RESUMO
OBJECTIVE: Atherosclerosis (AS) is a common pathogenesis of cardiovascular diseases. Puerarin (Pue) is a Chinese herbal remedy used to prevent and treat AS. Here, this research investigated the effect of Pue on AS progression. METHODS: ApoE-/- mice were induced with acrolein. Body weight, blood lipid index, inflammatory factors, mitochondrial oxidative stress, and lipid deposition were detected. IL-6 and TNF-α were detected by ELISA. Oil red staining and H&E staining were used to observe the aortic sinus plaque lesions. Serum expressions of inflammatory factors IL-6, TNF-a, SOD, GSH and MDA were detected by ELISA, the mRNA expression levels of HDAC1 in the aorta were detected by RT-qPCR, and IL-6 and TNF-α in the aorta were detected by immunohistochemistry. JNK, p-JNK, OPA-1, and HDAC1 were detected by Western blotting. RESULTS: Pue administration can effectively reduce lipid accumulation in AS mice induced by acrolein. Pue promoted the activity of SOD, GSH and MDA, and inhibited the formation of atherosclerotic plaques and the process of aortic histological changes. Pue reduced IL-6 and TNF-α. HDAC1 expression was down-regulated and p-JNK-1 and JNK protein expression was up-regulated. CONCLUSION: Pue reduces inflammation and alleviates AS induced by acrolein by mediating the JNK pathway to inhibit HDAC1-mediated oxidative stress disorder.
Assuntos
Acroleína , Aterosclerose , Histona Desacetilase 1 , Isoflavonas , Estresse Oxidativo , Animais , Aterosclerose/induzido quimicamente , Aterosclerose/metabolismo , Aterosclerose/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Histona Desacetilase 1/metabolismo , Isoflavonas/farmacologia , Isoflavonas/uso terapêutico , Acroleína/farmacologia , Masculino , Fator de Necrose Tumoral alfa/metabolismo , Interleucina-6/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Western Blotting , Aorta/efeitos dos fármacos , Aorta/patologiaRESUMO
Atherosclerosis (AS) has become the leading cause of cardiovascular disease worldwide. Our previous study had observed that Nippostrongylus brasiliensis (Nb) infection or its derived products could inhibit AS development by inducing an anti-inflammatory response. We performed a metabolic analysis to screen Nb-derived metabolites with anti-inflammation activity and evaluated the AS-prevention effect. We observed that the metabolite uridine had higher expression levels in mice infected with the Nb and ES (excretory-secretory) products and could be selected as a key metabolite. ES and uridine interventions could reduce the pro-inflammatory responses and increase the anti-inflammatory responses in vitro and in vivo. The apolipoprotein E gene knockout (ApoE-/-) mice were fed with a high-fat diet for the AS modeling. Following the in vivo intervention, ES products or uridine significantly reduced serum and liver lipid levels, alleviated the formation of atherosclerosis, and reduced the pro-inflammatory responses in serum or plaques, while the anti-inflammatory responses showed opposite trends. After blocking with 5-HD (5-hydroxydecanoate sodium) in vitro, the mRNA levels of M2 markers were significantly reduced. When blocked with 5-HD in vivo, the degree of atherosclerosis was worsened, the pro-inflammatory responses were increased compared to the uridine group, while the anti-inflammatory responses decreased accordingly. Uridine, a key metabolite from Nippostrongylus brasiliensis, showed anti-inflammatory and anti-atherosclerotic effects in vitro and in vivo, which depend on the activation of the mitochondrial ATP-sensitive potassium channel.
Assuntos
Anti-Inflamatórios , Aterosclerose , Nippostrongylus , Uridina , Animais , Masculino , Camundongos , Anti-Inflamatórios/farmacologia , Apolipoproteínas E/genética , Apolipoproteínas E/deficiência , Aterosclerose/metabolismo , Aterosclerose/genética , Modelos Animais de Doenças , Canais KATP/metabolismo , Canais KATP/genética , Camundongos Knockout , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacos , Uridina/farmacologiaRESUMO
LOX-1, ORL-1, or lectin-like oxidized low-density lipoprotein receptor 1 is a transmembrane glycoprotein that binds and internalizes ox-LDL in foam cells. LOX-1 is the main receptor for oxidized low-density lipoproteins (ox-LDL). The LDL comes from food intake and circulates through the bloodstream. LOX-1 belongs to scavenger receptors (SR), which are associated with various cardiovascular diseases. The most important and severe of these is the formation of atherosclerotic plaques in the intimal layer of the endothelium. These plaques can evolve into complicated thrombi with the participation of fibroblasts, activated platelets, apoptotic muscle cells, and macrophages transformed into foam cells. This process causes changes in vascular endothelial homeostasis, leading to partial or total obstruction in the lumen of blood vessels. This obstruction can result in oxygen deprivation to the heart. Recently, LOX-1 has been involved in other pathologies, such as obesity and diabetes mellitus. However, the development of atherosclerosis has been the most relevant due to its relationship with cerebrovascular accidents and heart attacks. In this review, we will summarize findings related to the physiologic and pathophysiological processes of LOX-1 to support the detection, diagnosis, and prevention of those diseases.
