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1.
Hypertension ; 79(1): 150-158, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34775788

RESUMO

Elastic arteries stiffen via 2 main mechanisms: (1) load-dependent stiffening from higher blood pressure and (2) structural stiffening due to changes in the vessel wall. Differentiating these closely coupled mechanisms is important to understanding vascular aging. MESA (Multi-Ethnic Study of Atherosclerosis) participants with B-mode carotid ultrasound and brachial blood pressure at exam 1 and exam 5 (year 10) were included in this study (n=2604). Peterson and Young elastic moduli were calculated to represent total stiffness. Structural stiffness was calculated by adjusting Peterson and Young elastic moduli to a standard blood pressure of 120/80 mm Hg with participant-specific models. Load-dependent stiffness was the difference between total and structural stiffness. Changes in carotid artery stiffness mechanisms over 10 years were compared by age groups with ANCOVA models adjusted for baseline cardiovascular disease risk factors. The 75- to 84-year age group had the greatest change in total, structural, and load-dependent stiffening compared with younger groups (P<0.05). Only age and cessation of antihypertensive medication were predictive of structural stiffening, whereas age, race/ethnicity, education, blood pressure, cholesterol, and antihypertensive medication were predictive of increased load-dependent stiffening. On average, structural stiffening accounted for the vast majority of total stiffening, but 37% of participants had more load-dependent than structural stiffening. Rates of structural and load-dependent carotid artery stiffening increased with age. Structural stiffening was consistently observed, and load-dependent stiffening was highly variable. Heterogeneity in arterial stiffening mechanisms with aging may influence cardiovascular disease development.


Assuntos
Envelhecimento/fisiologia , Aterosclerose/fisiopatologia , Doenças Cardiovasculares/fisiopatologia , Artérias Carótidas/fisiopatologia , Rigidez Vascular/fisiologia , Idoso , Idoso de 80 Anos ou mais , Pressão Sanguínea/fisiologia , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ultrassonografia
2.
Int J Mol Sci ; 22(24)2021 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-34948083

RESUMO

In this review, we focus on the actual understanding of the role of IL-33 in vascular biology in the context of the historical development since the description of IL-33 as a member of IL-1 superfamily and the ligand for ST2 receptor in 2005. We summarize recent data on the biology, structure and signaling of this dual-function factor with both nuclear and extracellular cytokine properties. We describe cellular sources of IL-33, particularly within vascular wall, changes in its expression in different cardio-vascular conditions and mechanisms of IL-33 release. Additionally, we summarize the regulators of IL-33 expression as well as the effects of IL-33 itself in cells of the vasculature and in monocytes/macrophages in vitro combined with the consequences of IL-33 modulation in models of vascular diseases in vivo. Described in murine atherosclerosis models as well as in macrophages as an atheroprotective cytokine, extracellular IL-33 induces proinflammatory, prothrombotic and proangiogenic activation of human endothelial cells, which are processes known to be involved in the development and progression of atherosclerosis. We, therefore, discuss that IL-33 can possess both protective and harmful effects in experimental models of vascular pathologies depending on experimental conditions, type and dose of administration or method of modulation.


Assuntos
Aterosclerose/metabolismo , Interleucina-33/metabolismo , Animais , Aterosclerose/imunologia , Aterosclerose/fisiopatologia , Células Endoteliais , Regulação da Expressão Gênica , Humanos , Interleucina-33/genética , Interleucina-33/fisiologia , Macrófagos/metabolismo , Monócitos/metabolismo , Transdução de Sinais
3.
J Biomed Sci ; 28(1): 74, 2021 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-34749728

RESUMO

BACKGROUND: Toll-like receptor-2 (TLR2) promotes vascular smooth muscle cell (VSMC) transdifferentiation to chondrocytes and calcification in a p38 MAPK-dependent manner. Vascular 5-methoxytryptophan (5-MTP) is a newly identified factor with anti-inflammatory actions. As 5-MTP targets p38 MAPK for its actions, we postulated that 5-MTP protects against vascular chondrogenesis and calcification. METHODS: High-fat diet-induced advanced atherosclerosis in mice were performed to investigate the effect of 5-MTP on atherosclerotic lesions and calcification. VSMCs were used to determine the role of 5-MTP in VSMC chondrogenic differentiation and calcification. Alizarin red S and Alcian blue staining were used to measure VSMC calcification and chondrogenic differentiation, respectively. RESULTS: 5-MTP was detected in aortic tissues of ApoE-/- mice fed control chow. It was reduced in ApoE-/- mice fed high-fat diet (HFD), but was restored in ApoE-/-Tlr2-/- mice, suggesting that HFD reduces vascular 5-MTP production via TLR2. Intraperitoneal injection of 5-MTP or its analog into ApoE-/- mice fed HFD reduced aortic atherosclerotic lesions and calcification which was accompanied by reduction of chondrogenesis and calcium deposition. Pam3CSK4 (Pam3), ligand of TLR2, induced SMC phenotypic switch to chondrocytes. Pretreatment with 5-MTP preserved SMC contractile proteins and blocked Pam3-induced chondrocyte differentiation and calcification. 5-MTP inhibited HFD-induced p38 MAPK activation in vivo and Pam3-induced p38 MAPK activation in SMCs. 5-MTP suppressed HFD-induced CREB activation in aortic tissues and Pam3-induced CREB and NF-κB activation in SMCs. CONCLUSIONS: These findings suggest that 5-MTP is a vascular arsenal against atherosclerosis and calcification by inhibiting TLR2-mediated SMC phenotypic switch to chondrocytes and the consequent calcification. 5-MTP exerts these effects by blocking p38 MAPK activation and inhibiting CREB and NF-κB transactivation activity.


