Molecular evidence for arterial repair in atherosclerosis.
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ABSTRACT:
SUBMITTER: Karra R
PROVIDER: S-EPMC1277970 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BACKGROUND:The CXCL12/CXCR4 chemokine ligand/receptor axis controls (progenitor) cell homeostasis and trafficking. So far, an atheroprotective role of CXCL12/CXCR4 has only been implied through pharmacological intervention, in particular, because the somatic deletion of the CXCR4 gene in mice is embryonically lethal. Moreover, cell-specific effects of CXCR4 in the arterial wall and underlying mechanisms remain elusive, prompting us to investigate the relevance of CXCR4 in vascular cell types for atheroprotection. METHODS:We examined the role of vascular CXCR4 in atherosclerosis and plaque composition by inducing an endothelial cell (BmxCreERT2-driven)-specific or smooth muscle cell (SMC, SmmhcCreERT2- or TaglnCre-driven)-specific deficiency of CXCR4 in an apolipoprotein E-deficient mouse model. To identify underlying mechanisms for effects of CXCR4, we studied endothelial permeability, intravital leukocyte adhesion, involvement of the Akt/WNT/?-catenin signaling pathway and relevant phosphatases in VE-cadherin expression and function, vascular tone in aortic rings, cholesterol efflux from macrophages, and expression of SMC phenotypic markers. Finally, we analyzed associations of common genetic variants at the CXCR4 locus with the risk for coronary heart disease, along with CXCR4 transcript expression in human atherosclerotic plaques. RESULTS:The cell-specific deletion of CXCR4 in arterial endothelial cells (n=12-15) or SMCs (n=13-24) markedly increased atherosclerotic lesion formation in hyperlipidemic mice. Endothelial barrier function was promoted by CXCL12/CXCR4, which triggered Akt/WNT/?-catenin signaling to drive VE-cadherin expression and stabilized junctional VE-cadherin complexes through associated phosphatases. Conversely, endothelial CXCR4 deficiency caused arterial leakage and inflammatory leukocyte recruitment during atherogenesis. In arterial SMCs, CXCR4 sustained normal vascular reactivity and contractile responses, whereas CXCR4 deficiency favored a synthetic phenotype, the occurrence of macrophage-like SMCs in the lesions, and impaired cholesterol efflux. Regression analyses in humans (n=259?796) identified the C-allele at rs2322864 within the CXCR4 locus to be associated with increased risk for coronary heart disease. In line, C/C risk genotype carriers showed reduced CXCR4 expression in carotid artery plaques (n=188), which was furthermore associated with symptomatic disease. CONCLUSIONS:Our data clearly establish that vascular CXCR4 limits atherosclerosis by maintaining arterial integrity, preserving endothelial barrier function, and a normal contractile SMC phenotype. Enhancing these beneficial functions of arterial CXCR4 by selective modulators might open novel therapeutic options in atherosclerosis.
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Project description:Peritoneal macrophages were obtained by intraperitoneal injection of cold PBS from Ldlr−/− mice reconstituted with Lyz2Cre+/− Nrp1flox/flox or Lyz2Cre+/− Nrp1+/+ bone marrow.
2024-07-30 | E-MTAB-12761 | biostudies-arrayexpress
Project description:Mice deficient in the LDL receptor (LDLR KO mice) fed with high fat diet (HFD) feeding have been widely used as a model to mimic human atherosclerosis. RNA-seq using aortic macrophages to investigate the effects of aortic macrophages on the plaque size progression. LDLR KO mice, 6-8 weeks old, were used, and fed with either an alternative HFD or a regular HFD. After aorta macrophages were isolated, RNeasy Mini Kit (Qiagen) was used to isolate mRNA. Single end (50bp), unstranded, SMART-Seq v4 plus nextera (SMART-Seq v4 Ultra Low Input RNA Kit (Takara) ). The RNA-seq libraries were prepared with SMART-Seq v4 Ultra Low Input RNA Kit (Takara).
2024-07-31 | E-MTAB-12759 | biostudies-arrayexpress
Project description:Cardiovascular diseases (CVDs) are disorders associated with the heart and circulatory system. Atherosclerosis is its major underlying cause. CVDs are chronic and can remain hidden for a long time. Moreover, CVDs are the leading cause of global morbidity and mortality, thus creating a major public health concern. This review summarizes the available information on the pathophysiological implications of CVDs, focusing on coronary artery disease along with atherosclerosis as its major cause and arterial hypertension. We discuss the endothelium dysfunction, inflammatory factors, and oxidation associated with atherosclerosis. Mechanisms such as dysfunction of the endothelium and inflammation, which have been identified as critical pathways for development of coronary artery disease, have become easier to diagnose in recent years. Relatively recently, evidence has been found indicating that interactions of the molecular and cellular elements such as matrix metalloproteinases, elements of the immune system, and oxidative stress are involved in the pathophysiology of arterial hypertension. Many studies have revealed several important inflammatory and genetic risk factors associated with CVDs. However, further investigation is crucial to improve our knowledge of CVDs progression and, more importantly, accelerate basic research to improve our understanding of the mechanism of pathophysiology.
