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1.
Curr Cardiol Rep ; 26(10): 1047-1062, 2024 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-39066990

RESUMEN

PURPOSE OF REVIEW: To summarize the current use of cardiac computed tomography (CT) technologies as well as their pertinent evidence in regards to prevention of coronary artery disease (CAD). RECENT FINDINGS: Cardiac CTA has now become a main non-invasive method for the evaluation of symptomatic CAD. In addition to coronary calcium score, other CT technologies such as atherosclerotic plaque analysis, fractional flow reserve estimation by CT, pericoronary fat attenuation, and endothelial wall shear stress have emerged. Whether the use of CT modalities can enhance risk prediction and prevention in CAD has not been fully answered. We discuss the evidence for coronary artery calcium scoring and coronary CT angiography in primary prevention and the current barriers to their use. We attempt to delineate what can be done to expand use and what studies are needed to broaden adoption in the future. We also examine the potential roles of emerging CT technologies. Finally, we describe potential clinical approaches to prevention that would incorporate cardiac CT technologies.


Asunto(s)
Angiografía por Tomografía Computarizada , Angiografía Coronaria , Enfermedad de la Arteria Coronaria , Prevención Primaria , Humanos , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Enfermedad de la Arteria Coronaria/prevención & control , Prevención Primaria/métodos , Angiografía Coronaria/métodos , Placa Aterosclerótica/diagnóstico por imagen , Placa Aterosclerótica/prevención & control , Tomografía Computarizada por Rayos X/métodos , Medición de Riesgo , Vasos Coronarios/diagnóstico por imagen , Calcificación Vascular/diagnóstico por imagen , Calcificación Vascular/prevención & control , Reserva del Flujo Fraccional Miocárdico
2.
Int J Pharm ; 662: 124469, 2024 Sep 05.
Artículo en Inglés | MEDLINE | ID: mdl-39004292

RESUMEN

Recognizing the significance of drug carriers in the treatment of atherosclerotic plaque is crucial in light of the worldwide repercussions of ischemic stroke. Conservative methodologies, specifically targeted drug delivery, present encouraging substitutes that mitigate the hazards linked to invasive procedures. With the intention of illuminating their considerable significance and prospective benefits, this study examines the impact of the geometry and dimensions of drug-loaded nano-microcarriers on atherosclerotic plaque. The research utilizes a finite element approach to simulate the motion and fluid dynamics of nano-microcarriers loaded with drugs within the carotid arteries. Carriers are available in a variety of shapes and sizes to accommodate patient-specific geometries, pulsatile fluid flow, and non-Newtonian blood properties. Optimization of drug delivery is achieved through the examination of carrier interaction with the inner wall. The results demonstrated that the interaction data between particles and the inner wall of atherosclerotic plaques exhibits micro- and nanoscale patterns that are distinct. Symmetric plaques demonstrate that nanoparticles with a 0.4 shape factor and diameters below 200 nm show the highest interaction rate. Conversely, larger particles (200 and 500 nm) with shape factors of 1 demonstrate comparatively elevated interaction rates. The optimal shape factor for drug-loaded microparticles has been determined to be one, and the number of interactions increases as the diameter of the nanoparticles increases, with a significant increase observed at a shape factor of one. Asymmetric plaques exhibit the maximum interaction rates among particles that have a shape factor of 0.4 and have diameters smaller than 500 µm. The findings establish a foundation for novel therapeutic strategies, establishing nano-microparticles as auspicious contenders for accurate and efficacious drug delivery systems that inhibit plaque proliferation.


Asunto(s)
Portadores de Fármacos , Sistemas de Liberación de Medicamentos , Accidente Cerebrovascular Isquémico , Nanopartículas , Tamaño de la Partícula , Placa Aterosclerótica , Placa Aterosclerótica/prevención & control , Placa Aterosclerótica/tratamiento farmacológico , Sistemas de Liberación de Medicamentos/métodos , Accidente Cerebrovascular Isquémico/prevención & control , Accidente Cerebrovascular Isquémico/tratamiento farmacológico , Portadores de Fármacos/química , Nanopartículas/química , Nanopartículas/administración & dosificación , Humanos , Arterias Carótidas/efectos de los fármacos , Análisis de Elementos Finitos
3.
Aging (Albany NY) ; 16(13): 10784-10798, 2024 Jul 10.
Artículo en Inglés | MEDLINE | ID: mdl-38990203

RESUMEN

Atherosclerosis (AS) is the main pathological basis of cardiovascular diseases such as coronary heart disease. Black phosphorus quantum dots (BPQDs) are a novel nanomaterial with good optical properties and biocompatibility, which was applied in the treatment of AS in mice, with good results shown in our previous study. In this study, BPQDs were injected into high-fat diet-fed apolipoprotein E knockout mice as a preventive drug for 12 weeks. Simvastatin, a classic preventive drug for AS, was used as a control to verify the preventive effect of BPQDs. The results showed that after preventive treatment with BPQDs, the plaque area in mice was significantly reduced, the vascular elasticity was increased, and serum lipid levels were significantly lower than those in the model group. To explore the mechanism, macrophages were induced to become foam cells using oxidized low-density lipoprotein. We found that BPQDs treatment could increase cell autophagy, thereby regulating intracellular lipid metabolism. Taken together, these data revealed that BPQDs may serve as a functional drug in preventing the development of AS.


