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1.
Artigo em Inglês | MEDLINE | ID: mdl-34909660

RESUMO

This article summarizes the current literature and documents new evidence concerning drug-drug interactions (DDI) stemming from pharmacogenomic and circadian rhythm determinants of therapies used to treat common cardiovascular diseases (CVD), such as atherosclerosis and hypertension. Patients with CVD often have more than one pathophysiologic condition, namely metabolic syndromes, hypertension, hyperlipidemia, and hyperglycemia, among others, which necessitate polytherapeutic or polypharmaceutic management. Interactions between drugs, drugs and food/food supplements, or drugs and genetic/epigenetic factors may have adverse impacts on the cardiovascular and other systems of the body. The mechanisms underlying cardiovascular DDI may involve the formation of a complex pharmacointeractome, including the absorption, distribution, metabolism, and elimination of drugs, which affect their respective bioavailability, efficacy, and/or harmful metabolites. The pharmacointeractome of cardiovascular drugs is likely operated with endogenous rhythms controlled by circadian clock genes. Basic and clinical investigations have improved the knowledge and understanding of cardiovascular pharmacogenomics and pharmacointeractomes, and additionally they have presented new evidence that the staging of deterministic circadian rhythms, according to the dosing time of drugs, e.g., upon awakening vs. at bedtime, cannot only differentially impact their pharmacokinetics and pharmacodynamics but also mediate agonistic/synergetic or antagonistic DDI. To properly manage CVD patients and avoid DDI, it is important that clinicians have sufficient knowledge of their multiple risk factors, i.e., age, gender, and life style elements (like diet, smoking, psychological stress, and alcohol consumption), and comorbidities, such as diabetes, hypertension, dyslipidemia, and depression, and the potential interactions between genetic or epigenetic background of their prescribed therapeutics.

3.
J Cell Mol Med ; 25(12): 5381-5390, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33949765

RESUMO

Cardiac stromal cells (CSCs) contain a pool of cells with supportive and paracrine functions. Various types of mesenchymal stromal cells (MSCs) can influence CSCs in the cardiac niche through their paracrine activity. Ischaemia/reperfusion (I/R) leads to cell death and reduction of the paracrine activity of CSCs. The forced co-expression of telomerase reverse transcriptase (TERT) and myocardin (MYOCD), known to potentiate anti-apoptotic, pro-survival and pro-angiogenic activities of MSCs isolated from the adipose tissue (AT-MSCs), may increase CSC survival, favouring their paracrine activities. We aimed at investigating the hypothesis that CSCs feature improved resistance to simulated I/R (SI/R) and increased commitment towards the cardiovascular lineage when preconditioned with conditioned media (CM) or extracellular vesicles (EV) released from AT-MSCs overexpressing TERT and MYOCD (T/M AT-MSCs). Murine CSCs were isolated with the cardiosphere (CSps) isolation technique. T/M AT-MSCs and their secretome improved spontaneous intracellular calcium changes and ryanodine receptor expression in aged CSps. The cytoprotective effect of AT-MSCs was tested in CSCs subjected to SI/R. SI/R induced cell death as compared to normoxia (28 ± 4 vs 10 ± 3%, P = .02). Pre-treatment with CM (15 ± 2, P = .02) or with the EV-enriched fraction (10 ± 1%, P = .02) obtained from mock-transduced AT-MSCs in normoxia reduced cell death after SI/R. The effect was more pronounced with CM (7 ± 1%, P = .01) or the EV-enriched fraction (2 ± 1%, P = .01) obtained from T/M AT-MSCs subjected to SI/R. In parallel, we observed lower expression of the apoptosis marker cleaved caspase-3 and higher expression of cardiac and vascular markers eNOS, sarcomeric α-actinin and cardiac actin. The T/M AT-MSCs secretome exerts a cytoprotective effect and promotes development of CSCs undergoing SI/R towards a cardiovascular phenotype.


