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1.
Nutrients ; 13(7)2021 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-34371840

RESUMO

Atherosclerosis is a pro-oxidative and pro-inflammatory disease state, which is the underlying cause of most cardiovascular events, estimated to affect 5.2% of the Australian population. Diet, and specifically vitamin C, through its antioxidant properties can play a role in impeding the development and progression of atherosclerosis. This systematic review conducted comprehensive searches in Medline, Emcare, Scopus, PubMed, and Cochrane using key search terms for vitamin C, plasma vitamin C, supplementation, and cardiovascular disease (CVD). The results demonstrated that vitamin C supplementation resulted in a significant increase in vitamin C levels in populations with or without CVD, except for one study on the CVD population. It was also seen that the healthy population baseline and post-intervention vitamin C levels were high compared to the CVD population. However, further research is indicated for CVD population groups with varying baseline vitamin C levels, such as low baseline vitamin C, within a more representative elderly cohort in order to formulate and update vitamin C repletion guidelines.


Assuntos
Ácido Ascórbico/sangue , Aterosclerose/sangue , Doenças Cardiovasculares/sangue , Dieta/estatística & dados numéricos , Suplementos Nutricionais , Antioxidantes/administração & dosagem , Antioxidantes/metabolismo , Ácido Ascórbico/administração & dosagem , Aterosclerose/complicações , Aterosclerose/terapia , Doenças Cardiovasculares/etiologia , Ingestão de Alimentos/fisiologia , Feminino , Fatores de Risco de Doenças Cardíacas , Humanos , Masculino , Pessoa de Meia-Idade , Estado Nutricional
2.
Biomed Pharmacother ; 139: 111668, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34243630

RESUMO

Metabolic Syndrome (MetS) is a complex and multifactorial condition often characterised by obesity, hypertension, hyperlipidaemia, insulin resistance, glucose intolerance and fasting hyperglycaemia. Collectively, MetS can increase the risk of atherosclerotic-cardiovascular disease, which is the leading cause of death worldwide. However, no animal model currently exists to study MetS in the context of atherosclerosis. In this study we developed a pre-clinical mouse model that recapitulates the spectrum of MetS features while developing atherosclerosis. When BPHx mice were placed on a western type diet for 16 weeks, all the classical characteristics of MetS were observed. Comprehensive metabolic analyses and atherosclerotic imaging revealed BPHx mice to be obese and hypertensive, with elevated total plasma cholesterol and triglyceride levels, that accelerated atherosclerosis. Altogether, we demonstrate that the BPHx mouse has all the major components of MetS, and accelerates the development of atherosclerosis.


Assuntos
Aterosclerose/patologia , Dieta/efeitos adversos , Hipertensão/patologia , Síndrome Metabólica/patologia , Animais , Aterosclerose/sangue , Aterosclerose/metabolismo , Glicemia/metabolismo , Colesterol/sangue , Modelos Animais de Doenças , Feminino , Intolerância à Glucose/sangue , Intolerância à Glucose/metabolismo , Intolerância à Glucose/patologia , Hipercolesterolemia/sangue , Hipercolesterolemia/metabolismo , Hipercolesterolemia/patologia , Hiperglicemia/sangue , Hiperglicemia/metabolismo , Hiperglicemia/patologia , Hiperlipidemias/sangue , Hiperlipidemias/metabolismo , Hiperlipidemias/patologia , Hipertensão/sangue , Hipertensão/metabolismo , Resistência à Insulina/fisiologia , Síndrome Metabólica/sangue , Síndrome Metabólica/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/sangue , Obesidade/metabolismo , Obesidade/patologia , Triglicerídeos/sangue
3.
Medicine (Baltimore) ; 100(28): e26617, 2021 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-34260548

RESUMO

BACKGROUND: Stroke is the third leading cause of global year of life lost in all-age and second-ranked cause of disability adjusted life years in middle-aged and elder population. Therefore, it is critical to study the relationship between vascular-related risk factors and cerebrovascular diseases. Several cross-sectional studies have shown that Cystatin C (Cys C) is an independent risk factor for cerebrovascular diseases and levels of Cys C are significantly higher in stroke patients than in healthy individuals. In this meta-analysis, we introduce a Cox proportional hazards model to evaluate the causality between Cys C and the risk of cerebrovascular accident in the elderly. METHODS: We searched PubMed, EMBASE, the Web of Science, and the Cochrane Library from 1985 to 2019 for studies on the relationship between serum Cys C and incidence stroke with Cox proportional hazards models. We conducted a subgroup analysis of the selected studies to determine a connection between atherosclerosis and stroke. Finally, 7 research studies, including 26,768 patients without a history of cerebrovascular, were studied. RESULTS: After comparing the maximum and minimum Cys C levels, the hazard ratio for all types of stroke, including ischemic and hemorrhagic stroke, was 1.18 (95% confidence interval 1.04-1.31) with moderate heterogeneity (I2 = 43.0%; P = .119) in a fixed-effect model after pooled adjustment for other potential risk factors. In the subgroup analysis, the hazard ratio and 95% confidence interval for Cys C stratified by atherosclerosis was 1.85 (0.97-2.72). As shown in Egger linear regression test, there was no distinct publication bias (P = .153). CONCLUSION: Increased serum Cys C is significantly associated with future stroke events in the elderly, especially in patients with carotid atherosclerosis. Thus, serum levels of Cys C could serve as a predicted biomarker for stroke attack.