Assuntos
Aterosclerose/prevenção & controle , Calcinose/prevenção & controle , Condrogênese , Dieta Hiperlipídica/efeitos adversos , Triptofano/análogos & derivados , Animais , Aterosclerose/metabolismo , Aterosclerose/fisiopatologia , Calcinose/metabolismo , Calcinose/fisiopatologia , Camundongos , Triptofano/metabolismo
4.
Int J Mol Sci ; 22(17)2021 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-34502027

RESUMO

Monocytes play a key role in cardiovascular disease (CVD) as their influx into the vessel wall is necessary for the development of an atherosclerotic plaque. Monocytes are, however, heterogeneous differentiating from classical monocytes through the intermediate subset to the nonclassical subset. While it is recognized that the percentage of intermediate and nonclassical monocytes are higher in individuals with CVD, accompanying changes in inflammatory markers suggest a functional impact on disease development that goes beyond the increased proportion of these 'inflammatory' monocyte subsets. Furthermore, emerging evidence indicates that changes in monocyte proportion and function arise in dyslipidemia, with lipid lowering medication having some effect on reversing these changes. This review explores the nature and number of monocyte subsets in CVD addressing what they are, when they arise, the effect of lipid lowering treatment, and the possible implications for plaque development. Understanding these associations will deepen our understanding of the clinical significance of monocytes in CVD.


Assuntos
Aterosclerose/etiologia , Doenças Cardiovasculares/etiologia , Dislipidemias/complicações , Monócitos , Animais , Aterosclerose/fisiopatologia , Doenças Cardiovasculares/fisiopatologia , Humanos , Inflamação
5.
Int J Med Sci ; 18(15): 3533-3543, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34522180

RESUMO

Importance: Despite the availability of a vaccine against the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), humans will have to live with this virus and the after-effects of the coronavirus disease 2019 (COVID-19) infection for a long time. Cholesterol plays an important role in the infection and prognosis of SARS-CoV-2, and the study of its mechanism is of great significance not only for the treatment of COVID-19 but also for research on generic antiviral drugs. Observations: Cholesterol promotes the development of atherosclerosis by activating NLR family pyrin domain containing 3 (NLRP3), and the resulting inflammatory environment indirectly contributes to COVID-19 infection and subsequent deterioration. In in vitro studies, membrane cholesterol increased the number of viral entry sites on the host cell membrane and the number of angiotensin-converting enzyme 2 (ACE2) receptors in the membrane fusion site. Previous studies have shown that the fusion protein of the virus interacts with cholesterol, and the spike protein of SARS-CoV-2 also requires cholesterol to enter the host cells. Cholesterol in blood interacts with the spike protein to promote the entry of spike cells, wherein the scavenger receptor class B type 1 (SR-B1) plays an important role. Because of the cardiovascular protective effects of lipid-lowering therapy and the additional anti-inflammatory effects of lipid-lowering drugs, it is currently recommended to continue lipid-lowering therapy for patients with COVID-19, but the safety of extremely low LDL-C is questionable. Conclusions and Relevance: Cholesterol can indirectly increase the susceptibility of patients to SARS-CoV-2 and increase the risk of death from COVID-19, which are mediated by NLRP3 and atherosclerotic plaques, respectively. Cholesterol present in the host cell membrane, virus, and blood may also directly participate in the virus cell entry process, but the specific mechanism still needs further study. Patients with COVID-19 are recommended to continue lipid-lowering therapy.


Assuntos
COVID-19/complicações , Hipercolesterolemia/complicações , Enzima de Conversão de Angiotensina 2/metabolismo , Antivirais/uso terapêutico , Aterosclerose/fisiopatologia , COVID-19/diagnóstico , COVID-19/tratamento farmacológico , COVID-19/terapia , Membrana Celular/metabolismo , HDL-Colesterol/metabolismo , LDL-Colesterol/metabolismo , Endocitose , Humanos , Hipercolesterolemia/diagnóstico , Hipercolesterolemia/terapia , Inflamação , Macrófagos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/sangue , Prognóstico , SARS-CoV-2 , Receptores Depuradores Classe B/metabolismo
6.
Nutrients ; 13(9)2021 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-34578930