Assuntos
Biomarcadores/metabolismo , Doenças Cardiovasculares/terapia , Coração/crescimento & desenvolvimento , Células-Tronco Mesenquimais/citologia , Proteínas Nucleares/metabolismo , Traumatismo por Reperfusão/complicações , Telomerase/metabolismo , Transativadores/metabolismo , Animais , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/patologia , Masculino , Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Mesenquimais/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Nucleares/genética , Telomerase/genética , Transativadores/genética
4.
Epidemiol Infect ; 149: e4, 2021 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-33397519

RESUMO

Hypertension represents one of the most common pre-existing conditions and comorbidities in Coronavirus disease 2019 (COVID-19) patients. To explore whether hypertension serves as a risk factor for disease severity, a multi-centre, retrospective study was conducted in COVID-19 patients. A total of 498 consecutively hospitalised patients with lab-confirmed COVID-19 in China were enrolled in this cohort. Using logistic regression, we assessed the association between hypertension and the likelihood of severe illness with adjustment for confounders. We observed that more than 16% of the enrolled patients exhibited pre-existing hypertension on admission. More severe COVID-19 cases occurred in individuals with hypertension than those without hypertension (21% vs. 10%, P = 0.007). Hypertension associated with the increased risk of severe illness, which was not modified by other demographic factors, such as age, sex, hospital geological location and blood pressure levels on admission. More attention and treatment should be offered to patients with underlying hypertension, who usually are older, have more comorbidities and more susceptible to cardiac complications.


Assuntos
COVID-19/complicações , Hipertensão/complicações , Adulto , Idoso , COVID-19/diagnóstico , China , Comorbidade , Feminino , Hospitalização , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Fatores de Risco
5.
Chronobiol Int ; 38(1): 1-26, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33342316

RESUMO

Current hypertension guidelines fail to provide a recommendation on when-to-treat, thus disregarding relevant circadian rhythms that regulate blood pressure (BP) level and 24 h patterning and medication pharmacokinetics and pharmacodynamics. The ideal purpose of ingestion-time (chronopharmacology, i.e. biological rhythm-dependent effects on the kinetics and dynamics of medications, and chronotherapy, i.e. the timing of pharmaceutical and other treatments to optimize efficacy and safety) trials should be to explore the potential impact of endogenous circadian rhythms on the effects of medications. Such investigations and outcome trials mandate adherence to the basic standards of human chronobiology research. In-depth review of the more than 150 human hypertension pharmacology and therapeutic trials published since 1974 that address the differential impact of upon-waking/morning versus at-bedtime/evening schedule of treatment reveals diverse protocols of sometimes suboptimal or defective design and conduct. Many have been "time-of-day," i.e. morning versus evening, rather than circadian-time-based, and some relied on wake-time office BP rather than around-the-clock ambulatory BP measurements (ABPM). Additionally, most past studies have been of too small sample size and thus statistically underpowered. As of yet, there has been no consensual agreement on the proper design, methods and conduct of such trials. This Position Statement recommends ingestion-time hypertension trials to follow minimum guidelines: (i) Recruitment of participants should be restricted to hypertensive individuals diagnosed according to ABPM diagnostic thresholds and of a comparable activity/sleep routine. (ii) Tested treatment-times should be selected according to internal biological time, expressed by the awakening and bed times of the sleep/wake cycle. (iii) ABPM should be the primary or sole method of BP assessment. (iv) The minimum-required features for analysis of the ABPM-determined 24 h BP pattern ought to be the asleep (not "nighttime") BP mean and sleep-time relative BP decline, calculated in reference to the activity/rest cycle per individual. (v) ABPM-obtained BP means should be derived by the so-called adjusted calculation procedure, not by inaccurate arithmetic averages. (vi) ABPM should be performed with validated and calibrated devices at least hourly throughout two or more consecutive 24 h periods (48 h in total) to achieve the highest reproducibility of mean wake-time, sleep-time and 48 h BP values plus the reliable classification of dipping status. (vii) Calculation of minimum required sample size in adherence with proper statistical methods must be provided. (viii) Hypertension chronopharmacology and chronotherapy trials should preferably be randomized double-blind, randomized open-label with blinded-endpoint, or crossover in design, the latter with sufficient washout period between tested treatment-time regimens.