Asunto(s)
Aterosclerosis , Dieta Alta en Grasa , Fósforo , Puntos Cuánticos , Animales , Dieta Alta en Grasa/efectos adversos , Aterosclerosis/prevención & control , Ratones , Fósforo/sangre , Ratones Noqueados , Apolipoproteínas E/genética , Masculino , Autofagia/efectos de los fármacos , Ratones Noqueados para ApoE , Metabolismo de los Lípidos/efectos de los fármacos , Modelos Animales de Enfermedad , Placa Aterosclerótica/prevención & control , Lipoproteínas LDL/metabolismo , Lipoproteínas LDL/sangre , Simvastatina/farmacología , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Células Espumosas/efectos de los fármacos , Células Espumosas/metabolismo
4.
ACS Appl Mater Interfaces ; 16(27): 35421-35437, 2024 Jul 10.
Artículo en Inglés | MEDLINE | ID: mdl-38940349

RESUMEN

Natural products have been widely recognized in clinical treatment because of their low toxicity and high activity. It is worth paying attention to modifying the biopolymer into nanostructures to give natural active ingredients additional targeting effects. In this study, based on the multifunctional modification of ß-cyclodextrin (ß-CD), a nanoplatform encapsulating the unstable drug (-)-epicatechin gallate (ECG) was designed to deliver to atherosclerotic plaques. Acetalization cyclodextrin (PH-CD), which responds to low-pH environments, and hyaluronic acid cyclodextrin, which targets the CD44 receptor on macrophage membranes, were synthesized from ß-CD and hyaluronic acid using acetalization and transesterification, respectively. The resulting dual-carrier nanoparticles (Double-NPs) loaded with ECG were prepared using a solvent evaporation method. The Double-NPs effectively scavenged reactive oxygen species, promoted macrophage migration, inhibited macrophage apoptosis, and suppressed abnormal proliferation and migration of vascular smooth muscle cells. Furthermore, the Double-NPs actively accumulated in atherosclerotic plaques in ApoE-/- mice fed with a high-fat diet, leading to a reduced plaque area, inflammatory infiltration, and plaque instability. Our findings demonstrate that the newly developed ECG nanopreparation represents an effective and safe nanotherapy for diseases such as atherosclerosis.


Asunto(s)
Aterosclerosis , Ácido Hialurónico , Nanopartículas , beta-Ciclodextrinas , Ácido Hialurónico/química , Animales , Aterosclerosis/tratamiento farmacológico , Aterosclerosis/prevención & control , Ratones , beta-Ciclodextrinas/química , Nanopartículas/química , Catequina/análogos & derivados , Catequina/química , Catequina/farmacología , Células RAW 264.7 , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Apoptosis/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Portadores de Fármacos/química , Movimiento Celular/efectos de los fármacos , Humanos , Placa Aterosclerótica/tratamiento farmacológico , Placa Aterosclerótica/prevención & control , Proliferación Celular/efectos de los fármacos
7.
Zhongguo Zhong Yao Za Zhi ; 49(1): 243-250, 2024 Jan.
Artículo en Chino | MEDLINE | ID: mdl-38403357

RESUMEN

This article aims to investigate the effect of Zhuyu Pills on atherosclerosis and decipher the underlying mechanism. The mouse model of atherosclerosis was induced by a high-fat diet, and the total modeling period was 12 weeks. A total of 47 ApoE~(-/-) mice successfully modeled were randomized into 5 groups, including 10 in the model group, 9 in each of low-, medium-, and high-dose(130.54, 261.08 and 522.16 mg·kg~(-1)·d~(-1), respectively) Zhuyu Pills groups, and 10 in the atorvastatin calcium(10.40 mg·kg~(-1)·d~(-1)) group. In addition, 10 C57BL/6J mice were included as the normal group. The mice in the normal group and model group were administrated with an equal volume of sterile distilled water, and those in other groups with corresponding agents by gavage once a day for 12 weeks. At the end of drug intervention, the levels of total cholesterol(TC), triglyceride(TG), high-density lipoprotein cholesterol(HDL-C), and low-density lipoprotein cholesterol(LDL-C) were measured by the biochemical method. Hematoxylin-eosin(HE) staining was employed to observe the plaque distribution in the aortic region. The serum levels of pro-inflammatory cytokines tumor necrosis factor-α(TNF-α) and interleukin(IL)-6 in M1 macrophages and anti-inflammatory cytokines IL-13 and IL-4 in M2 macrophages were determined by enzyme-linked immunosorbent assay(ELISA). The expression levels of inducible nitric oxide synthase(iNOS) and arginase-1(Arg-1) were examined by immunofluorescence. Real-time fluorescence quantitative polymerase chain reaction(real-time PCR) was employed to measure the mRNA levels of peroxisome proliferator-activated receptor γ(PPARγ), nuclear factor-κB(NF-κB), Arg-1, and iNOS in the aorta. Western blot was employed to determine the protein levels of PPARγ and NF-κB in the aorta. The results showed that compared with the normal group, the modeling elevated the TC, TG, and LDL-C levels, lowered the HDL-C level, caused large area thickening of the aortic intima, elevated the TNF-α and IL-6 levels, lowered the IL-4 and IL-13 levels, down-regulated the mRNA and protein levels of PPARγ and Arg-1, and up-regulated the mRNA and protein levels of iNOS and NF-κB in the aorta(P<0.01). Compared with the model group, low-, medium-, and high-dose Zhuyu Pills and atorvastatin calcium lowered the TC, TG, and LDL-C levels, elevated the HDL-C level, reduced the plaque area in a concentration-dependent manner, lowered the TNF-α and IL-6 levels, elevated the IL-4 and IL-13 levels, up-regulated the mRNA and protein levels of PPARγ and Arg-1, and down-regulated the mRNA and protein levels of NF-κB and iNOS in the aorta(P<0.05 or P<0.01). In conclusion, Zhuyu Pills may play an anti-atherosclerosis role by regulating PPARγ/NF-κB signaling pathway, inhibiting the polarization of macrophages toward the M1 phenotype, promoting the polarization of macrophages toward the M2 phenotype, and improving the inflammatory microenvironment of macrophages.