Assuntos
Aterosclerose/epidemiologia , Doenças das Artérias Carótidas/epidemiologia , Cistatina C/sangue , Acidente Vascular Cerebral/epidemiologia , Idoso , Aterosclerose/sangue , Doenças das Artérias Carótidas/sangue , Causalidade , Transtornos Cerebrovasculares/sangue , Transtornos Cerebrovasculares/epidemiologia , Humanos , Modelos de Riscos Proporcionais , Fatores de Risco , Acidente Vascular Cerebral/sangue
4.
Medicine (Baltimore) ; 100(28): e26630, 2021 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-34260553

RESUMO

ABSTRACT: Type 2 diabetes (T2DM) represents a major risk factor for atherosclerosis that is the underlying cause of most cardiovascular diseases. Identifying reliable predictive biomarkers are needed to improve the long-term outcome in diabetic patients. Autophagy plays a pivotal role in the pathogenesis of atherosclerosis. Beclin1 is a key regulatory protein of autophagy and has been localized in human atherosclerotic lesions. However, the relation of serum level of Beclin1 and atherosclerosis in patients with diabetes has not been clarified yet.To assess the relationship between serum level of Beclin1 and carotid intima-media thickness (CIMT) in patients with T2DM.In this case-control study participants were recruited from tertiary care hospitals in Egypt. The study enrolled 50 patients with T2DM and 25 healthy subjects between January, 2019 and January, 2020. Age, gender, and body mass index were recorded for all subjects. Laboratory works up including glycated hemoglobin, lipid panel, and serum Beclin1 (by enzyme-linked immunosorbent assay) were measured. CIMT was assessed by color Doppler. Comparisons between patients and the control group were done using analysis of variance and Chi-square test. Correlations between CIMT and Beclin1 level and different variables were done using the Pearson correlation coefficient. Receiver operator characteristic curve was constructed with the area under curve analysis performed to detect the best cutoff value of Beclin1 for detection of CIMT > 0.05 cm.The level of Beclin1 in the patient group was significantly lower compared with that in the control group (1.28 ±â€Š0.51 vs 5.24 ±â€Š1.22 ng/dL, P < .001). The level of Beclin1 apparently decreased in the higher CIMT group in T2DM patients. Serum Beclin1 levels were negatively correlated with CIMT (r = -0.762; P < .001), low-density lipoprotein-cholesterol (r = -0.283; P = .04), and triglycerides (r = -0.350; P = .01) but positively correlated with high-density lipoprotein-cholesterol (r = 0.491; P < .001) in patients with T2DM. Beclin1 level >2.2 ng/dL was an accurate predictor of CIMT >0.05 cm with an area under the curve value of 0.997, 93.9% sensitivity, and 100% specificity.Beclin1 levels were negatively correlated with atherosclerotic load in patients with T2DM and it may be considered as a promising diagnostic and therapeutic target.


Assuntos
Aterosclerose/sangue , Aterosclerose/epidemiologia , Proteína Beclina-1/sangue , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/epidemiologia , Adulto , Fatores Etários , Biomarcadores , Índice de Massa Corporal , Espessura Intima-Media Carotídea , Estudos de Casos e Controles , Humanos , Pessoa de Meia-Idade , Curva ROC , Fatores Sexuais
5.
Am J Cardiol ; 153: 43-50, 2021 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-34210501

RESUMO

Lipoprotein (a) [Lp(a)] is associated with increased risk of atherosclerotic cardiovascular disease (ASCVD). As directed therapy for Lp(a) emerges, it is important to understand patterns of Lp(a) testing in routine clinical practice. We set out to characterize Lp(a) testing across a large academic health system. Using electronic health record (EHR) data from 2014 to 2019, we compared patients who underwent Lp(a) testing to date-matched peers who had low density lipoprotein (LDL-C) assessment alone. We analyzed ordering provider characteristics and rates of initiation of new lipid lowering therapy (LLT) within 12 months after testing. Of 1,296 adults with Lp(a) test results, 629 (48.5%) had prior history of ASCVD and 667 (51.4%) did not. Compared with those with LDL-C testing alone, individuals who underwent Lp(a) testing were more like to have a myocardial infarction or ischemic stroke at a young age and multiple prior cardiovascular events. Though the majority of Lp(a) tests were ordered in outpatient encounters, a higher proportion of Lp(a) tests compared with LDL-C tests were performed in the inpatient setting. Neurology and psychiatry were the most common specialty to order Lp(a) tests in our cohort. There was a significantly increased initiation of LLT after Lp(a) testing compared with LDL-C testing across all medication types. Consistent with guidelines, Lp(a) testing is used in those with early onset ASCVD, and among those with multiple cardiovascular events. Lp(a) testing is associated with more aggressive LLT in following year. Further research is needed to characterize Lp(a) testing across larger populations.