RESUMO

Backgrounds and aims: Elevated common carotid artery intima-media thickness (carotid IMT) and diminished flow-mediated dilation (FMD) are early subclinical indicators of atherosclerosis. Serum total non-esterified fatty acid (NEFA) concentrations have been positively associated with subclinical atherosclerosis. The relations between individual NEFA, carotid IMT and FMD have as yet to be assessed. Methods: We investigated the associations between fasting serum individual NEFA, carotid IMT and FMD among Cardiovascular Health Study (CHS) participants with (n = 255 for carotid IMT, 301 for FMD) or without (n = 1314 for carotid IMT, 1462 for FMD) known atherosclerotic cardiovascular disease (ASCVD). Using archived samples (fasting) collected from 1996-1997 (baseline), 35 individual NEFAs were measured using gas chromatography. Carotid IMT and estimated plaque thickness (mean of maximum internal carotid IMT) were determined in 1998-1999. FMD was measured in 1997-1998. Linear regression adjusted by the Holm-Bonferroni method was used to assess relations between individual NEFA, carotid IMT and FMD. Results: In multivariable adjusted linear regression models per SD increment, the non-esterified trans fatty acid conjugated linoleic acid (trans-18:2 CLA) was positively associated with carotid IMT [ß (95% CI): 44.8 (19.2, 70.4), p = 0.025] among participants with, but not without, ASCVD [2.16 (-6.74, 11.5), p = 1.000]. Non-esterified cis-palmitoleic acid (16:1n-7c) was positively associated with FMD [19.7 (8.34, 31.0), p = 0.024] among participants without, but not with ASCVD. No significant associations between NEFAs and estimated plaque thickness were observed. Conclusions: In older adults, serum non-esterified CLA and palmitoleic acid were positively associated with carotid IMT and FMD, respectively, suggesting potential modifiable biomarkers for arteriopathy.


Assuntos
Aterosclerose/sangue , Espessura Intima-Media Carotídea , Ácidos Graxos não Esterificados/sangue , Fluxo Sanguíneo Regional , Idoso , Idoso de 80 Anos ou mais , Aterosclerose/fisiopatologia , Biomarcadores/sangue , Artéria Braquial/diagnóstico por imagem , Artéria Carótida Primitiva/diagnóstico por imagem , Artéria Carótida Primitiva/fisiopatologia , Dilatação , Ácidos Graxos Monoinsaturados/sangue , Feminino , Humanos , Ácido Linoleico/sangue , Masculino , Fatores de Risco , Ultrassonografia/métodos
7.
Int J Mol Sci ; 22(18)2021 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-34576157

RESUMO

DNA damage and mitochondrial dysfunction are defining characteristics of aged vascular smooth muscle cells (VSMCs) found in atherosclerosis. Pink1 kinase regulates mitochondrial homeostasis and recycles dysfunctional organelles critical for maintaining energetic homeostasis. Here, we generated a new vascular-specific Pink1 knockout and assessed its effect on VSMC-dependent atherogenesis in vivo and VSMC energetic metabolism in vitro. A smooth muscle cell-specific and MHC-Cre-inducible flox'd Pink1f/f kinase knockout was made on a ROSA26+/0 and ApoE-/- C57Blk6/J background. Mice were high fat fed for 10 weeks and vasculature assessed for physiological and pathogical changes. Mitochondrial respiratory activity was then assessed in wild-type and knockout animals vessels and isolated cells for their reliance on oxidative and glycolytic metabolism. During atherogenesis, we find that Pink1 knockout affects development of plaque quality rather than plaque quantity by decreasing VSMC and extracellular matrix components, collagen and elastin. Pink1 protein is important in the wild-type VSMC response to metabolic stress and induced a compensatory increase in hexokinase II, which catalyses the first irreversible step in glycolysis. Pink1 appears to play an important role in VSMC energetics during atherogenesis but may also provide insight into the understanding of mitochondrial energetics in other diseases where the regulation of energetic switching between oxidative and glycolytic metabolism is found to be important.


Assuntos
Músculo Liso Vascular/metabolismo , Proteínas Quinases/metabolismo , Animais , Aterosclerose/metabolismo , Aterosclerose/fisiopatologia , Dano ao DNA/genética , Dano ao DNA/fisiologia , Glicólise/genética , Glicólise/fisiologia , Camundongos , Camundongos Knockout , Microdissecção , Músculo Liso Vascular/citologia , Miócitos de Músculo Liso , Estresse Oxidativo/genética , Estresse Oxidativo/fisiologia , Fosforilação/genética , Fosforilação/fisiologia , Proteínas Quinases/genética , Transdução de Sinais/genética , Transdução de Sinais/fisiologia
8.
Int J Mol Sci ; 22(16)2021 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-34445154