Assuntos
Doenças Cardiovasculares , Receptores Depuradores Classe E , Humanos , Receptores Depuradores Classe E/metabolismo , Receptores Depuradores Classe E/genética , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/etiologia , Animais , Lipoproteínas LDL/metabolismo , Aterosclerose/metabolismo , Aterosclerose/patologiaRESUMO
In the modern world, cardiovascular diseases have a special place among the most common causes of death. Naturally, this widespread problem cannot escape the attention of scientists and researchers. One of the main conditions preceding the development of fatal cardiovascular diseases is atherosclerosis. Despite extensive research into its pathogenesis and possible prevention and treatment strategies, many gaps remain in our understanding of this disease. For example, the concept of multiple low-density lipoprotein modifications was recently stated, in which desialylation is of special importance. Apart from this, sialic acids are known to be important contributors to processes such as endothelial dysfunction and inflammation, which in turn are major components of atherogenesis. In this review, we have collected information on sialic acid metabolism, analyzed various aspects of its implication in atherosclerosis at different stages, and provided an overview of the role of particular groups of enzymes responsible for sialic acid metabolism in the context of atherosclerosis.
Assuntos
Aterosclerose , Doenças Cardiovasculares , Humanos , Ácido N-Acetilneuramínico/metabolismo , Metabolismo dos Lipídeos , Aterosclerose/etiologia , Aterosclerose/metabolismo , Ácidos Siálicos/metabolismo , InflamaçãoRESUMO
CETP activity reduces plasma HDL-cholesterol concentrations, a correlate of an increased risk of atherosclerotic events. However, our recent findings suggest that CETP expression in macrophages promotes an intracellular antioxidant state, reduces free cholesterol accumulation and phagocytosis, and attenuates pro-inflammatory gene expression. To determine whether CETP expression in macrophages affects atherosclerosis development, we transplanted bone marrow from transgenic mice expressing simian CETP or non-expressing littermates into hypercholesterolemic LDL-receptor-deficient mice. The CETP expression did not change the lipid-stained lesion areas but decreased the macrophage content (CD68), neutrophil accumulation (LY6G), and TNF-α aorta content of young male transplanted mice and decreased LY6G, TNF-α, iNOS, and nitrotyrosine (3-NT) in aged female transplanted mice. These findings suggest that CETP expression in bone-marrow-derived cells reduces the inflammatory features of atherosclerosis. These novel mechanistic observations may help to explain the failure of CETP inhibitors in reducing atherosclerotic events in humans.
Assuntos
Aterosclerose , Medula Óssea , Humanos , Camundongos , Animais , Masculino , Feminino , Idoso , Medula Óssea/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Proteínas de Transferência de Ésteres de Colesterol/genética , Proteínas de Transferência de Ésteres de Colesterol/metabolismo , Aterosclerose/metabolismo , Colesterol/metabolismo , Camundongos Transgênicos , Camundongos Endogâmicos C57BLRESUMO
Oxidized low-density lipoprotein (ox-LDL) is the most harmful form of cholesterol associated with vascular atherosclerosis and hepatic injury, mainly due to inflammatory cell infiltration and subsequent severe tissue injury. Lox-1 is the central ox-LDL receptor expressed in endothelial and immune cells, its activation regulating inflammatory cytokines and chemotactic factor secretion. Recently, a Lox-1 truncated protein isoform lacking the ox-LDL binding domain named LOXIN has been described. We have previously shown that LOXIN overexpression blocked Lox-1-mediated ox-LDL internalization in human endothelial progenitor cells in vitro. However, the functional role of LOXIN in targeting inflammation or tissue injury in vivo remains unknown. In this study, we investigate whether LOXIN modulated the expression of Lox-1 and reduced the inflammatory response in a high-fat-diet mice model. Results indicate that human LOXIN blocks Lox-1 mediated uptake of ox-LDL in H4-II-E-C3 cells. Furthermore, in vivo experiments showed that overexpression of LOXIN reduced both fatty streak lesions in the aorta and inflammation and fibrosis in the liver. These findings were associated with the down-regulation of Lox-1 in endothelial cells. Then, LOXIN prevents hepatic and aortic tissue damage in vivo associated with reduced Lox-1 expression in endothelial cells. We encourage future research to understand better the underlying molecular mechanisms and potential therapeutic use of LOXIN.