Assuntos
Aterosclerose/sangue , Doenças Cardiovasculares/sangue , LDL-Colesterol/sangue , Hiperlipidemias/diagnóstico , Hipolipemiantes/uso terapêutico , Lipoproteína(a)/sangue , Padrões de Prática Médica/estatística & dados numéricos , Centros Médicos Acadêmicos , Idoso , Assistência Ambulatorial/estatística & dados numéricos , Aterosclerose/epidemiologia , Análise Química do Sangue/estatística & dados numéricos , Doenças Cardiovasculares/epidemiologia , Feminino , Fatores de Risco de Doenças Cardíacas , Hospitalização , Humanos , Hiperlipidemias/sangue , Hiperlipidemias/tratamento farmacológico , AVC Isquêmico/epidemiologia , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/epidemiologia
6.
Postgrad Med ; 133(7): 822-829, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34281466

RESUMO

BACKGROUND: Recent studies have identified monocyte to high-density lipoprotein ratio (MHR) as a simple, practical surrogate of atherosclerosis. Considering atherosclerosis is a major mechanism of coronary heart disease (CHD). The present study aims to evaluate the association between MHR and the prevalence of CHD. METHODS AND RESULTS: The present cross-sectional work included 6442 participants (mean age: 59.57 years, 60.2% females), all of them were included from rural areas of northern China between October 2019 to April 2020. MHR was acquired as monocytes count divided by high-density lipoprotein concentration. Prevalent CHD researched 3.14%. After adjustment of sex, age, current drinking and smoking, BMI, WC, diabetes, hypertension, LDL-C, TG, eGFR, lipid-lowering therapy and cerebrovascular disease history, each standard deviation increase of MHR cast a 39.5% additional CHD risk. Furthermore, the top quartile of MHR had an additional 89.0% CHD risk than the bottom quartile. Besides, smooth curve fitting revealed a linear pattern of the association. Additionally, the stratified evaluation showed a robust correlation among the subgroups divided by CHD risk factors. Finally, area under the curve demonstrated an advancement when including MHR into common CHD risk factors (0.744 vs 0.761, p < 0.001). Consistently, reclassification analysis indicated the improvement from MHR (all P = 0.003). CONCLUSION: Our work suggests the robust and linear relationship between MHR and the prevalent CHD in a general population, providing epidemiological evidence for laboratory studies. More importantly, the findings implicate the efficacy of MHR to be a potential indicator to identify the prevalent CHD.


Assuntos
Doença das Coronárias/sangue , Lipoproteínas HDL/análise , Monócitos/citologia , Idoso , Aterosclerose/sangue , China , Comorbidade , Estudos Transversais , Feminino , Comportamentos Relacionados com a Saúde , Humanos , Lipídeos/sangue , Masculino , Pessoa de Meia-Idade
7.
Nutrients ; 13(6)2021 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-34067469

RESUMO

While targeting elevated serum levels of low-density lipoprotein cholesterol has been the mainstay of atherosclerosis prevention and treatment for decades, the evidence regarding the atherogenic role of hypertriglyceridemia is still controversial. Various epidemiological population-based studies on statin-treated subjects nominated triglycerides, triglyceride-rich lipoproteins (namely, chylomicrons and very-low-density lipoprotein particles), and their remnants as major determinants of the substantial residual cardiovascular risk. With the triglyceride-glucose index and triglyceride to high-density lipoprotein ratio emerging as surrogate indicators of peripheral artery disease and atherosclerotic cerebrovascular disease, one can conclude that further research addressing the intricate relationship between triglycerides and atherosclerosis is warranted. Therefore, this review aims to provide insight into the current clinical and epidemiological state of knowledge on the relationship between triglycerides and atherosclerotic cardiovascular disease. It also intends to highlight the connection between triglycerides and other metabolic disorders, including diabetes mellitus, and the potential benefits of triglyceride-lowering agents on cardiovascular outcomes and all-cause mortality.


Assuntos
Aterosclerose/epidemiologia , Lipoproteínas/sangue , Doenças Metabólicas/epidemiologia , Triglicerídeos/sangue , Adulto , Aterosclerose/sangue , Aterosclerose/tratamento farmacológico , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/epidemiologia , Transtornos Cerebrovasculares/epidemiologia , LDL-Colesterol/sangue , Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus/epidemiologia , Feminino , Fatores de Risco de Doenças Cardíacas , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipertrigliceridemia/tratamento farmacológico , Hipertrigliceridemia/epidemiologia , Hipolipemiantes/uso terapêutico , Masculino , Doenças Metabólicas/sangue , Pessoa de Meia-Idade , Adulto Jovem
9.
Nat Commun ; 12(1): 3391, 2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-34099646