Assuntos
Monitorização Ambulatorial da Pressão Arterial , Hipertensão , Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea , Cronoterapia , Ritmo Circadiano , Ingestão de Alimentos , Humanos , Hipertensão/tratamento farmacológico , Reprodutibilidade dos Testes , Fatores de Risco , Fatores de Tempo
6.
Curr Opin Pharmacol ; 57: 41-48, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33279870

RESUMO

Circadian rhythms impact cardiac and vascular pathophysiology, resulting in 24-hour patterning of symptoms and life-threatening/ending events (chronopathology), plus kinetics and dynamics of medications (chronopharmacology), resulting in administration-time differences in efficacy and safety. Scheduling medications according to circadian rhythm determinants (chronotherapy) can improve treatment effects, for example, before dinner/bedtime ingestion of cholesterol-lowering medications and acetylsalicylic acid, respectively, exerts enhanced control of hypercholesterolemia and after-awakening peak of platelet aggregation; bedtime ingestion of conventional hypertension medications optimizes normalization of sleep-time blood pressure (BP)-strongest independent BP marker of cardiovascular disease (CVD) risk-and most effectively prevents (chronoprevention) CVD morbidity and mortality. Exploration of chronotherapeutic strategies to improve management of cardiac arrhythmias and vascular pathophysiology is still awaited.


Assuntos
Ritmo Circadiano , Hipertensão , Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea , Monitorização Ambulatorial da Pressão Arterial , Cronoterapia , Humanos , Hipertensão/tratamento farmacológico
7.
Vascul Pharmacol ; 135: 106807, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33130246

RESUMO

AIM: Cell therapies are hampered by poor survival and growth of grafts. We tested whether forced co-expression of telomerase reverse transcriptase (TERT) and myocardin (MYOCD) improves post-infarct revascularization and tissue repair by adipose tissue-derived mesenchymal stromal cells (AT-MSCs). METHODS AND RESULTS: We transplanted AT-MSCs overexpressing MYOCD and TERT in a murine model of acute myocardial infarction (AMI). We characterized paracrine effects of AT-MSCs. When transplanted into infarcted hearts of C57BL/6 mice, AT-MSCs overexpressing TERT and MYOCD decreased scar tissue and the intra-scar CD3 and B220 lymphocyte infiltration; and increased arteriolar density as well as ejection fraction compared with saline or mock-transduced AT-MSCs. These effects were accompanied by higher persistence of the injected cells in the heart, increased numbers of Ki-67+ and CD117+ cells, and the expression of cardiac actin and ß-myosin heavy chain. Intramyocardial delivery of the secretome and its extracellular vesicle (EV)-enriched fraction also decreased scar tissue formation and increased arteriolar density in the murine AMI model. Proteomic analysis of AT-MSCs-EV-enriched fraction predicted the activation of vascular development and the inhibition of immune cell trafficking. Elevated concentrations of miR-320a, miR-150-5p and miR-126-3p associated with regulation of apoptosis and vasculogenesis were confirmed in the AT-MSCs-EV-enriched fraction. CONCLUSIONS: AT-MSCs overexpressing TERT and MYOCD promote persistence of transplanted aged AT-MSCs and enhance arteriolar density in a murine model of AMI. EV-enriched fraction is the component of the paracrine secretion by AT-MSCs with pro-angiogenic and anti-fibrotic activities.


Assuntos
Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/enzimologia , Infarto do Miocárdio/cirurgia , Miocárdio/metabolismo , Proteínas Nucleares/metabolismo , Regeneração , Telomerase/metabolismo , Transativadores/metabolismo , Proteínas Angiogênicas/genética , Proteínas Angiogênicas/metabolismo , Animais , Células Cultivadas , Modelos Animais de Doenças , Vesículas Extracelulares/enzimologia , Vesículas Extracelulares/transplante , Fibrose , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , MicroRNAs/genética , MicroRNAs/metabolismo , Infarto do Miocárdio/enzimologia , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Miocárdio/patologia , Proteínas Nucleares/genética , Comunicação Parácrina , Recuperação de Função Fisiológica , Transdução de Sinais , Telomerase/genética , Transativadores/genética
8.
Cell Rep ; 32(11): 108140, 2020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32937135