Asunto(s)
Aterosclerosis , Placa Aterosclerótica , Ratones , Animales , FN-kappa B/genética , FN-kappa B/metabolismo , PPAR gamma/genética , Factor de Necrosis Tumoral alfa , Interleucina-6 , Interleucina-13/genética , LDL-Colesterol , Atorvastatina/farmacología , Interleucina-4 , Ratones Endogámicos C57BL , Aterosclerosis/tratamiento farmacológico , Aterosclerosis/genética , Aterosclerosis/prevención & control , Transducción de Señal , Placa Aterosclerótica/tratamiento farmacológico , Placa Aterosclerótica/genética , Placa Aterosclerótica/prevención & control , Citocinas/metabolismo , Macrófagos/metabolismo , Fenotipo , ARN Mensajero
8.
Minerva Gastroenterol (Torino) ; 70(1): 22-28, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-37943250

RESUMEN

BACKGROUND: Atherosclerosis progression is possible in subjects with limited alteration of body weight, lipid profile, and oxidative stress. The ultrasound carotid thickness (IMT) and arterial wall modification (granulation and bubbles) are evident signs of the disease. Intestinal fats absorption shifting (IFAS) is expected to prevent or reduce the arterial damage. The aim of the registry was to evaluate the effects of a mild diet in association with lifestyle modifications (standard management [SM]) and SM+ a polyglucosamine biopolymer (BP) shifting the intestinal absorption of dietary fats. METHODS: The present is a two-year registry comparing two groups of otherwise healthy subjects, respectively 150 (SM) and 144 (SM+BP). BP was administered at the dosage of 3g/day. IMT and relative arterial damages were measured together with lipid profile, oxidative stress, anthropometric and vital measures. RESULTS: The two groups at the baseline were comparable for all variables: 8 cases of drop out were found limited to SM. Compliance with BP was optimal (>97%) and no side effect were observed. IMT showed a significant decrease in thickness (P<0.05) using BP+SM, while increased in SM group. Intimal granulations and lipid wall bubbles were also significantly decreased with BP in comparison to SM only (P<0.05). BMI significantly decreased with BP (P<0.05) as well as BW, fat mass, lipid profile and oxidative stress in comparison to SM only. A positive variation in blood pressure and heart rate (P<0.05) was also observed. CONCLUSIONS: BP allows IFAS to improve early subclinical arterial lesions that tend to progress to plaques and clinical events. The long-term and safe treatment of BP is effective on IMT, lipids, BW, and early lesions of the arterial wall structure in subjects with subclinical conditions. BP also reduces oxidative stress which contributes to lipid oxidation and deposition into the arterial wall layer in areas of high dynamic stress (arterial bifurcations).


Asunto(s)
Aterosclerosis , Placa Aterosclerótica , Humanos , Aterosclerosis/prevención & control , Placa Aterosclerótica/prevención & control , Arterias Carótidas/diagnóstico por imagen , Grosor Intima-Media Carotídeo , Lípidos
10.
Eur J Nutr ; 62(4): 1845-1857, 2023 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-36853380