RESUMO

Increased risk of premature cardiovascular disease (CVD) is well recognized in systemic lupus erythematosus (SLE). Aberrant type I-Interferon (IFN)-neutrophil interactions contribute to this enhanced CVD risk. In lupus animal models, the Janus kinase (JAK) inhibitor tofacitinib improves clinical features, immune dysregulation and vascular dysfunction. We conducted a randomized, double-blind, placebo-controlled clinical trial of tofacitinib in SLE subjects (ClinicalTrials.gov NCT02535689). In this study, 30 subjects are randomized to tofacitinib (5 mg twice daily) or placebo in 2:1 block. The primary outcome of this study is safety and tolerability of tofacitinib. The secondary outcomes include clinical response and mechanistic studies. The tofacitinib is found to be safe in SLE meeting study's primary endpoint. We also show that tofacitinib improves cardiometabolic and immunologic parameters associated with the premature atherosclerosis in SLE. Tofacitinib improves high-density lipoprotein cholesterol levels (p = 0.0006, CI 95%: 4.12, 13.32) and particle number (p = 0.0008, CI 95%: 1.58, 5.33); lecithin: cholesterol acyltransferase concentration (p = 0.024, CI 95%: 1.1, -26.5), cholesterol efflux capacity (p = 0.08, CI 95%: -0.01, 0.24), improvements in arterial stiffness and endothelium-dependent vasorelaxation and decrease in type I IFN gene signature, low-density granulocytes and circulating NETs. Some of these improvements are more robust in subjects with STAT4 risk allele.


Assuntos
Aterosclerose/prevenção & controle , Inibidores de Janus Quinases/administração & dosagem , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Piperidinas/administração & dosagem , Pirimidinas/administração & dosagem , Adulto , Idoso , Animais , Aterosclerose/sangue , Aterosclerose/genética , Aterosclerose/imunologia , HDL-Colesterol/sangue , Método Duplo-Cego , Feminino , Predisposição Genética para Doença , Fatores de Risco de Doenças Cardíacas , Humanos , Inibidores de Janus Quinases/efeitos adversos , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/imunologia , Masculino , Pessoa de Meia-Idade , Piperidinas/efeitos adversos , Pirimidinas/efeitos adversos , Fator de Transcrição STAT4/genética , Resultado do Tratamento , Rigidez Vascular/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Adulto Jovem
10.
Aging (Albany NY) ; 13(10): 14159-14169, 2021 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-34015766

RESUMO

Atherosclerosis correlates with ischemic cardio-cerebrovascular diseases such as coronary heart disease. Long non-coding RNAs (lncRNAs) can promote atherosclerosis. We investigated the role of the lncRNA AK136714 in atherosclerosis. Compared with the healthy group, lncRNA AK136714 expression was elevated in the plaque and plasma of the atherosclerosis patients in a GEO dataset. AK136714 silencing inhibited atherosclerosis formation in ApoE-/- mice. AK136714 silencing also protected the endothelial barrier and inhibited endothelial cell inflammation. In vitro assays showed that knockdown of AK136714 suppressed the inflammatory response and apoptosis in human umbilical vein endothelial cells (HUVECs). Moreover, AK136714 was found to bind directly to HuR to increase the mRNA stability of TNF-α, IL-1ß and IL-6 mRNAs. In addition, AK136714 promoted the transcription of Bim. This study expands our understanding of the role of lncRNA AK136714 in atherosclerosis and provides potential drug targets for the treatment of atherosclerosis.


Assuntos
Aterosclerose/genética , Células Endoteliais/patologia , Inativação Gênica , RNA Longo não Codificante/metabolismo , Animais , Apoptose/genética , Aterosclerose/sangue , Proteína Semelhante a ELAV 1/metabolismo , Células Endoteliais/metabolismo , Proteína Forkhead Box O3/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Inflamação/patologia , Masculino , Camundongos Endogâmicos C57BL , Placa Aterosclerótica/sangue , Placa Aterosclerótica/genética , Placa Aterosclerótica/patologia , Ligação Proteica , RNA Longo não Codificante/genética
11.
Diabetes Res Clin Pract ; 176: 108858, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34015391