RESUMO

FBXL21 is a clock-controlled E3 ligase modulating circadian periodicity via subcellular-specific CRYPTOCHROME degradation. How FBXL21 regulates tissue-specific circadian physiology and what mechanism operates upstream is poorly understood. Here we report the sarcomere component TCAP as a cytoplasmic substrate of FBXL21. FBXL21 interacts with TCAP in a circadian manner antiphasic to TCAP accumulation in skeletal muscle, and circadian TCAP oscillation is disrupted in Psttm mice with an Fbxl21 hypomorph mutation. GSK-3ß phosphorylates FBXL21 and TCAP to activate FBXL21-mediated, phosphodegron-dependent TCAP degradation. GSK-3ß inhibition or knockdown diminishes FBXL21-Cul1 complex formation and delays FBXL21-mediated TCAP degradation. Finally, Psttm mice show significant skeletal muscle defects, including impaired fiber size, exercise tolerance, grip strength, and response to glucocorticoid-induced atrophy, in conjunction with cardiac dysfunction. These data highlight a circadian regulatory pathway where a GSK-3ß-FBXL21 functional axis controls TCAP degradation via SCF complex formation and regulates skeletal muscle function.


Assuntos
Ritmo Circadiano , Conectina/metabolismo , Proteínas F-Box/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Músculo Esquelético/fisiologia , Proteólise , Sequência de Aminoácidos , Animais , Conectina/química , Células HEK293 , Humanos , Lisina/metabolismo , Camundongos Endogâmicos C57BL , Fibras Musculares Esqueléticas/metabolismo , Mutação/genética , Fosforilação , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteínas Ligases SKP Culina F-Box/metabolismo , Especificidade por Substrato , Ubiquitinação
9.
Eur J Heart Fail ; 22(11): 1994-2006, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32683753

RESUMO

The outbreak of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, has become a major health crisis and a worldwide pandemic. COVID-19 is characterized by high infectivity, long incubation period, diverse clinical presentations, and strong transmission intensity. COVID-19 can cause myocardial injury as well as other cardiovascular complications, particularly in senior patients with pre-existing medical conditions. The current review summarizes the epidemiological characteristics, potential mechanisms, clinical manifestations, and recent progress in the management of COVID-19 cardiovascular complications.


Assuntos
COVID-19/complicações , Doenças Cardiovasculares/virologia , COVID-19/epidemiologia , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/terapia , Humanos , Pandemias , Fatores de Risco , SARS-CoV-2
10.
Open Heart ; 7(1)2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32393654

RESUMO

OBJECTIVE: To test whether intensive atorvastatin (ATV) increases the efficacy of transplantation with autologous bone marrow mononuclear cells (MNCs) in patients suffering from anterior ST-elevated myocardial infarction (STEMI). METHODS: This clinical trial was under a 2×2 factorial design, enrolling 100 STEMI patients, randomly into four groups of regular (RA) or intensive ATV (IA) with MNCs or placebo. The primary endpoint was the change of left ventricular ejection fraction (LVEF) at 1-year follow-up from baseline, primarily assessed by MRI. The secondary endpoints included other parameters of cardiac function, remodelling and regeneration determined by MRI, echocardiography, positron emission tomography (PET) and biomarkers. RESULTS: All the STEMI patients with transplantation of MNCs showed significantly increased LVEF change values than those with placebo (p=0.01) with only in the IA+MNCs patients group demonstrating significantly elevation of LVEF than in the IA+placebo group (+12.6% (95%CI 10.4 to 19.3) vs +5.0% (95%CI 4.0 to 10.0), p=0.001), pointing to a better synergy between ATV and MNCs (p=0.019). PET analysis revealed significantly increased viable areas of myocardium (p=0.015), while the scar sizes (p=0.026) and blood aminoterminal pro-B-type natriuretic peptide (p<0.034) reduced. All these above benefits of MNCs were also attributed to IA+MNCs instead of RA+MNCs group of patients with STEMI. CONCLUSIONS: Intensive ATV treatment augments the therapeutic efficacy of MNCs in patients with anterior STEMI at the convalescent stage. The treatment with the protocol of intensive ATV and MNC combination offers a clinically essential approach for myocardial infarction. TRIAL REGISTRATION NUMBER: NCT00979758.