RESUMO

The continuous relationship between blood pressure (BP) and cardiovascular events makes the distinction between elevated BP and hypertension based on arbitrary cut-off values for BP. Even mild BP elevations manifesting as high-normal BP have been associated with cardiovascular risk. We hypothesize that persistent elevated BP increases atherosclerotic plaque development. To evaluate this causal link, we developed a new mouse model of elevated BP based on adeno-associated virus (AAV) gene transfer. We constructed AAV vectors to support transfer of the hRenin and hAngiotensinogen genes. A single injection of AAV-Ren/Ang (1011 total viral particles) induced sustained systolic BP increase (130 ± 20 mmHg, vs. 110 ± 15 mmHg in controls; p = 0.05). In ApoE-/- mice, AAV-induced mild BP elevation caused larger atherosclerotic lesions evaluated by histology (10-fold increase vs. normotensive controls). In this preclinical model, atheroma plaques development was attenuated by BP control with a calcium channel blocker, indicating that a small increase in BP within a physiological range has a substantial impact on plaque development in a preclinical model of atherosclerosis. These data support that non-optimal BP represents a risk for atherosclerosis development. Earlier intervention in elevated BP may prevent or delay morbidity and mortality associated with atherosclerosis.


Assuntos
Aterosclerose/etiologia , Pressão Sanguínea , Hipertensão/complicações , Animais , Aterosclerose/fisiopatologia , Modelos Animais de Doenças , Humanos , Hipertensão/fisiopatologia , Masculino , Camundongos Endogâmicos C57BL
9.
Am J Cardiol ; 154: 41-47, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34256942

RESUMO

Saphenous vein grafts are imperfect yet indispensable conduits commonly used for coronary artery bypass grafting. Their degeneration ultimately leading to occlusion results from the pathological response of the vein to altered blood rheology and several types of vascular injury. Surgical techniques minimizing vessel damage, and prolonged antiplatelet and lipid-lowering treatment are established methods of mitigating the degeneration process hence preventing graft occlusions. Percutaneous interventions in degenerated vein grafts carry high risk of embolization, periprocedural myocardial infarction and restenosis. Thus, native vessel should be the preferred treatment target in case of graft failure whenever technically feasible.


Assuntos
Aterosclerose/prevenção & controle , Ponte de Artéria Coronária , Doença da Artéria Coronariana/cirurgia , Oclusão de Enxerto Vascular/prevenção & controle , Complicações Pós-Operatórias/prevenção & controle , Veia Safena/transplante , Trombose/prevenção & controle , Aterosclerose/fisiopatologia , Aterosclerose/terapia , Oclusão de Enxerto Vascular/fisiopatologia , Oclusão de Enxerto Vascular/terapia , Humanos , Hipolipemiantes/uso terapêutico , Intervenção Coronária Percutânea , Inibidores da Agregação Plaquetária/uso terapêutico , Complicações Pós-Operatórias/fisiopatologia , Complicações Pós-Operatórias/terapia , Recidiva , Trombose/fisiopatologia , Trombose/terapia
10.
Biomed Res Int ; 2021: 6894623, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34250090

RESUMO

Background: Carotid plaque is an undefined risk factor in ischemic stroke and is driven by inflammation. Mounting evidence suggests that neutrophil-to-lymphocyte ratio (NLR) is crucial not only for cerebrovascular events but also in atherosclerosis progression. Here, we aimed to explore the association between the admission NLR and carotid plaque vulnerability as well as the occurrence of vulnerable carotid plaque detected by carotid ultrasonography in patients with acute ischemic stroke (AIS) among Chinese. Methods: We conducted a retrospective study composed of 588 patients with AIS and 309 healthy controls free of carotid plaque in the Department of Neurology in The Second Hospital of Lanzhou University from March 2014 to February 2015. All patients were classified as nonplaque, stable plaque, and vulnerable plaque groups on the basis of carotid ultrasonography results. The baseline information was collected and compared among the four different groups. The correlation between variables and carotid plaque vulnerability was tested by Spearman linear correlation analysis. To identify the independent predictors for vulnerable carotid plaque, univariate and multivariate logistic regression analysis was performed. Results: The comparisons of age, sex proportion, history of hypertension, diabetes, and smoking, the levels of HDL-C, Lp(a), BMI, SBP, DBP, Fib, CRP, leukocyte, and NLR among the four groups showed a statistically significant difference (P < 0.05); in particular, the NLR was significantly higher in the vulnerable plaque group as compared to the control (P = 0.043), nonplaque (P = 0.022), and stable plaque groups (P = 0.015). The Spearman correlation analysis presented a positive correlation between carotid plaque vulnerability and age (r = 0.302; P < 0.001), SBP (r = 0.163; P < 0.001), and NLR (r = 0.087; P = 0.034), while the lymphocyte was negatively related to the carotid plaque vulnerability (r = -0.089; P = 0.030). The multivariate logistic regression analysis adjusted for confounding factors revealed that age (odds ratio [OR], 1.042; 95% confidence interval [CI], 1.025-1.060; P < 0.001), male gender (OR, 2.005; 95% CI, 1.394-2.884; P < 0.001), diabetes (OR, 1.481; 95% CI, 1.021-2.149; P = 0.039), SBP (OR, 1.012; 95% CI, 1.003-1.021; P = 0.010), and NLR (OR, 1.098; 95% CI, 1.018-1.184; P = 0.015) are independent predictors of vulnerable carotid plaque in patients with AIS. Conclusion: The admission NLR is a novel and meaningful biomarker that can be used in predicting carotid plaque vulnerability and the presence of vulnerable carotid plaque assessed by carotid ultrasonography in patients with AIS among Chinese.