Assuntos
Aterosclerose , Células Progenitoras Endoteliais , Ftalazinas , Animais , Aorta/metabolismo , Aorta/patologia , Aterosclerose/tratamento farmacológico , Aterosclerose/etiologia , Aterosclerose/metabolismo , Aterosclerose/patologia , Células Cultivadas , Dieta Hiperlipídica/efeitos adversos , Células Progenitoras Endoteliais/efeitos dos fármacos , Células Progenitoras Endoteliais/metabolismo , Células Progenitoras Endoteliais/patologia , Inflamação/tratamento farmacológico , Inflamação/genética , Inflamação/metabolismo , Inflamação/patologia , Lipoproteínas LDL/metabolismo , Fígado/metabolismo , Camundongos , Ftalazinas/farmacologia , Receptores Depuradores Classe E/genética , Receptores Depuradores Classe E/metabolismoRESUMO
FOXA3 is a transcription factor involved in the macrophage cholesterol efflux and macrophage reverse cholesterol transport reducing the atherosclerotic lesions. Thus, the present study aimed to establish if the FOXA3 polymorphisms are associated with subclinical atherosclerosis (SA) and cardiometabolic parameters. Two FOXA3 polymorphisms (rs10410870 and rs10412574) were determined in 386 individuals with SA and 1070 controls. No association with SA was observed. The rs10410870 polymorphism was associated with a low risk of having total cholesterol >200 mg/dL, non-HDL-cholesterol > 160 mg/dL, and a high risk of having LDL pattern B and insulin resistance adipose tissue in individuals with SA, and with a high risk of having interleukin 10
Assuntos
Aterosclerose , Resistência à Insulina , Deficiência de Magnésio , Aterosclerose/genética , Aterosclerose/metabolismo , Colesterol , Predisposição Genética para Doença , Genótipo , Fator 3-gama Nuclear de Hepatócito , Humanos , Resistência à Insulina/genética , Polimorfismo de Nucleotídeo ÚnicoAssuntos
Aterosclerose , Calcinose , Calcificação Vascular , Aterosclerose/genética , Aterosclerose/metabolismo , Calcinose/metabolismo , Epigênese Genética , Humanos , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Calcificação Vascular/genética , Calcificação Vascular/metabolismoRESUMO
Cardiovascular disease (CVD) is a global public health issue due to its high morbidity, mortality, and economic impact. The implementation of innovative therapeutic alternatives for CVD is urgently required. Specialized proresolving lipid mediators (SPMs) are bioactive compounds derived from ω-3 and ω-6 fatty acids, integrated into four families: Lipoxins, Resolvins, Protectins, and Maresins. SPMs have generated interest in recent years due to their ability to promote the resolution of inflammation associated with the pathogeneses of numerous illnesses, particularly CVD. Several preclinical studies in animal models have evidenced their ability to decrease the progression of atherosclerosis, intimal hyperplasia, and reperfusion injury via diverse mechanisms. Large-scale clinical trials are required to determine the effects of SPMs in humans. This review integrates the currently available knowledge of the therapeutic impact of SPMs in CVD from preclinical and clinical studies, along with the implicated molecular pathways. In vitro results have been promising, and as such, SPMs could soon represent a new therapeutic alternative for CVD.
Assuntos
Aterosclerose , Doenças Cardiovasculares , Ácidos Graxos Ômega-3 , Animais , Aterosclerose/metabolismo , Doenças Cardiovasculares/tratamento farmacológico , Ácidos Docosa-Hexaenoicos/metabolismo , Ácidos Docosa-Hexaenoicos/farmacologia , Ácidos Docosa-Hexaenoicos/uso terapêutico , Ácidos Graxos Ômega-3/metabolismo , Ácidos Graxos Ômega-3/farmacologia , Ácidos Graxos Ômega-3/uso terapêutico , Humanos , Inflamação/metabolismo , Mediadores da Inflamação/metabolismoRESUMO
Atherogenic events promote changes in vessel walls, with alteration of the redox state, and increased activity of matrix metalloproteinases (MMPs). Thus, this study aims to evaluate aortic remodeling, MMP activity, and reactive oxygen species (ROS) levels after treatment with doxycycline in ApoE-/- and ovariectomized mice (OVX). Female ApoE-/--knockout mice (5 weeks) were submitted to ovariectomy surgery to induce experimental menopause. They then received chow enriched with 1% cholesterol to induce hypercholesterolemia. The animals were divided into two experimental groups: ApoE-/-/OVX vehicle and ApoE-/-/OVX doxycycline (30 mg/kg) administered by gavage once a day for 28 days (15th to the 18th week of life). Blood samples were collected to measure total cholesterol and fractions. The aorta was used for morphometry and to measure the activity and expression of MMP-2 and ROS levels. The ApoE-/-/OVX doxycycline group showed no change in total and fraction cholesterol levels. However, there was a reduction in ROS levels, MMP-2 expression, and activity that correlated with a decrease in atherosclerotic lesions relative to the ApoE-/-/OVX vehicle (p > 0.05). Therefore, we conclude that doxycycline in ApoE-/-/OVX animals promotes a reduction in atherosclerotic lesions by reducing ROS and MMP-2 activity and expression.