RESUMO

AIMS: Atherogenic dyslipidemia, associated with small, dense low-density lipoprotein-cholesterol (S-LDL) particles and impaired metabolism of triglycerides (TGs) and high-density lipoprotein-cholesterol (HDL-c), leads to the development of atherosclerosis-related complications of type 2 diabetes mellitus. Based on the hypothesis that an LDL-c-to-apolipoprotein B ratio (LDL/ApoB) < 1.2 may predict the prevalence of S-LDL, this study aimed to evaluate the LDL/ApoB ratio in patients with type 2 diabetes with moderately elevated TG levels. METHODS: The study population consisted of 121 outpatients with type 2 diabetes (S-LDL group, LDL/ApoB < 1.2, n = 79; L-LDL group, LDL/ApoB > 1.2, n = 42) and 58 healthy subjects. The LDL/ApoB ratio was calculated from the measured LDL-c and ApoB levels in participants with TG levels lower than 4.5 mmol/L. Since TGs and HDL-c are included in the atherogenic index of plasma (AIP), we evaluated the relationship between LDL/ApoB and the AIP. RESULTS: Higher levels of AIP, TG (both P < 0.0001), and lipid hydroperoxides (LOOH) (P < 0.001) and lower levels of HDL-c, total cholesterol, and non-HDL-c (P < 0.001, <0.01, <0.05, respectively) were found in the S-LDL group compared to the L-LDL group. There were significant relationships between the LDL/ApoB ratio and the AIP, TG (both P < 0.0001), LOOH (P < 0.0005), and HDL-c levels (P < 0.05) in the S-LDL group. CONCLUSIONS: The prevalence of S-LDL particles (65%) and the close association of LDL/ApoB with the AIP suggest that this ratio may be a potential indicator of increased cardiovascular risk in patients with type 2 diabetes.


Assuntos
Apolipoproteína B-100/sangue , Aterosclerose/diagnóstico , LDL-Colesterol/sangue , Diabetes Mellitus Tipo 2/sangue , Angiopatias Diabéticas/diagnóstico , Adulto , Aterosclerose/sangue , Biomarcadores/sangue , Estudos de Casos e Controles , HDL-Colesterol/sangue , Diabetes Mellitus Tipo 2/complicações , Angiopatias Diabéticas/sangue , Dislipidemias/sangue , Dislipidemias/diagnóstico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tamanho da Partícula , Prognóstico , Triglicerídeos/sangue
12.
Int J Radiat Biol ; 97(9): 1270-1281, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34032557

RESUMO

BACKGROUND: Radiation exposure is known to increase the risk of chronic inflammatory diseases, such as atherosclerosis, by modulating inflammation. METHODS: To investigate the infiltration of leukocytes in radiation-aggravated atherosclerosis, we examined low-density lipoprotein receptor-deficient (Ldlr-/-) mice and C57BL/6j mice after exposure to 0.5 or 1 Gy radiation over 16 weeks. RESULTS: We found that radiation exposure induced atherosclerosis development in Ldlr-/- mice, as demonstrated by increased lipid-laden plaque size, reactive oxygen species levels, and levels of the pro-inflammatory cytokines, IL-1ß and TNF-α, in the aortas and spleens. Total plasma cholesterol, triglyceride, and LDL cholesterol levels were also increased by radiation exposure, along with cardiovascular risk. We also showed dose-dependent increases in neutrophils and monocytes that coincided with a reduction in lymphocytes in the spleens of Ldlr-/- mice. The correlation between the infiltration of leukocytes and cytokine production was also confirmed in the hearts and spleens of these mice. CONCLUSIONS: We concluded that chronic radiation exposure increased the production of pro-inflammatory mediators, which was associated with the migration of neutrophils and inflammatory monocytes into sites of atherosclerosis. Thus, our data suggest that the accumulation of neutrophils and inflammatory monocytes, together with the reduction of lymphocytes, contribute to aggravated atherosclerosis in Ldlr-/- mice under prolonged exposure to radiation.


Assuntos
Aterosclerose/imunologia , Infiltração de Neutrófilos/efeitos da radiação , Animais , Aterosclerose/sangue , Aterosclerose/patologia , Mediadores da Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptores de LDL/deficiência , Fator de Necrose Tumoral alfa/sangue
13.
Life Sci ; 284: 119615, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34004248

RESUMO

BACKGROUND: Atherosclerosis (AS) is a multifocal, smoldering immune inflammatory disease of medium and large arteries driven by lipids. The aim of this study is to discuss the mechanism of microRNA-146a-3p (miR-146a-3p)/histone deacetylase 1 (HDAC1)/Krüppel-like factor 5 (KLF5)/inhibitors of kappa B α (IKBα) signal axis in plaque formation of AS mice. METHODS: ApoE-/- mice were fed with high-fat feed for 12 weeks to establish AS mice model. The expression of miR-146a-3p, KLF5, HDAC1 and IKBα in aortic wall tissues of AS mice was tested. The targeting relationship between miR-146a-3p and HDAC1 was verified. AS mice were injected with miR-146a-3p antagomir or HDAC1 overexpression to verify the impacts of miR-146a-3p and HDAC1 on blood lipids and inflammatory factors in serum, aortic wall apoptotic cells, antioxidant stress capacity and the plaque area in AS mice. VECs proliferation and apoptosis were also measured in vitro. RESULTS: miR-146a-3p and KLF5 were increased while HDAC1 and IKBα were reduced in aortic wall tissues of AS mice. miR-146a-3p directly targeted to HDAC1. Depletion of miR-146a-3p or restoration of HDAC1 was correlated to lower plasma lipid level, reduced inflammatory factors in serum, attenuated aortic wall apoptosis, increased antioxidant stress capacity and improved the stability of pathological plaque of AS mice. miR-146a-3p down-regulation or HDAC1 up-regulation promoted VECs proliferation and inhibited apoptosis. CONCLUSION: Functional studies show that depleted miR-146a-3p advances HDAC1 and IKBα expression as well as inhibits KLF5 expression to facilitate the stability of pathological plaques in AS mice.


