabolismo , Cardiotoxicidade/prevenção & controle , Estresse Oxidativo/fisiologia , Antineoplásicos/efeitos adversos , Arritmias Cardíacas/complicações , Arritmias Cardíacas/fisiopatologia , Cardiotoxicidade/metabolismo , Coração/fisiopatologia , Cardiopatias/tratamento farmacológico , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/fisiopatologia , Humanos , Neoplasias/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/genética , Qualidade de Vida
19.
Eur J Pharmacol ; 858: 172468, 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31226249

RESUMO

As heart failure (HF) is a growing public health problem worldwide, rapid therapeutic development is required to improve HF management. Decreased myocardial contractility in HF is associated with the persistent sympathetic activation of ß1/ß2-adrenoceptors (ß1/ß2-ARs). Although it is initially activated to compensate for a decline in myocardial contractility, it plays a pivotal role in organ damage and functional deterioration over time, resulting in the desensitization of receptors involved. The third ß-AR subtype, ß3-AR, is resistant to desensitization, and as a result, the expression of this subtype is enhanced in human failing myocardium. In addition, this upregulation and the stimulation of this subtype have been demonstrated to mediate cardioprotective effects such as antihypertrophic, antioxidant and antifibrotic effects via various signaling pathways in different cell types. However, the role of this attractive therapeutic intervention in heart diseases must be clarified through clinical trials.


Assuntos
Cardiopatias/tratamento farmacológico , Terapia de Alvo Molecular/métodos , Receptores Adrenérgicos beta 3/metabolismo , Antagonistas de Receptores Adrenérgicos beta 3/farmacologia , Antagonistas de Receptores Adrenérgicos beta 3/uso terapêutico , Animais , Regulação da Expressão Gênica/efeitos dos fármacos , Cardiopatias/metabolismo , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/metabolismo , Humanos
20.
Eur J Clin Pharmacol ; 75(10): 1361-1367, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31250045

RESUMO

PURPOSE: The influence of the aldehyde dehydrogenase 2 (ALDH2) gene polymorphism on the pharmacokinetics and haemodynamics of nitroglycerin (GTN) was determined in human subjects. METHODS: Eighteen infants (nine each with and without ALDH2 gene polymorphism) with congenital heart disease and pulmonary arterial hypertension participated in this study. GTN treatment started at a dose of 2 µg/kg/min, and the dose was escalated by 1-2 µg/kg/min until pulmonary vascular resistance (PVR) was reduced by more than 30%. The plasma GTN concentration and PVR were measured at the end of each infusion period. RESULTS: Plasma GTN concentrations were significantly higher in patients with the ALDH2 gene polymorphism than in those without the polymorphism. Conversely, the reduction in PVR was smaller in patients with the ALDH2 gene polymorphism than in those without. CONCLUSIONS: These data suggest that the ALDH2 gene polymorphism influences the pharmacokinetics and haemodynamics of GTN in human subjects.


Assuntos
Aldeído-Desidrogenase Mitocondrial/genética , Cardiopatias/genética , Cardiopatias/metabolismo , Nitroglicerina/farmacocinética , /metabolismo , Vasodilatadores/farmacocinética , Feminino , Genótipo , Cardiopatias/tratamento farmacológico , Humanos , Lactente , Masculino , Nitroglicerina/sangue , Nitroglicerina/uso terapêutico , Polimorfismo Genético , Vasodilatação/efeitos dos fármacos , Vasodilatadores/sangue , Vasodilatadores/uso terapêutico
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