RESUMEN

BACKGROUND AND AIMS: Atherosclerosis is associated with a reduction in the bioavailability and/or bioactivity of endogenous nitric oxide (NO). Dietary nitrate has been proposed as an alternate source when endogenous NO production is reduced. Our previous study demonstrated a protective effect of dietary nitrate on the development of atherosclerosis in the apoE-/- mouse model. However most patients do not present clinically until well after the disease is established. The aims of this study were to determine whether chronic dietary nitrate supplementation can prevent or reverse the progression of atherosclerosis after disease is already established, as well as to explore the underlying mechanism of these cardiovascular protective effects. METHODS: 60 apoE-/- mice were given a high fat diet (HFD) for 12 weeks to allow for the development of atherosclerosis. The mice were then randomized to (i) control group (HFD + 1 mmol/kg/day NaCl), (ii) moderate-dose group (HFD +1 mmol/kg/day NaNO3), or (iii) high-dose group (HFD + 10 mmol/kg/day NaNO3) (20/group) for a further 12 weeks. A group of apoE-/- mice (n = 20) consumed a normal laboratory chow diet for 24 weeks and were included as a reference group. RESULTS: Long-term supplementation with high dose nitrate resulted in ~ 50% reduction in plaque lesion area. Collagen expression and smooth muscle accumulation were increased, and lipid deposition and macrophage accumulation were reduced within atherosclerotic plaques of mice supplemented with high dose nitrate. These changes were associated with an increase in nitrite reductase as well as activation of the endogenous eNOS-NO pathway. CONCLUSION: Long-term high dose nitrate significantly attenuated the progression of established atherosclerosis in the apoE-/- mice fed a HFD. This appears to be mediated in part through a XOR-dependent reduction of nitrate to NO, as well as enhanced eNOS activation via increased Akt and eNOS phosphorylation.


Asunto(s)
Aterosclerosis , Placa Aterosclerótica , Animales , Ratones , Apolipoproteínas E/genética , Aterosclerosis/prevención & control , Aterosclerosis/metabolismo , Dieta Alta en Grasa/efectos adversos , Suplementos Dietéticos , Ratones Endogámicos C57BL , Ratones Noqueados , Nitratos , Óxido Nítrico , Placa Aterosclerótica/prevención & control
11.
Eur Heart J ; 43(19): 1799-1808, 2022 05 14.
Artículo en Inglés | MEDLINE | ID: mdl-35567558

RESUMEN

Decades of research have established atherosclerosis as an inflammatory disease. Only recently though, clinical trials provided proof-of-concept evidence for the efficacy of anti-inflammatory strategies with respect to cardiovascular events, thus offering a new paradigm for lowering residual vascular risk. Efforts to target the inflammasome-interleukin-1ß-interleukin-6 pathway have been highly successful, but inter-individual variations in drug response, a lack of reduction in all-cause mortality, and a higher rate of infections also highlight the need for a second generation of anti-inflammatory agents targeting atherosclerosis-specific immune mechanisms while minimizing systemic side effects. CC-motif chemokine ligand 2/monocyte-chemoattractant protein-1 (CCL2/MCP-1) orchestrates inflammatory monocyte trafficking between the bone marrow, circulation, and atherosclerotic plaques by binding to its cognate receptor CCR2. Adding to a strong body of data from experimental atherosclerosis models, a coherent series of recent large-scale genetic and observational epidemiological studies along with data from human atherosclerotic plaques highlight the relevance and therapeutic potential of the CCL2-CCR2 axis in human atherosclerosis. Here, we summarize experimental and human data pinpointing the CCL2-CCR2 pathway as an emerging drug target in cardiovascular disease. Furthermore, we contextualize previous efforts to interfere with this pathway, scrutinize approaches of ligand targeting vs. receptor targeting, and discuss possible pathway-intrinsic opportunities and challenges related to pharmacological targeting of the CCL2-CCR2 axis in human atherosclerotic disease.


Asunto(s)
Aterosclerosis , Quimiocina CCL2 , Placa Aterosclerótica , Receptores CCR2 , Antiinflamatorios/uso terapéutico , Aterosclerosis/tratamiento farmacológico , Aterosclerosis/prevención & control , Quimiocina CCL2/metabolismo , Humanos , Ligandos , Monocitos , Placa Aterosclerótica/tratamiento farmacológico , Placa Aterosclerótica/prevención & control , Receptores CCR2/metabolismo
12.
J Diabetes Investig ; 13(7): 1114-1121, 2022 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-35377559

RESUMEN

Type 2 diabetes mellitus and impaired glucose tolerance (IGT) significantly induce advanced coronary artery disease and systemic atherosclerosis. Thus, type 2 diabetes mellitus and IGT are traditional risk factors of cardiovascular disease. In contrast, acute coronary syndrome is frequently caused by the rupture of coronary atherosclerotic plaques, which reduces patients' quality of life and might result in death. To date, many trials have sought to identify ways to determine the coronary plaque volume and its vulnerability, and many studies have shown that some specific antihyperglycemic agents might prevent coronary or carotid plaque progression, decrease plaque volume, induce plaque stability, and improve clinical outcomes in patients with type 2 diabetes mellitus and IGT. This article reviews the following: (i) the association between coronary or carotid plaques and abnormal glucose tolerance, including type 2 diabetes mellitus; and (ii) the effects of oral antihyperglycemic drugs to improve clinical outcomes and stabilize atherosclerotic plaques in patients with type 2 diabetes mellitus and IGT.