Assuntos
Aterosclerose/genética , Histona Desacetilase 1/metabolismo , Fatores de Transcrição Kruppel-Like/metabolismo , MicroRNAs/metabolismo , Inibidor de NF-kappaB alfa/metabolismo , Placa Aterosclerótica/genética , Transdução de Sinais , Animais , Antioxidantes/metabolismo , Apoptose/genética , Aterosclerose/sangue , Aterosclerose/patologia , Sequência de Bases , Proliferação de Células/genética , Regulação para Baixo/genética , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Histona Desacetilase 1/genética , Inflamação/sangue , Inflamação/patologia , Fatores de Transcrição Kruppel-Like/genética , Lipídeos/sangue , Masculino , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Placa Aterosclerótica/sangue , Transdução de Sinais/genética , Regulação para Cima/genética
14.
J Intern Med ; 290(1): 179-189, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33951242

RESUMO

BACKGROUND: Rupture of atherosclerotic plaques is the major cause of acute cardiovascular events. The biomarker PRO-C6 measuring Endotrophin, a matrikine of collagen type VI, may provide valuable information detecting subjects in need of intensified strategies for secondary prevention. OBJECTIVE: In this study, we evaluate endotrophin in human atherosclerotic plaques and circulating levels of PRO-C6 in patients with atherosclerosis, to determine the predictive potential of the biomarker. METHODS: Sections from the stenotic human carotid plaques were stained with the PRO-C6 antibody. PRO-C6 was measured in serum of patients enrolled in the Carotid Plaque Imagining Project (CPIP) (discovery cohort, n = 577) and the innovative medicines initiative surrogate markers for micro- and macrovascular hard end-points for innovative diabetes tools (IMI-SUMMIT, validation cohort, n = 1,378). Median follow-up was 43 months. Kaplan-Meier curves and log-rank tests were performed in the discovery cohort. Cox proportional hazard regression analysis (HR with 95% CI) was used in the discovery cohort and binary logistic regression (OR with 95% CI) in the validation cohort. RESULTS: PRO-C6 was localized in the core and shoulder of the atherosclerotic plaque. In the discovery cohort, PRO-C6 independently predicted future cardiovascular events (HR 1.089 [95% CI 1.019 -1.164], p = 0.01), cardiovascular death (HR 1.118 [95% CI 1.008 -1.241], p = 0.04) and all-cause death (HR 1.087 [95% CI 1.008 -1.172], p = 0.03). In the validation cohort, PRO-C6 predicted future cardiovascular events (OR 1.063 [95% CI 1.011 -1.117], p = 0.017). CONCLUSION: PRO-C6 is present in the atherosclerotic plaque and associated with future cardiovascular events, cardiovascular death and all-cause mortality in two large prospective cohorts.


Assuntos
Aterosclerose/sangue , Aterosclerose/complicações , Estenose das Carótidas/sangue , Estenose das Carótidas/complicações , Colágeno Tipo VI/sangue , Fragmentos de Peptídeos/sangue , Placa Aterosclerótica/sangue , Placa Aterosclerótica/complicações , Idoso , Aterosclerose/mortalidade , Biomarcadores/sangue , Estenose das Carótidas/mortalidade , Causas de Morte , Complicações do Diabetes , Diabetes Mellitus/sangue , Feminino , Fatores de Risco de Doenças Cardíacas , Humanos , Hipertensão/sangue , Hipertensão/complicações , Masculino , Obesidade/sangue , Obesidade/complicações , Placa Aterosclerótica/mortalidade , Fumar/efeitos adversos , Fumar/sangue
15.
PLoS One ; 16(5): e0246600, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33983975

RESUMO

Atherosclerotic vascular disease resulting from unstable plaques is the leading cause of morbidity and mortality in subjects with type 2 diabetes (T2D), and thus a major therapeutic goal is to discover T2D drugs that can also promote atherosclerotic plaque stability. Genetic or pharmacologic inhibition of mitogen-activated protein kinase-activated protein kinase-2 (MAPKAPK2 or MK2) in obese mice improves glucose homeostasis and enhances insulin sensitivity. We developed two novel orally active small-molecule inhibitors of MK2, TBX-1 and TBX-2, and tested their effects on metabolism and atherosclerosis in high-fat Western diet (WD)-fed Ldlr-/- mice. Ldlr-/- mice were first fed the WD to allow atherosclerotic lesions to become established, and the mice were then treated with TBX-1 or TBX-2. Both compounds improved glucose metabolism and lowered plasma cholesterol and triglyceride, without an effect on body weight. Most importantly, the compounds decreased lesion area, lessened plaque necrosis, and increased fibrous cap thickness in the aortic root lesions of the mice. Thus, in a preclinical model of high-fat feeding and established atherosclerosis, MK2 inhibitors improved metabolism and also enhanced atherosclerotic plaque stability, suggesting potential for further clinical development to address the epidemic of T2D associated with atherosclerotic vascular disease.