Assuntos
Atorvastatina/administração & dosagem , Transplante de Medula Óssea , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Infarto do Miocárdio com Supradesnível do Segmento ST/terapia , Adulto , Idoso , Atorvastatina/efeitos adversos , Pequim , Transplante de Medula Óssea/efeitos adversos , Terapia Combinada , Método Duplo-Cego , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Masculino , Pessoa de Meia-Idade , Recuperação de Função Fisiológica , Infarto do Miocárdio com Supradesnível do Segmento ST/diagnóstico por imagem , Infarto do Miocárdio com Supradesnível do Segmento ST/fisiopatologia , Volume Sistólico , Fatores de Tempo , Transplante Autólogo , Resultado do Tratamento , Função Ventricular Esquerda , Remodelação Ventricular
11.
Cardiovasc Pathol ; 47: 107228, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32375085

RESUMO

The pandemic of coronavirus disease 2019 (COVID-19) has emerged as a major health crisis, with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) having infected over a million people around the world within a few months of its identification as a human pathogen. Initially, SARS-CoV-2 infects cells in the respiratory system and causes inflammation and cell death. Subsequently, the virus spreads out and damages other vital organs and tissues, triggering a complicated spectrum of pathophysiological changes and symptoms, including cardiovascular complications. Acting as the receptor for SARS-CoV entering mammalian cells, angiotensin converting enzyme-2 (ACE2) plays a pivotal role in the regulation of cardiovascular cell function. Diverse clinical manifestations and laboratory abnormalities occur in patients with cardiovascular injury in COVID-19, characterizing the development of this complication, as well as providing clues to diagnosis and treatment. This review provides a summary of the rapidly appearing laboratory and clinical evidence for the pathophysiology and therapeutic approaches to COVID-19 pulmonary and cardiovascular complications.


Assuntos
Doenças Cardiovasculares/virologia , Infecções por Coronavirus/complicações , Infecções por Coronavirus/fisiopatologia , Lesão Pulmonar/virologia , Pneumonia Viral/complicações , Pneumonia Viral/fisiopatologia , Betacoronavirus , COVID-19 , Infecções por Coronavirus/terapia , Humanos , Pandemias , Pneumonia Viral/terapia , SARS-CoV-2
12.
Vascul Pharmacol ; 127: 106651, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32044414

RESUMO

Aspirin is a widely used drug with anti-coagulating and anti-inflammatory effects on atherosclerotic vascular disease. The goal of this study was to investigate expression of microRNA (miR) in association with changes in arachidonic acid (AA) metabolism in cardiac and surrounding fat mesenchymal stem cells (MSCs) treated with or without aspirin. Aspirin-targeted endogenous lipid metabolites that impact specific miRNA expression were examined by mass spectrometry. The pattern of miR expression was characterized using a microarray of 1100 miRs. There were a dozen miRs expressed differentially in MSCs from human myocardium and peri-myocardial fat tissue at baseline, including hsa-miR-1307-3p, 765, 4739, 3613-3p, 4281, 6816-5p, 2861, and 146b-5p. After exposure to aspirin, cardiac MSCs expressed an array of of miRs (eg, hsa-miR-4734, 10a-5p, 4267, 3197, and 3182), while generation of their endogenous AA metabolites was depressed. However, in the peri-cardiac adipose tissue-derived MSCs, treatment with the same doses of aspirin caused mild changes in the miR expression levels. In conclusion, MSCs from human myocardium and peri-myocardial fat tissue respond differentially to aspirin treatment by alterations in miR expression and AA metabolism. The study further raises an intriguing issue as to whether the copious amounts of aspirin taken worldwide by patients with cardiovascular disease may have direct impacts on their heart repair processes by regulation of stromal cell miR expression and AA metabolism.


Assuntos
Tecido Adiposo/citologia , Anticoagulantes/farmacologia , Ácido Araquidônico/metabolismo , Aspirina/farmacologia , Inibidores de Ciclo-Oxigenase/farmacologia , Células-Tronco Mesenquimais/efeitos dos fármacos , MicroRNAs/metabolismo , Miocárdio/citologia , Células Cultivadas , Humanos , Células-Tronco Mesenquimais/metabolismo , MicroRNAs/genética , Fenótipo , Transcriptoma
13.
Vascular ; 28(4): 465-474, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32089109