Asunto(s)
Síndrome Coronario Agudo , Aterosclerosis , Diabetes Mellitus Tipo 2 , Intolerancia a la Glucosa , Placa Aterosclerótica , Aterosclerosis/complicaciones , Aterosclerosis/prevención & control , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Intolerancia a la Glucosa/complicaciones , Intolerancia a la Glucosa/tratamiento farmacológico , Humanos , Hipoglucemiantes/uso terapéutico , Placa Aterosclerótica/complicaciones , Placa Aterosclerótica/prevención & control , Calidad de Vida , Factores de Riesgo
13.
Nature ; 605(7908): 152-159, 2022 05.
Artículo en Inglés | MEDLINE | ID: mdl-35477759

RESUMEN

Atherosclerotic plaques develop in the inner intimal layer of arteries and can cause heart attacks and strokes1. As plaques lack innervation, the effects of neuronal control on atherosclerosis remain unclear. However, the immune system responds to plaques by forming leukocyte infiltrates in the outer connective tissue coat of arteries (the adventitia)2-6. Here, because the peripheral nervous system uses the adventitia as its principal conduit to reach distant targets7-9, we postulated that the peripheral nervous system may directly interact with diseased arteries. Unexpectedly, widespread neuroimmune cardiovascular interfaces (NICIs) arose in mouse and human atherosclerosis-diseased adventitia segments showed expanded axon networks, including growth cones at axon endings near immune cells and media smooth muscle cells. Mouse NICIs established a structural artery-brain circuit (ABC): abdominal adventitia nociceptive afferents10-14 entered the central nervous system through spinal cord T6-T13 dorsal root ganglia and were traced to higher brain regions, including the parabrachial and central amygdala neurons; and sympathetic efferent neurons projected from medullary and hypothalamic neurons to the adventitia through spinal intermediolateral neurons and both coeliac and sympathetic chain ganglia. Moreover, ABC peripheral nervous system components were activated: splenic sympathetic and coeliac vagus nerve activities increased in parallel to disease progression, whereas coeliac ganglionectomy led to the disintegration of adventitial NICIs, reduced disease progression and enhanced plaque stability. Thus, the peripheral nervous system uses NICIs to assemble a structural ABC, and therapeutic intervention in the ABC attenuates atherosclerosis.


Asunto(s)
Aterosclerosis , Placa Aterosclerótica , Animales , Aterosclerosis/prevención & control , Progresión de la Enfermedad , Ganglios Espinales , Ganglios Simpáticos , Ratones , Neuronas/fisiología , Placa Aterosclerótica/prevención & control
14.
Mol Nutr Food Res ; 66(9): e2101114, 2022 05.
Artículo en Inglés | MEDLINE | ID: mdl-35297565

RESUMEN

SCOPE: Whole grain consumption has been proven to be inversely associated with the risk of cardiovascular diseases. As a biomarker for whole grain dietary intake, 5-heptadecylresorcinol (AR-C17) has attracted increased attention due to its potential health-improving activity. However, the beneficial effect of AR-C17 on atherosclerosis prevention and the underlying mechanism remain unclear. METHODS AND RESULTS: High-fat diet fed apolipoprotein E-deficient (ApoE-/- ) mice are administrated with or without AR-C17 (30 and 150 mg kg-1 ) for 16 weeks. Histological staining is performed for plaque analysis. Immunofluorescence, western blot, and seahorse cell analysis are carried out to investigate the action of mechanism of AR-C17. The results indicate that AR-C17 supplementation lowered serum total cholesterol, triglyceride, VLDL-C, and LDL-C levels. Moreover, the atherosclerotic plaques in the aortic root region of mice heart are significantly reduced by AR-C17 intervention compared with ApoE-/- control group. In addition, AR-C17 treatment alleviates endothelial cell damage and apoptosis by improving mitochondrial function via sirtuin3 signaling pathway both in ApoE-/- mice and oxidized-LDL-treated human umbilical vein endothelial cells. CONCLUSION: AR-C17 may be applied as a promising grain-based dietary bioactive ingredient for atherosclerosis prevention. Meanwhile, as a mitochondrial protective agent, it can offer support for the suggested health claim of whole grain diet.


Asunto(s)
Aterosclerosis , Transducción de Señal , Granos Enteros , Animales , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Aterosclerosis/metabolismo , Aterosclerosis/prevención & control , Células Endoteliales de la Vena Umbilical Humana , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Placa Aterosclerótica/metabolismo , Placa Aterosclerótica/prevención & control , Resorcinoles , Sirtuina 3/metabolismo
15.
Circulation ; 145(9): 675-687, 2022 03.
Artículo en Inglés | MEDLINE | ID: mdl-35189703