Assuntos
Aterosclerose/enzimologia , Aterosclerose/patologia , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Placa Aterosclerótica/enzimologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Regulação Alostérica/efeitos dos fármacos , Animais , Aorta/patologia , Aterosclerose/sangue , Glucose/metabolismo , Homeostase/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Lipídeos/sangue , Masculino , Camundongos Endogâmicos C57BL , Necrose , Placa Aterosclerótica/sangue , Placa Aterosclerótica/patologia , Inibidores de Proteínas Quinases/farmacocinética , Proteínas Serina-Treonina Quinases/metabolismo
16.
Maturitas ; 148: 1-6, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34024345

RESUMO

OBJECTIVE: To assess the association between the atherogenic index of plasma (AIP) and the trabecular bone score (TBS) in postmenopausal women. Furthermore, to analyze its relationship with bone mineral density (BMD), and serum concentrations of 25OHD, PTH, and bone turnover markers. STUDY DESIGN: Cross-sectional study nested in a population-based cohort of 1,367 postmenopausal women aged 44-94 years. Participants were classified according to TBS values (<1.230, between 1.230-1.310 and >1.310) and regarding a widely accepted cut-off point of ≥0.11 for AIP. We analyzed TBS, BMD, serum levels of 25OHD, PTH, P1NP, CTX, and clinical covariates. A multivariate analysis was performed to assess the adjusted association between AIP and TBS. RESULTS: The mean age of participants was 63±10 years. Women with TBS values <1.230 were older, had greater BMI, greater prevalence of fractures after the age of 40 years, more years since menopause, higher values of AIP, and significantly lower levels of HDL-C, serum phosphate, and 25OHD. AIP values ≥0.11 were not associated with the presence of densitometric osteoporosis (OR=0.83, 95%CI 0.58-1.18; p = 0.30) but, in multivariate analysis, AIP values ≥0.11 were related to a degraded microarchitecture after controlling for age, BMI, smoking, diabetes status, ischemic heart disease, statin use, GFR, a fragility fracture at over 40 years of age and lumbar osteoporosis by DXA, with an adjusted OR=1.61 (95%CI 1.06-2.46; p = 0.009). CONCLUSIONS: AIP is significantly and independently associated with a degraded bone microarchitecture as measured by TBS. In this sense, AIP might be a useful tool in the overall assessment of bone metabolism in postmenopausal women.


Assuntos
Aterosclerose/epidemiologia , Densidade Óssea , Osso Esponjoso/patologia , Vértebras Lombares/patologia , Fraturas por Osteoporose/epidemiologia , Pós-Menopausa , Absorciometria de Fóton , Adulto , Idoso , Idoso de 80 Anos ou mais , Aterosclerose/sangue , Aterosclerose/patologia , Estudos de Casos e Controles , Estudos de Coortes , Estudos Transversais , Feminino , Humanos , Pessoa de Meia-Idade , Fraturas por Osteoporose/patologia , Espanha/epidemiologia
17.
Aging (Albany NY) ; 13(8): 12239-12257, 2021 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-33872218

RESUMO

Endothelial dysfunction, and the differentiation of smooth muscle cells (SMCs) into proliferative, secretory phenotypes, are two major pathophysiological processes in atherosclerosis. SMCs have the potential to recruit macrophages in atherosclerotic plaques, in which macrophages drive inflammatory responses. In this study, we found that microRNA-503-5p (miR-503-5p) was enriched in either extracellular vesicles (EVs), secreted by oxidized low-density lipoprotein-treated macrophages, or the EVs from peripheral blood mononuclear cells of atherosclerosis patients. miR-503-5p was transferred intercellularly from macrophages to the co-cultured human coronary artery endothelial cells (HCAECs) and HCASMCs via EVs, thus reducing the proliferative and angiogenic abilities of HCAECs and accelerating the proliferative and migrating abilities of HCASMCs. Smad family members 1, 2 and 7 were negatively regulated by miR-503-5p in HCAECs and HCASMCs. miR-503-5p was verified as an enhancer of inflammatory cytokines and adhesion molecules released by macrophages, in part via the down-regulation of smad family members 1, 2 and 7. The inhibition of miR-503-5p by lentivirus reduced atherosclerotic lesion formations in the aorta of atherosclerotic mice. Our work demonstrated a miR-503-5p- and EV-mediated mechanism for macrophage communication with HCAECs and HCASMCs in atherosclerosis. miR-503-5p is pro-atherosclerotic stimuli that may be a therapeutic target for atherosclerosis treatment.