Assuntos
Estenose das Carótidas/fisiopatologia , AVC Isquêmico/fisiopatologia , Linfócitos/citologia , Neutrófilos/citologia , Idoso , Aterosclerose/complicações , Aterosclerose/fisiopatologia , Biomarcadores Tumorais , Artérias Carótidas , Espessura Intima-Media Carotídea , Estenose das Carótidas/complicações , China , Progressão da Doença , Feminino , Humanos , Inflamação , AVC Isquêmico/complicações , Modelos Lineares , Contagem de Linfócitos , Linfócitos/metabolismo , Masculino , Pessoa de Meia-Idade , Neutrófilos/metabolismo , Placa Aterosclerótica , Análise de Regressão , Estudos Retrospectivos , Fatores de Risco
11.
Sci Rep ; 11(1): 13922, 2021 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-34230513

RESUMO

Our recent studies indicate that thyroid cysts have clinical implications. Thyroid cysts could have a positive effect on the supply of thyroid hormones. Both hyperthyroidism and hypothyroidism cause hypertension. Hypothyroidism, but not hyperthyroidism, is a risk factor for atherosclerosis. Therefore, thyroid cysts could be associated with hypertension, and atherosclerosis might influence the association between thyroid cysts and hypertension. To evaluate the clinical significance of thyroid cysts, a cross-sectional study was conducted with 1801 Japanese aged 40-74 years. Thyroid cysts were significantly positively associated with hypertension in participants without atherosclerosis. However, there was a significant inverse association in those with atherosclerosis. The potential confounding factor adjusted odd ratios and 95% confidence intervals (95% CIs) were 1.49 (95% CI 1.17-1.90) for participants without atherosclerosis and 0.49 (95% CI 0.24-0.98) for those with atherosclerosis. The present study demonstrates that thyroid cysts have clinical implications because thyroid cysts support thyroid hormone activity. Our findings provide sufficient evidence to develop a risk assessment for hypertension for the general population, even though further research is required.


Assuntos
Aterosclerose/complicações , Cistos/complicações , Hipertensão/complicações , Glândula Tireoide/patologia , Adulto , Idoso , Anti-Hipertensivos/uso terapêutico , Aterosclerose/sangue , Aterosclerose/fisiopatologia , Estudos Transversais , Cistos/sangue , Cistos/fisiopatologia , Feminino , Humanos , Hipertensão/sangue , Hipertensão/tratamento farmacológico , Hipertensão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Glândula Tireoide/fisiopatologia , Tri-Iodotironina/sangue
12.
Int J Mol Sci ; 22(14)2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-34299213

RESUMO

The MEK5/ERK5 mitogen-activated protein kinases (MAPK) cascade is a unique signaling module activated by both mitogens and stress stimuli, including cytokines, fluid shear stress, high osmolarity, and oxidative stress. Physiologically, it is mainly known as a mechanoreceptive pathway in the endothelium, where it transduces the various vasoprotective effects of laminar blood flow. However, it also maintains integrity in other tissues exposed to mechanical stress, including bone, cartilage, and muscle, where it exerts a key function as a survival and differentiation pathway. Beyond its diverse physiological roles, the MEK5/ERK5 pathway has also been implicated in various diseases, including cancer, where it has recently emerged as a major escape route, sustaining tumor cell survival and proliferation under drug stress. In addition, MEK5/ERK5 dysfunction may foster cardiovascular diseases such as atherosclerosis. Here, we highlight the importance of the MEK5/ERK5 pathway in health and disease, focusing on its role as a protective cascade in mechanical stress-exposed healthy tissues and its function as a therapy resistance pathway in cancers. We discuss the perspective of targeting this cascade for cancer treatment and weigh its chances and potential risks when considering its emerging role as a protective stress response pathway.