RESUMEN

BACKGROUND: High blood cholesterol accelerates the progression of atherosclerosis, which is an asymptomatic process lasting for decades. Rupture of atherosclerotic plaques induces thrombosis, which results in myocardial infarction or stroke. Lowering cholesterol levels is beneficial for preventing atherosclerotic cardiovascular disease. METHODS: Low-density lipoprotein (LDL) receptor (LDLR) was used as bait to identify its binding proteins in the plasma, and the coagulation factor prekallikrein (PK; encoded by the KLKB1 gene) was revealed. The correlation between serum PK protein content and lipid levels in young Chinese Han people was then analyzed. To investigate the effects of PK ablation on LDLR and lipid levels in vivo, we genetically deleted Klkb1 in hamsters and heterozygous Ldlr knockout mice and knocked down Klkb1 using adeno-associated virus-mediated shRNA in rats. The additive effect of PK and proprotein convertase subtilisin/kexin 9 inhibition also was evaluated. In addition, we applied the anti-PK neutralizing antibody that blocked the PK and LDLR interaction in mice. Mice lacking both PK and apolipoprotein e (Klkb1-/-Apoe-/-) were generated to assess the role of PK in atherosclerosis. RESULTS: PK directly bound LDLR and induced its lysosomal degradation. The serum PK concentrations positively correlated with LDL cholesterol levels in 198 young Chinese Han adults. Genetic depletion of Klkb1 increased hepatic LDLR and decreased circulating cholesterol in multiple rodent models. Inhibition of proprotein convertase subtilisin/kexin 9 with evolocumab further decreased plasma LDL cholesterol levels in Klkb1-deficient hamsters. The anti-PK neutralizing antibody could similarly lower plasma lipids through upregulating hepatic LDLR. Ablation of Klkb1 slowed the progression of atherosclerosis in mice on Apoe-deficient background. CONCLUSIONS: PK regulates circulating cholesterol levels through binding to LDLR and inducing its lysosomal degradation. Ablation of PK stabilizes LDLR, decreases LDL cholesterol, and prevents atherosclerotic plaque development. This study suggests that PK is a promising therapeutic target to treat atherosclerotic cardiovascular disease.


Asunto(s)
Aterosclerosis/metabolismo , Aterosclerosis/prevención & control , LDL-Colesterol/metabolismo , Placa Aterosclerótica/metabolismo , Placa Aterosclerótica/prevención & control , Precalicreína/deficiencia , Receptores de LDL/metabolismo , Animales , Aterosclerosis/genética , LDL-Colesterol/genética , Lisosomas/genética , Lisosomas/metabolismo , Ratones , Ratones Noqueados , Placa Aterosclerótica/genética , Precalicreína/metabolismo , Proteolisis , Receptores de LDL/genética
16.
Hum Cell ; 35(1): 51-62, 2022 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-34606042

RESUMEN

The vascular endothelium plays a key role in the pathobiology of atherosclerotic cardiovascular disease. Endothelial cell Piezo1 mediates blood vessel formation, angiogenesis and regulation of blood pressure. However, changes of Piezo1 expression in atherosclerosis (AS) and the role of Piezo1 in the progression of atherosclerotic diseases remains obscure. Thus, the current study is to elucidate the role and mechanism of which Piezo1 mediates vascular inflammation in atherosclerotic mice and vascular endothelial inflammation induced by oxidized low density lipoprotein (ox-LDL) in vitro. Here, we have shown that the expression of Piezo1 was significantly increased in the stenotic carotid artery of ApoE-/- mice fed by high-fat diet (HFD). Pharmacological inhibition of Piezo1 (GsMTx-4) attenuated plaque formation, decreased the level of inflammation related factors (JNK, TNF-α, NF-κB, VCAM-1) of carotid plaque in atherosclerotic mice. Meanwhile, ox-LDL also upregulates Piezo1 and inflammation proteins (NF-κB, JNK and TNF-α) in endothelium cells (ECs). YAP/TAZ is activated accompanied by the enhanced Piezo1 activity in ECs induced by ox-LDL. Interference by siRNA of Piezo1 abolished the expression of YAP/TAZ and inflammation proteins (JNK, NF-κB and TNF-α). In addition, Ca2+ influx in ECs induced by ox-LDL was increased than control group, Piezo1 siRNA can reduce the calcium content. Piezo1 agonist Yoda1 increased Ca2+ influx and promote YAP nucleus translocation in ECs, genetic deletion of Piezo1 reversed it. Our results indicate that Piezo1 could mediate endothelial atherogenic inflammatory responses via regulation of YAP/TAZ activation and nuclear localization. Piezo1 may be a potential therapeutic target for atherosclerotic diseases in the future.


Asunto(s)
Enfermedad de la Arteria Coronaria/genética , Regulación de la Expresión Génica , Expresión Génica , Canales Iónicos/genética , Canales Iónicos/fisiología , Proteínas Coactivadoras Transcripcionales con Motivo de Unión a PDZ/metabolismo , Proteínas Señalizadoras YAP/metabolismo , Animales , Calcio/metabolismo , Enfermedad de la Arteria Coronaria/terapia , Dieta Alta en Grasa/efectos adversos , Endotelio Vascular/metabolismo , Células Endoteliales de la Vena Umbilical Humana , Humanos , Mediadores de Inflamación/metabolismo , Péptidos y Proteínas de Señalización Intercelular/farmacología , Canales Iónicos/antagonistas & inhibidores , Canales Iónicos/metabolismo , Ratones , Terapia Molecular Dirigida , Placa Aterosclerótica/prevención & control , ARN Interferente Pequeño , Venenos de Araña/farmacología
17.
Transl Res ; 240: 33-49, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-34478893