RESUMO

OBJECTIVE: Calcification serves as a surrogate for atherosclerosis-associated vascular diseases, and coronary artery calcification is mediated by multiple pathogenic factors. Estrogen is a known factor that protects the arterial wall against atherosclerosis, but its role in the coronary artery calcification development remains largely unclear. This study tested the hypothesis that estrogen inhibits coronary artery calcification via the hypoxia-induced factor-1α pathway. METHODS: Eight-week-old healthy female Sprague-Dawley rats were castrated, and vitamin D3 was administered orally to establish. Hypoxia-induced factor-1 inhibitor was administered to test its effect on vascular calcification and expression of bone morphogenetic protein 2 and runt-related transcription factor-2. Vascular smooth muscle cell calcification was induced with CaCl2 in rat aortic smooth muscle cells in the presence or absence of E2(17ß-estradiol) and bone morphogenetic protein 2 siRNA intervention. RESULTS: The estrogen levels in ovariectomized rats were significantly decreased, as determined by ELISA. Expression of hypoxia-induced factor-1α mRNA and protein was significantly increased in vascular cells with calcification as compared to those without calcification (p < 0.01). E2 treatment decreased the calcium concentration in vascular cell calcification and cell calcium nodules in vitro (p < 0.05). E2 also lowered the levels of hypoxia-induced factor-1α mRNA and protein (p < 0.01). Oral administration of the hypoxia-induced factor-1α inhibitor dimethyloxetane in castrated rats alleviated vascular calcification and expression of osteogenesis-related transcription factors, bone morphogenetic protein 2 and RUNX2 (p < 0.01). Finally, bone morphogenetic protein 2 siRNA treatment decreased the levels of p-Smad1/5/8 in A7r5 calcification cells (p < 0.01). CONCLUSION: Estrogen deficiency enhances vascular calcification. Treatment with estrogen reduces the expression of hypoxia-induced factor-1α as well as vascular calcification in rats. The estrogen effects occur in a fashion dependent on hypoxia-induced factor-1α regulation of bone morphogenetic protein-2 and downstream Smad1/5/8.


Assuntos
Doenças da Aorta/prevenção & controle , Estradiol/farmacologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Músculo Liso Vascular/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Calcificação Vascular/prevenção & controle , Animais , Aorta/efeitos dos fármacos , Aorta/metabolismo , Aorta/patologia , Doenças da Aorta/genética , Doenças da Aorta/metabolismo , Doenças da Aorta/patologia , Proteína Morfogenética Óssea 2/genética , Proteína Morfogenética Óssea 2/metabolismo , Linhagem Celular , Subunidade alfa 1 de Fator de Ligação ao Core/genética , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Modelos Animais de Doenças , Feminino , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Ovariectomia , Fosforilação , Ratos Sprague-Dawley , Transdução de Sinais , Proteínas Smad Reguladas por Receptor/metabolismo , Calcificação Vascular/genética , Calcificação Vascular/metabolismo , Calcificação Vascular/patologia
14.
J Cell Mol Med ; 24(5): 2857-2865, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31970899

RESUMO

Increased stiffness characterizes the early change in the arterial wall with subclinical atherosclerosis. Proteins inducing arterial stiffness in diabetes and hypercholesterolaemia are largely unknown. This study aimed at determining the pattern of protein expression in stiffening aorta of diabetic and hypercholesterolaemic mice. Male Ins2+/Akita mice were crossbred with ApoE-/- (Ins2+/Akita : ApoE-/- ) mice. Relative aortic distension (relD) values were determined by ultrasound analysis and arterial stiffness modulators by immunoblotting. Compared with age- and sex-matched C57/BL6 control mice, the aortas of Ins2+/Akita , ApoE-/- and Ins2+/Akita :ApoE-/- mice showed increased aortic stiffness. The aortas of Ins2+/Akita , ApoE-/- and Ins2+/Akita :ApoE-/- mice showed greater expression of VCAM-1, collagen type III, NADPH oxidase and iNOS, as well as reduced elastin, with increased collagen type III-to-elastin ratio. The aorta of Ins2+/Akita and Ins2+/Akita :ApoE-/- mice showed higher expression of eNOS and cytoskeletal remodelling proteins, such as F-actin and α-smooth muscle actin, in addition to increased glycosylated aquaporin (AQP)-1 and transcription factor NFAT5, which control the expression of genes activated by high glucose-induced hyperosmotic stress. Diabetic and hypercholesterolaemic mice have increased aortic stiffness. The association of AQP1 and NFAT5 co-expression with aortic stiffness in diabetes and hypercholesterolaemia may represent a novel molecular pathway or therapeutic target.