Assuntos
Aterosclerose/fisiopatologia , MAP Quinase Quinase 5/metabolismo , Sistema de Sinalização das MAP Quinases , Proteína Quinase 7 Ativada por Mitógeno/metabolismo , Animais , Aterosclerose/metabolismo , Humanos , Neoplasias/enzimologia , Neoplasias/metabolismo
13.
Int J Mol Sci ; 22(14)2021 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-34299240

RESUMO

Glucocorticoids are steroid hormones with key roles in the regulation of many physiological systems including energy homeostasis and immunity. However, chronic glucocorticoid excess, highlighted in Cushing's syndrome, is established as being associated with increased cardiovascular disease (CVD) risk. Atherosclerosis is the major cause of CVD, leading to complications including coronary artery disease, myocardial infarction and heart failure. While the associations between glucocorticoid excess and increased prevalence of these complications are well established, the mechanisms underlying the role of glucocorticoids in development of atheroma are unclear. This review aims to better understand the importance of glucocorticoids in atherosclerosis and to dissect their cell-specific effects on key processes (e.g., contractility, remodelling and lesion development). Clinical and pre-clinical studies have shown both athero-protective and pro-atherogenic responses to glucocorticoids, effects dependent upon their multifactorial actions. Evidence indicates regulation of glucocorticoid bioavailability at the vasculature is complex, with local delivery, pre-receptor metabolism, and receptor expression contributing to responses linked to vascular remodelling and inflammation. Further investigations are required to clarify the mechanisms through which endogenous, local glucocorticoid action and systemic glucocorticoid treatment promote/inhibit atherosclerosis. This will provide greater insights into the potential benefit of glucocorticoid targeted approaches in the treatment of cardiovascular disease.


Assuntos
Aterosclerose/tratamento farmacológico , Aterosclerose/fisiopatologia , Glucocorticoides/farmacologia , Aterosclerose/metabolismo , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/fisiopatologia , Síndrome de Cushing , Glucocorticoides/metabolismo , Humanos , Inflamação/tratamento farmacológico , Receptores de Glucocorticoides/metabolismo , Fatores de Risco
14.
Int J Mol Sci ; 22(11)2021 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-34073119

RESUMO

Cells convey information among one another. One instrument employed to transmit data and constituents to specific (target) cells is extracellular vesicles (EVs). They originate from a variety of cells (endothelial, immune cells, platelets, mesenchymal stromal cells, etc.), and consequently, their surface characteristics and cargo vary according to the paternal cell. The cargo could be DNA, mRNA, microRNA, receptors, metabolites, cytoplasmic proteins, or pathological molecules, as a function of which EVs exert different effects upon endocytosis in recipient cells. Recently, EVs have become important participants in a variety of pathologies, including atherogenesis and coronavirus disease 2019 (COVID-19)-associated thrombosis. Herein, we summarize recent advances and some of our own results on the role of EVs in atherosclerotic cardiovascular diseases, and discuss their potential to function as signaling mediators, biomarkers and therapeutic agents. Since COVID-19 patients have a high rate of thrombotic events, a special section of the review is dedicated to the mechanism of thrombosis and the possible therapeutic potential of EVs in COVID-19-related thrombosis. Yet, EV mechanisms and their role in the transfer of information between cells in normal and pathological conditions remain to be explored.


Assuntos
Aterosclerose/metabolismo , COVID-19/metabolismo , Vesículas Extracelulares/metabolismo , Trombose/metabolismo , Aterosclerose/fisiopatologia , Aterosclerose/terapia , Aterosclerose/virologia , Biomarcadores/metabolismo , COVID-19/complicações , COVID-19/fisiopatologia , COVID-19/terapia , Células Endoteliais/metabolismo , Humanos , Inflamação/imunologia , Inflamação/metabolismo , Inflamação/virologia , Células-Tronco Mesenquimais/metabolismo , Transdução de Sinais/imunologia , Trombose/complicações , Trombose/fisiopatologia , Trombose/virologia
15.
Pharmacol Rev ; 73(3): 924-967, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34088867

RESUMO

The endothelium, a cellular monolayer lining the blood vessel wall, plays a critical role in maintaining multiorgan health and homeostasis. Endothelial functions in health include dynamic maintenance of vascular tone, angiogenesis, hemostasis, and the provision of an antioxidant, anti-inflammatory, and antithrombotic interface. Dysfunction of the vascular endothelium presents with impaired endothelium-dependent vasodilation, heightened oxidative stress, chronic inflammation, leukocyte adhesion and hyperpermeability, and endothelial cell senescence. Recent studies have implicated altered endothelial cell metabolism and endothelial-to-mesenchymal transition as new features of endothelial dysfunction. Endothelial dysfunction is regarded as a hallmark of many diverse human panvascular diseases, including atherosclerosis, hypertension, and diabetes. Endothelial dysfunction has also been implicated in severe coronavirus disease 2019. Many clinically used pharmacotherapies, ranging from traditional lipid-lowering drugs, antihypertensive drugs, and antidiabetic drugs to proprotein convertase subtilisin/kexin type 9 inhibitors and interleukin 1ß monoclonal antibodies, counter endothelial dysfunction as part of their clinical benefits. The regulation of endothelial dysfunction by noncoding RNAs has provided novel insights into these newly described regulators of endothelial dysfunction, thus yielding potential new therapeutic approaches. Altogether, a better understanding of the versatile (dys)functions of endothelial cells will not only deepen our comprehension of human diseases but also accelerate effective therapeutic drug discovery. In this review, we provide a timely overview of the multiple layers of endothelial function, describe the consequences and mechanisms of endothelial dysfunction, and identify pathways to effective targeted therapies. SIGNIFICANCE STATEMENT: The endothelium was initially considered to be a semipermeable biomechanical barrier and gatekeeper of vascular health. In recent decades, a deepened understanding of the biological functions of the endothelium has led to its recognition as a ubiquitous tissue regulating vascular tone, cell behavior, innate immunity, cell-cell interactions, and cell metabolism in the vessel wall. Endothelial dysfunction is the hallmark of cardiovascular, metabolic, and emerging infectious diseases. Pharmacotherapies targeting endothelial dysfunction have potential for treatment of cardiovascular and many other diseases.