RESUMEN

Identification of patients with high-risk asymptomatic atherosclerotic plaques remains an elusive but essential step in preventing stroke. However, there is a lack of animal model that provides a reproducible method to predict where, when and what types of plaque formation, which fulfils the American Heart Association (AHA) histological classification of human plaques. We have developed a predictive mouse model that reflects different stages of human plaques in a single carotid artery by means of shear-stress modifying cuff. Validated with over 30000 histological sections, the model generates a specific pattern of plaques with different risk levels along the same artery depending on their position relative to the cuff. The further upstream of the cuff-implanted artery, the lower the magnitude of shear stress, the more unstable the plaques of higher grade according to AHA classification; with characteristics including greater degree of vascular remodeling, plaque size, plaque vulnerability and inflammation, resulting in higher risk plaques. By weeks 20 and 30, this model achieved 80% and near 100% accuracy respectively, in predicting precisely where, when and what stages/AHA types of plaques develop along the same carotid artery. This model can generate clinically-relevant plaques with varying phenotypes fulfilling AHA classification and risk levels, in specific locations of the single artery with near 100% accuracy of prediction. The model offers a promising tool for development of diagnostic tools to target high-risk plaques, increasing accuracy in predicting which individual patients may require surgical intervention to prevent stroke, paving the way for personalized management of carotid atherosclerotic disease.


Asunto(s)
Arterias Carótidas/patología , Placa Aterosclerótica/patología , Animales , Apolipoproteínas E/deficiencia , Apolipoproteínas E/metabolismo , Biomarcadores/metabolismo , Arterias Carótidas/fisiopatología , Colágeno/metabolismo , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Humanos , Inflamación/complicaciones , Inflamación/patología , Lípidos/química , Ratones Noqueados , Miocitos del Músculo Liso/metabolismo , Placa Aterosclerótica/complicaciones , Placa Aterosclerótica/fisiopatología , Placa Aterosclerótica/prevención & control , Resistencia al Corte , Estrés Mecánico , Investigación Biomédica Traslacional , Remodelación Vascular
18.
Sci Rep ; 11(1): 22469, 2021 11 17.
Artículo en Inglés | MEDLINE | ID: mdl-34789834

RESUMEN

Atherosclerosis is a chronic inflammatory disease that may lead to the development of serious cardiovascular diseases. Aged garlic extract (AGE) has been reported to ameliorate atherosclerosis, although its mode of action remains unclear. We found that AGE increased the mRNA or protein levels of arginase1 (Arg1), interleukin-10 (IL-10), CD206 and hypoxia-inducible factor 2α (HIF2α) and decreased that of CD68, HIF1α and inducible nitric oxide synthase in the aorta and spleen of apolipoprotein E knockout mice. We also found that S-1-propenylcysteine (S1PC), a characteristic sulfur compound in AGE, increased the level of IL-10-induced Arg1 mRNA and the extent of M2c-like macrophage polarization in vitro. In addition, S1PC increased the population of M2c-like macrophages, resulting in suppressed the population of M1-like macrophages and decreased lipopolysaccharide-induced production of pro-inflammatory cytokines. These effects were accompanied by prolonged phosphorylation of the IL-10 receptor α (IL-10Rα) and signal transducer and activator of transcription 3 (STAT3) that inhibited the interaction between IL-10Rα and Src homology-2-containing inositol 5'-phosphatase 1 (SHIP1). In addition, administration of S1PC elevated the M2c/M1 macrophage ratio in senescence-accelerated mice. These findings suggest that S1PC may help improve atherosclerosis due to its anti-inflammatory effect to promote IL-10-induced M2c macrophage polarization.


Asunto(s)
Polaridad Celular/efectos de los fármacos , Cisteína/análogos & derivados , Ajo/química , Interleucina-10/farmacología , Macrófagos/metabolismo , Extractos Vegetales/administración & dosificación , Receptores de Interleucina-10/metabolismo , Factor de Transcripción STAT3/metabolismo , Transducción de Señal/efectos de los fármacos , Animales , Aterosclerosis/prevención & control , Células Cultivadas , Cisteína/administración & dosificación , Modelos Animales de Enfermedad , Activación de Macrófagos/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados para ApoE , Fosforilación/efectos de los fármacos , Fitoterapia/métodos , Placa Aterosclerótica/prevención & control , Proteínas Recombinantes/farmacología , Resultado del Tratamiento
19.
Int J Med Sci ; 18(16): 3652-3664, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34790037