Assuntos
Aquaporina 1/metabolismo , Aterosclerose/metabolismo , Aterosclerose/fisiopatologia , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/fisiopatologia , Fatores de Transcrição/metabolismo , Rigidez Vascular , Animais , Colágeno Tipo III/metabolismo , Citoesqueleto/metabolismo , Elastina/metabolismo , Glicosilação , Masculino , Camundongos Endogâmicos C57BL , Músculo Liso/metabolismo , NADPH Oxidases/metabolismo , Óxido Nítrico Sintase/metabolismo , Fenótipo , Isoformas de Proteínas/metabolismo , Molécula 1 de Adesão de Célula Vascular/metabolismo
16.
Front Cardiovasc Med ; 7: 585220, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33505992

RESUMO

Background: Myocardial injury is a life-threatening complication of coronavirus disease 2019 (COVID-19). Pre-existing health conditions and early morphological alterations may precipitate cardiac injury and dysfunction after contracting the virus. The current study aimed at assessing potential risk factors for COVID-19 cardiac complications in patients with pre-existing conditions and imaging predictors. Methods and Results: The multi-center, retrospective cohort study consecutively enrolled 400 patients with lab-confirmed COVID-19 in six Chinese hospitals remote to the Wuhan epicenter. Patients were diagnosed with or without the complication of myocardial injury by history and cardiac biomarker Troponin I/T (TnI/T) elevation above the 99th percentile upper reference limit. The majority of COVID-19 patients with myocardial injury exhibited pre-existing health conditions, such as hypertension, diabetes, hypercholesterolemia, and coronary disease. They had increased levels of the inflammatory cytokine interleukin-6 and more in-hospital adverse events (admission to an intensive care unit, invasive mechanical ventilation, or death). Chest CT scan on admission demonstrated that COVID-19 patients with myocardial injury had higher epicardial adipose tissue volume ([EATV] 139.1 (83.8-195.9) vs. 92.6 (76.2-134.4) cm2; P = 0.036). The optimal EATV cut-off value (137.1 cm2) served as a useful factor for assessing myocardial injury, which yielded sensitivity and specificity of 55.0% (95%CI, 32.0-76.2%) and 77.4% (95%CI, 71.6-82.3%) in adverse cardiac events, respectively. Multivariate logistic regression analysis showed that EATV over 137.1 cm2 was a strong independent predictor for myocardial injury in patients with COVID-19 [OR 3.058, (95%CI, 1.032-9.063); P = 0.044]. Conclusions: Augmented EATV on admission chest CT scan, together with the pre-existing health conditions (hypertension, diabetes, and hyperlipidemia) and inflammatory cytokine production, is associated with increased myocardial injury and mortality in COVID-19 patients. Assessment of pre-existing conditions and chest CT scan EATV on admission may provide a threshold point potentially useful for predicting cardiovascular complications of COVID-19.

17.
Regen Med ; 14(12): 1077-1087, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31829095

RESUMO

Aim: To determine the efficacy and safety of intracoronary infusion of autologous bone marrow mesenchymal stem cells (MSCINJ) in combination with intensive atorvastatin (ATV) treatment for patients with anterior ST-segment elevation myocardial infarction-elevation myocardial infarction. Patients & methods: The trial enrolls a total of 100 patients with anterior ST-elevation myocardial infarction. The subjects are randomly assigned (1:1:1:1) to receive routine ATV (20 mg/d) with placebo or MSCsINJ and intensive ATV (80 mg/d) with placebo or MSCsINJ. The primary end point is the absolute change of left ventricular ejection fraction within 12 months. The secondary end points include parameters in cardiac function, remodeling and regeneration, quality of life, biomarkers and clinical outcomes. Results & conclusion: The trial will implicate the essential of cardiac micro-environment improvement ('fertilizing') for cell-based therapy. Clinical Trial Registration: NCT03047772.


Assuntos
Atorvastatina/uso terapêutico , Transplante de Medula Óssea/métodos , Células-Tronco Mesenquimais/citologia , Infarto do Miocárdio/terapia , Projetos de Pesquisa , Doença Aguda , Terapia Combinada , Método Duplo-Cego , Seguimentos , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Infarto do Miocárdio/patologia , Prognóstico , Transplante Autólogo
18.
Sci Rep ; 9(1): 14035, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31575906