Assuntos
Aterosclerose , COVID-19 , Fármacos Cardiovasculares , Doenças Cardiovasculares , Endotélio Vascular , Aterosclerose/tratamento farmacológico , Aterosclerose/metabolismo , Aterosclerose/fisiopatologia , COVID-19/tratamento farmacológico , COVID-19/metabolismo , COVID-19/fisiopatologia , Fármacos Cardiovasculares/classificação , Fármacos Cardiovasculares/farmacologia , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/fisiopatologia , Descoberta de Drogas , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiopatologia , Humanos , Terapia de Alvo Molecular/métodos , Terapia de Alvo Molecular/tendências , SARS-CoV-2
16.
Am J Cardiol ; 152: 43-48, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34175106

RESUMO

The patient reported angina measurement with the Seattle Angina Questionnaire (SAQ) has shown to have prognostic implications and became an endpoint in clinical trials. Our objective was to study physician-reported and SAQ severity with the total coronary atherosclerotic burden as assessed by 4 angiographic scores. We prospectively analyzed data of consecutive patients scheduled for coronary angiography or percutaneous coronary intervention. The Canadian Cardiovascular Society (CCS) angina categories was used as physician-reported angina. SAQ domains were categorized as severe (0 to 24), moderate 25 to 75 and mild angina (>75). All angina assessments were done before coronary angiography. Gensini, Syntax, Friesinger, and Sullivan angiographic scores were used for total atherosclerotic burden quantification: 261 patients were included in the present analysis. The median age was 66.0 (59.0 to 71.8) years, 53.6% were male and 43.7% had diabetes. The median SYNTAX score was 6.0 (0 to 18.0). The worse the symptoms of CCS categories, the more severe was the atherosclerotic burden in all angiographic scores: SYNTAX (p = 0.01); Gensini (p <0.01); Friesinger (p = 0.02) and Sullivan (p = 0.03). Conversely, SAQ domains were not able to discriminate the severity of CAD in any of the scores. The only exception was the severe SAQ quality of life that had worse Gensini score than the mild SAQ quality of life (p = 0.04). In conclusion, CCS angina categories are related to the total atherosclerotic burden in coronary angiography, by all angiographic scores. SAQ domains should be used as a measure of patient functionality and quality of life but not as a measure of CAD severity.


Assuntos
Angina Pectoris/fisiopatologia , Aterosclerose/fisiopatologia , Angiografia Coronária , Doença da Artéria Coronariana/fisiopatologia , Intervenção Coronária Percutânea , Idoso , Angina Pectoris/diagnóstico por imagem , Aterosclerose/diagnóstico por imagem , Aterosclerose/cirurgia , Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/cirurgia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Medidas de Resultados Relatados pelo Paciente , Prognóstico , Estudos Prospectivos , Índice de Gravidade de Doença , Inquéritos e Questionários
17.
Clin Interv Aging ; 16: 1057-1070, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34135578

RESUMO

Introduction: The prevalence of metabolic syndrome among the elderly population is growing. The elements of metabolic syndrome in an aging society are currently being researched. Atherosclerosis is a slow process in which the first symptoms may be observed after many years. The mechanisms underlying the progression of atherosclerosis are oxidative stress and inflammation. Inflammation and oxidative stress are associated with the increased incidence of metabolic syndrome. Taking the above into consideration, metabolic syndrome is thought to be a clinical equivalent of atherosclerosis. Aim: The aim of this paper is to review the impact of the interplay of oxidant-antioxidant and inflammation markers in metabolic syndrome in general as well as its components in the pathophysiology which underlies development of atherosclerosis in elderly individuals. Methods: A systematic scan of online resources designed for elderly (≥65 years) published from 2005 to the end of 2020 were reviewed. This was supplemented with grey literature and then all resources were narratively analyzed. The analysis included the following terms: "atherosclerosis or metabolic syndrome" and "oxidative stress or inflammation" and "elderly" to find reports of atherosclerotic disease from asymptomatic to life-threatening among the elderly population with metabolic syndrome . Results: The work summarizes articles that were applicable to this study, including systematic reviews, qualitative studies and opinion pieces. Current knowledge focuses on monitoring the inflammation and oxidant-antioxidant imbalance in disentangling atherosclerosis in patients diagnosed with metabolic syndrome. The population-based studies described inflammation, increased oxidative stress and weak antioxidant defense systems as the mechanisms underlying atherosclerosis development. Moreover, there are discussions that these targets could potentially be a point of intervention to reduce the development of atherosclerosis in the elderly, especially those with altered glucose and lipid metabolism. Specific markers may be used as an approach for the prevention and lifestyle modification of atherosclerotic disease in such population. Conclusion: Metabolic syndrome and its components are important contributors in the progression of atherosclerotic disease in the elderly population but constant efforts should be made to broaden our knowledge of elderly groups who are the most susceptible for the development of atherosclerosis complications.