Assuntos
Aterosclerose/imunologia , Comunicação Celular/genética , Vesículas Extracelulares/metabolismo , Macrófagos/imunologia , MicroRNAs/metabolismo , Adulto , Animais , Aterosclerose/sangue , Aterosclerose/genética , Aterosclerose/patologia , Comunicação Celular/imunologia , Movimento Celular/genética , Movimento Celular/imunologia , Proliferação de Células/genética , Técnicas de Cocultura , Vasos Coronários/citologia , Vasos Coronários/patologia , Modelos Animais de Doenças , Células Endoteliais/citologia , Células Endoteliais/imunologia , Células Endoteliais/metabolismo , Endotélio Vascular/citologia , Endotélio Vascular/patologia , Feminino , Humanos , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/metabolismo , Lipoproteínas LDL/imunologia , Macrófagos/citologia , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Knockout para ApoE , Pessoa de Meia-Idade , Miócitos de Músculo Liso , Cultura Primária de Células , Células RAW 264.7 , Células THP-1
18.
Aging (Albany NY) ; 13(8): 11411-11432, 2021 04 04.
Artigo em Inglês | MEDLINE | ID: mdl-33839698

RESUMO

Atherosclerosis (AS)-related diseases remain among the leading causes of death worldwide. Modified Xiaoyaosan (also called Tiaogan-Liqi prescription, TGLQ), a traditional Chinese medical formulation, has been widely applied in the treatment of AS-related diseases. The aim of this study was to investigate the underlying pharmacological mechanisms of TGLQ in acting on AS. A total of 548 chemical compounds contained in TGLQ, and 969 putative targets, were collected from the Computation Platform for Integrative Pharmacology of Traditional Chinese Medicine, while 1005 therapeutic targets for the treatment of AS were obtained from the DisGeNET, TTD and CTD databases. Moreover, the 63 key targets were screened by the intersection of the targets above, and by network topological analysis. Further functional enrichment analysis showed that the key targets were significantly associated with regulation of the immune system and inflammation, improvement of lipid and glucose metabolism, regulation of the neuroendocrine system and anti-thrombosis effect. The in vivo experiments confirmed that TGLQ could reduce plasma lipid profiles and plasma inflammatory cytokines, and also inhibit AS plaque formation, within the AS model ApoE-/- mice. The in vitro experiments validated the hypothesis that TGLQ could significantly reduce intracellular lipid accumulation, suppress the production of inflammatory cytokines of macrophages induced by oxidized-LDL, and inhibit the protein expression of heat shock protein 90 and toll-like receptor 4. This study identified a list of key targets of TGLQ in the treatment of AS by applying an integrative pharmacology approach, which was validated by in vivo and in vitro experimentation.


Assuntos
Aterosclerose/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Animais , Aorta/efeitos dos fármacos , Aorta/patologia , Aterosclerose/sangue , Aterosclerose/imunologia , Aterosclerose/patologia , Citocinas/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Medicamentos de Ervas Chinesas/uso terapêutico , Humanos , Inflamação/sangue , Inflamação/tratamento farmacológico , Inflamação/imunologia , Inflamação/patologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipídeos/sangue , Masculino , Camundongos , Camundongos Knockout para ApoE , Células RAW 264.7 , Ratos
20.
Blood Coagul Fibrinolysis ; 32(5): 312-316, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-33859114

RESUMO

The number of patients with diabetes with a risk of cardiovascular diseases (CVDs) is increasing worldwide, leading to a higher demand for evaluating atherosclerosis. Recently, the mean platelet volume (MPV) available from complete blood count is gaining attention as a marker of underlying atherosclerotic lesions. In the current study, we examined whether MPV can predict carotid atherosclerosis in patients with diabetes at an intermediate or high risk for CVD. A total of 224 patients with diabetes aged 36-85 years who underwent carotid ultrasound examination were assessed. The risk of CVD was evaluated using the Suita score. The greatest carotid intima-media thickness (IMT) in each common carotid artery (CCA Max-IMT), carotid bulb, internal carotid artery, or external carotid artery (Total Max-IMT) was measured. Subsequently, the relationship between MPV and IMT was analyzed. Patients were divided into three groups according to their MPV values (<9.5 fl, tertile 1; 9.5-10.2 fl, tertile 2; and >10.2 fl, tertile 3). A correlation was observed between MPV and platelet count (P < 0.001), platelet distribution width (P < 0.001), and glycated hemoglobin (P = 0.04); however, multivariate logistic regression analyses demonstrated no relationship between MPV and CCA Max-IMT [odds ratio, 0.89 (0.60-1.29), P = 0.54] or Total Max-IMT [odds ratio, 0.87 (0.61-1.24), P = 0.45]. MPV did not correlate with carotid artery thickness. Therefore, it is difficult to determine the significance of MPV in atherosclerotic conditions from this study.


Assuntos
Aterosclerose/etiologia , Doenças Cardiovasculares/etiologia , Espessura Intima-Media Carotídea , Complicações do Diabetes/etiologia , Volume Plaquetário Médio , Adulto , Idoso , Idoso de 80 Anos ou mais , Aterosclerose/sangue , Aterosclerose/diagnóstico , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/diagnóstico , Complicações do Diabetes/sangue , Complicações do Diabetes/diagnóstico , Feminino , Fatores de Risco de Doenças Cardíacas , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico
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