RESUMEN

Aim: In the late stage of atherosclerosis, the endothelial barrier of plaque is destroyed. The rapid deposition of oxidized lipids in the circulation leads to migration of numerous smooth muscle cells and macrophages, as well as foaming necrosis. The plaque progresses rapidly, and vulnerable plaques can easily induce adverse cardiovascular events. Here, we take the principle of gene editing to transfer the liver to express the LOX-1 receptor which is more sensitive to Ox-LDL by using AAV8 containing a liver-specific promoter. In this way, we want to explore whether the progress of advanced atherosclerosis and the stability of advanced plaque can be improved when the liver continues to clear Ox-LDL from the circulation. Methods and Results: In order to explore the effect of the physiological and continuous elimination of Ox-LDL through the liver on advanced atherosclerosis, we chose ApoE-/- mice in high-fat diet for 20 weeks. After 16 weeks of high-fat diet, the baseline group was sacrificed and the specimens were collected. The virus group and the control group were injected with the same amount of virus dilution and normal saline through the tail vein, and continued to feed until 20 weeks of high-fat diet, and then sacrificed to collect specimens. The results showed that LOX-1 was ectopically and functionally expressed in the liver as an Ox-LDL receptor, reducing the content of it in circulation. Compared with the control group, the degree of plaque progression in the virus group was significantly reduced, similar to the baseline group, the plaque necrosis core decreased, and the collagen fiber content increased. In addition, there are more contractile smooth muscle cells in the plaques of the virus group instead of synthetic ones, and the content of macrophages was also reduced. These data suggested that the virus group mice have greatly increased advanced plaque stability compared with the control group mice. Conclusions: Due to the destruction of endothelial barrier in advanced plaques, rapid deposition of Ox-LDL can result in fast plaque progression, increased necrotic cores, and decreased stability. Our research shows that the use of AAV8 through gene editing allows the liver to express LOX-1 receptors that are more sensitive to Ox-LDL, so that it can continue to bind Ox-LDL in the circulation and exploit the liver's strong lipid metabolism ability to physiologically clear Ox-LDL, which can inhibit the rapid progress of advanced plaque and increase the stability of plaque.


Asunto(s)
Aterosclerosis/metabolismo , Lipoproteínas LDL/metabolismo , Hígado/metabolismo , Placa Aterosclerótica/metabolismo , Animales , Apolipoproteínas E/genética , Aterosclerosis/patología , Progresión de la Enfermedad , Humanos , Macrófagos/metabolismo , Macrófagos/patología , Masculino , Ratones , Ratones Noqueados , Placa Aterosclerótica/patología , Placa Aterosclerótica/prevención & control , Receptores Depuradores de Clase E/genética , Receptores Depuradores de Clase E/metabolismo , Células THP-1
20.
Acta Biochim Biophys Sin (Shanghai) ; 53(10): 1310-1320, 2021 Oct 12.
Artículo en Inglés | MEDLINE | ID: mdl-34409427

RESUMEN

Endothelial dysfunction is the pathological basis of atherosclerosis. Incomplete understanding of endothelial dysfunction etiology has impeded drug development for this devastating disease despite the currently available therapies. Floralozone, an aroma flavor, specifically exists in rabbit ear grass. Recently, floralozone has been demonstrated to inhibit atherosclerosis, but the underlying mechanisms are undefined. The present study was undertaken to explore whether floralozone pharmacologically targets endothelial dysfunction and therefore exerts therapeutic effects on atherosclerosis. The Na+/H+ exchanger 1 (NHE1), a channel protein, plays a vital role in atherosclerosis. Whether NHE1 is involved in the therapeutic effects of floralozone on endothelial dysfunction has yet to be further answered. By performing oil red staining and hematoxylin-eosin staining, vascular functional study, and oxidative stress monitoring, we found that floralozone not only reduced the size of carotid atherosclerotic plaque but also prevented endothelial dysfunction in atherosclerotic rats. NHE1 expression was upregulated in the inner membrane of carotid arteries and H2O2-induced primary rat aortic endothelial cells. Inspiringly, floralozone prevented the upregulation of NHE1 in vivo and in vitro. Notably, the administration of NHE1 activator LiCl significantly weakened the protective effect of floralozone on endothelial dysfunction in vivo and in vitro. Our study demonstrated that floralozone exerted its protective effect on endothelial dysfunction in atherosclerosis by ameliorating NHE1. NHE1 maybe a drug target for the treatment of atherosclerosis, and floralozone may be an effective drug to meet the urgent needs of atherosclerosis patients by dampening NHE1.


Asunto(s)
Aterosclerosis , Endotelio Vascular , Extractos Vegetales , Sustancias Protectoras , Intercambiador 1 de Sodio-Hidrógeno , Animales , Masculino , Aorta/citología , Aorta/metabolismo , Aterosclerosis/metabolismo , Aterosclerosis/patología , Aterosclerosis/prevención & control , Arterias Carótidas/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Modelos Animales de Enfermedad , Endotelio Vascular/efectos de los fármacos , Oxidación-Reducción/efectos de los fármacos , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , Placa Aterosclerótica/metabolismo , Placa Aterosclerótica/patología , Placa Aterosclerótica/prevención & control , Sustancias Protectoras/farmacología , Sustancias Protectoras/uso terapéutico , Ratas Sprague-Dawley , Intercambiador 1 de Sodio-Hidrógeno/antagonistas & inhibidores , Intercambiador 1 de Sodio-Hidrógeno/metabolismo
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