RESUMO

Cardiac hypertrophy often causes impairment of cardiac function. Xenon (Xe), a naturally occurring noble gas, is known to provide neurological and myocardial protection without side effects. The conventional method of Xe delivery by inhalation is not feasible on a chronic basis. We have developed an orally deliverable, effective Xe formulation for long-term administration. We employed 2-hydroxypropyl)-ß-cyclodextrin (HPCD), which was dissolved in water to increase the Xe concentration in solution. The beneficial effects of long-term oral administration of Xe-enriched solutions on cardiovascular function were evaluated in vivo. HPCD increased Xe solubility from 0.22 mM to 0.67 mM (3.8-fold). Aged ApoE knockout mice fed high-fat diet for 6 weeks developed hypertension, and myocardial hypertrophy with impaired cardiac function. Oral Xe prevented this ischemic damage, preserving normal blood pressure, while maintaining normal left ventricular mass and wall thickness. This novel formulation allows for gastrointestinal delivery and cardiovascular stabilization.


Assuntos
Cardiotônicos/administração & dosagem , Sistema Cardiovascular/efeitos dos fármacos , Xenônio/administração & dosagem , 2-Hidroxipropil-beta-Ciclodextrina/administração & dosagem , Administração Oral , Animais , Apolipoproteínas E/genética , Pressão Sanguínea/efeitos dos fármacos , Coração/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Hipertrofia Ventricular Esquerda/tratamento farmacológico , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Solubilidade , Soluções/administração & dosagem
19.
Am J Transl Res ; 11(7): 4214-4231, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31396330

RESUMO

The SDF-1/CXCR4 signaling plays a critical role in the trafficking of mesenchymal stem cells (MSCs) to the sites of tissue damage. Our recent study demonstrated that atorvastatin (ATV) treatment improved the survival of MSCs, and ATV pretreated MSCs (ATV-MSCs) exhibited enhanced engraftment to injured myocardium. In this study, we investigated whether combined treatment with ATV and ATV-MSCs enhances cardiac repair and regeneration by activating SDF-1/CXCR4 signaling in a rat model of acute myocardial infarction. Rats were randomized into eight groups: the Sham, AMI control and 6 other groups that were subjected to AMI followed by treatment with MSCs, ATV, ATV+MSCs, ATV-MSCs, ATV+ATV-MSCs, ATV+ATV-MSCs+AMD3100 (SDF-1/CXCR4 antagonist), respectively. ATV+ATV-MSCs significantly potentiated targeted recruitment of MSCs to peri-infarct myocardium and resulted in further improvements in cardiac function and reduction in scar size compared with MSCs treatment alone at 4-week after AMI. More importantly, the cardioprotective effects conferred by ATV+ATV-MSCs were almost completely abolished by AMD3100 treatment. Together, our study demonstrated that ATV+ATV-MSCs significantly enhanced the targeted recruitment and survival of transplanted MSCs, and resulted in subsequent cardiac function improvement by augmenting SDF-1/CXCR4 signaling.

20.
Coron Artery Dis ; 30(4): 297-302, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30888975

RESUMO

AIM: This study aimed to define the relationship between pulse pressure (PP) and coronary artery calcification (CAC), a proven surrogate marker for coronary heart disease. PATIENTS AND METHODS: A total of 170 participants 50-70 years of age from 11 villages of Yunnan Province of China were enrolled randomly into this study. They were examined routinely for diastolic and systolic blood pressure, PP, and CAC. RESULTS: The average PP in the CAC-positive group was significantly higher than that in the CAC-negative group. In the positive CAC group, there were significantly positive correlations between PP and CAC score, volume, mass, as well as density. The area under the receiver operating characteristic curve analysis showed that PP performed well in predicting CAC. CONCLUSION: In conclusion, among the rural people of southwest of China, PP correlates positively with the coronary calcium Agatston score, volume, mass, and density. PP predicted CAC as well as Framingham Risk Score. The measurement of PP widening may serve as an alternative and convenient method for assessing CAC risk in rural populations with poor accessibility and economic disadvantage over coronary computed tomography scanning.


Assuntos
Pressão Sanguínea , Doença da Artéria Coronariana/fisiopatologia , Saúde da População Rural , Calcificação Vascular/fisiopatologia , Idoso , China/epidemiologia , Angiografia por Tomografia Computadorizada , Angiografia Coronária , Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Medição de Risco , Fatores de Risco , Calcificação Vascular/diagnóstico por imagem , Calcificação Vascular/epidemiologia
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