Assuntos
Antioxidantes/metabolismo , Aterosclerose/metabolismo , Inflamação/metabolismo , Síndrome Metabólica/metabolismo , Oxidantes/metabolismo , Idoso , Envelhecimento/fisiologia , Aterosclerose/fisiopatologia , Biomarcadores/metabolismo , Humanos , Inflamação/fisiopatologia , Metabolismo dos Lipídeos , Masculino , Síndrome Metabólica/fisiopatologia , Obesidade/metabolismo , Estresse Oxidativo/fisiologia
18.
Clin Interv Aging ; 16: 1139-1149, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34168437

RESUMO

Background: Silent myocardial infarction (SMI) accounts for more than half of all MIs, and common risk factors and pathophysiological pathways coexist between SMI and frailty. The risk of frailty among patients with SMI is not well established. This study aimed to examine the association between SMI and frailty. Methods and Results: This analysis included data from the Atherosclerosis Risk in Communities study. Patients without MI at baseline were eligible for inclusion. SMI was defined as electrocardiographic evidence of MI without clinical MI (CMI) after the baseline and until the fourth visit. Frailty was assessed during the fifth visit. A total of 4953 participants were included with an average age of 52.2±5.1 years. Among these participants, 2.7% (n=135) developed SMI, and 2.9% (n=146) developed CMI. After a median follow-up time of 14.7 (14.0-15.3) years, 6.7% (n=336) of the participants developed frailty. Patients with SMI and CMI were significantly more likely to become frail than those without MI (15.6% vs 6.2%, P<0.001 and 16.4% vs 6.2%, P<0.001, respectively). After adjusting for confounders, SMI and CMI were found to be independent predictors of frailty (odds ratio [OR]=2.243, 95% confidence interval [CI]=1.307-3.850, P=0.003 and OR=2.164, 95% CI=1.259-3.721, P=0.005, respectively). The association was consistent among the subgroups of age, sex, race, diabetes, and hypertension. Conclusion: In conclusion, both SMI and CMI were found to be associated with a higher risk of frailty. Future studies are needed to confirm the beneficial effects of screening for SMI as well as to implement standardized preventive treatment to reduce the risk of frailty. Clinical Trial Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00005131.


Assuntos
Aterosclerose/epidemiologia , Fragilidade/epidemiologia , Infarto do Miocárdio/epidemiologia , Idoso , Aterosclerose/fisiopatologia , Eletrocardiografia/métodos , Fragilidade/fisiopatologia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/fisiopatologia , Prognóstico , Medição de Risco , Fatores de Risco
20.
Sci Rep ; 11(1): 11905, 2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-34099806

RESUMO

Retinal vein occlusion (RVO) is associated with atherosclerotic cardiovascular risk factors; however, its association with the specific markers of subclinical atherosclerosis has not yet been established. To investigate this association, we compared 70 patients with RVO to 70 age- and sex-matched patients without RVO. Low-density lipoprotein cholesterol (LDL-C) levels and brachial-ankle pulse wave velocity (baPWV) were significantly higher in the RVO group than in the control group. Carotid plaques (54.3% vs. 28.6%, p = 0.004) were more frequent in the RVO group. Multivariate logistic regression analysis showed that the presence of carotid plaques (odds ratio [OR]: 3.15, 95% confidence interval [CI] 1.38-7.16, p = 0.006), as well as smoking, LDL-C level, and baPWV were associated with RVO. Additionally, a multinomial logistic regression model showed that the presence of carotid plaques (OR: 3.94, 95% CI 1.65-9.41, p = 0.002) and LDL-C level were associated with branch RVO, whereas smoking and baPWV were associated with central RVO. In conclusion, RVO was associated with subclinical atherosclerosis markers, including carotid plaques and baPWV. These results support the hypothesis that atherosclerosis contributes to the etiology of RVO and suggest the evaluation of subclinical atherosclerosis in patients with RVO.


Assuntos
Índice Tornozelo-Braço , Aterosclerose/diagnóstico , Biomarcadores/análise , LDL-Colesterol/metabolismo , Análise de Onda de Pulso , Oclusão da Veia Retiniana/diagnóstico , Adulto , Idoso , Aterosclerose/complicações , Aterosclerose/fisiopatologia , Artérias Carótidas/patologia , Estudos de Casos e Controles , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estudos Prospectivos , Oclusão da Veia Retiniana/etiologia , Oclusão da Veia Retiniana/fisiopatologia , Fatores de Risco , Rigidez Vascular
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