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Project description:New imaging methods are urgently needed to identify high-risk atherosclerotic lesions prior to the onset of myocardial infarction, stroke, and ischemic limbs. Molecular imaging offers a new approach to visualize key biological features that characterize high-risk plaques associated with cardiovascular events. While substantial progress has been realized in clinical molecular imaging of plaques in larger arterial vessels (carotid, aorta, iliac), there remains a compelling, unmet need to develop molecular imaging strategies targeted to high-risk plaques in human coronary arteries. We present recent developments in intravascular near-IR fluorescence catheter-based strategies for in vivo detection of plaque inflammation in coronary-sized arteries. In particular, the biological, light transmission, imaging agent, and engineering principles that underlie a new intravascular near-IR fluorescence sensing method are discussed. Intravascular near-IR fluorescence catheters appear highly translatable to the cardiac catheterization laboratory, and thus may offer a new in vivo method to detect high-risk coronary plaques and to assess novel atherosclerosis biologics.
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Project description:PurposeElastin is a major arterial structural protein, and elastin-derived peptides are related to arterial change. We previously reported on a novel assay developed using aortic elastin peptides; however, its clinical implications remain unclear. In this study, we assessed whether anti-elastin antibody titers reflect the risk of coronary artery disease (CAD) or its characteristics.Materials and methodsWe included 174 CAD patients and 171 age- and sex-matched controls. Anti-elastin antibody titers were quantified by enzyme-linked immunosorbent assay. Parameters of arterial stiffness, including the augmentation index (AI) and heart-to-femoral pulse wave velocity (hfPWV), were measured non-invasively. The clinical and angiographic characteristics of CAD patients were also evaluated. Associations between anti-elastin levels and vascular characteristics were examined by linear regression analysis.ResultsThe median blood level of anti-elastin was significantly lower in the CAD group than in the controls [197 arbitrary unit (a.u.) vs. 63 a.u., p<0.001]. Levels of anti-elastin were significantly lower in men and in subjects with hypertension, diabetes mellitus, hyperlipidemia, or high hfPWV. Nevertheless, anti-elastin levels were not dependent on atherothrombotic events or the angiographic severity of CAD. In a multivariate analysis, male sex (?=-0.38, p<0.001), diabetes mellitus (?=-0.62, p<0.001), hyperlipidemia (?=-0.29, p<0.001), and AI (?=-0.006, p=0.02) were ultimately identified as determinants of anti-elastin levels.ConclusionLower levels of anti-elastin are related to CAD. The association between antibody titers and CAD is linked to arterial stiffness rather than the advancement of atherosclerosis.
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Project description:AimsImpaired lymphatic drainage of the arterial wall results in intimal lipid accumulation and atherosclerosis. However, the mechanisms regulating lymphangiogenesis in atherosclerotic arteries are not well understood. Our studies identified elevated levels of matrix protein R-spondin 2 (RSPO2) in atherosclerotic arteries. In this study, we investigated the role of RSPO2 in lymphangiogenesis, arterial cholesterol efflux into lesion-draining lymph nodes (LNs) and development of atherosclerosis.Methods and resultsThe effect of RSPO2 on lymphangiogenesis was investigated using human lymphatic endothelial cells (LEC) in vitro and implanted Matrigel plugs in vivo. Cellular and molecular approaches, pharmacological agents, and siRNA silencing of RSPO2 receptor LGR4 were used to investigate RSPO2-mediated signalling in LEC. In vivo low-density lipoprotein (LDL) tracking and perivascular blockade of RSPO2-LGR4 signalling using LGR4-extracellular domain (ECD) pluronic gel in hypercholesterolemic mice were utilized to investigate the role of RSPO2 in arterial reverse cholesterol transport and atherosclerosis. Immunoblotting and imaging experiments demonstrated increased RSPO2 expression in human and mouse atherosclerotic arteries compared to non-atherosclerotic controls. RSPO2 treatment inhibited lymphangiogenesis both in vitro and in vivo. LGR4 silencing and inhibition of RSPO2-LGR4 signalling abrogated RSPO2-induced inhibition of lymphangiogenesis. Mechanistically, we found that RSPO2 suppresses PI3K-AKT-endothelial nitric oxide synthase (eNOS) signalling via LGR4 and inhibits activation of the canonical Wnt-β-catenin pathway. ApoE-/- mice treated with LGR4-ECD developed significantly less atherosclerosis compared with control treatment. Finally, increased arterial lymphatic vessel density and improved lymphatic drainage of fluorescently labelled LDL to deep cervical LNs were observed in LGR4-ECD-treated mice.ConclusionThese findings demonstrate that RSPO2 inhibits lymphangiogenesis via LGR4 and downstream impairment of AKT-eNOS-nitric oxide signalling. These results may also inform new therapeutic strategies to promote lymphangiogenesis and improve cholesterol efflux from atherosclerotic arteries.
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Project description:The commensal gut microbiota is an environmental factor that has been implicated in the development of cardiovascular disease. The development of atherosclerotic lesions is largely influenced not only by the microbial-associated molecular patterns of the gut microbiota but also by the meta-organismal trimethylamine N-oxide pathway. Recent studies have described a role for the gut microbiota in platelet activation and arterial thrombosis. This review summarizes the results from gnotobiotic mouse models and clinical data that linked microbiota-induced pattern recognition receptor signalling with atherogenesis. Based on recent insights, we here provide an overview of how the gut microbiota could affect endothelial cell function and platelet activation, to promote arterial thrombosis. LINKED ARTICLES: This article is part of a themed section on When Pharmacology Meets the Microbiome: New Targets for Therapeutics? To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.24/issuetoc.
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Project description:Aging is believed to be among the most important contributors to atherosclerosis, through mechanisms that remain largely obscure. Serum levels of tumor necrosis factor (TNF) rise with aging and have been correlated with the incidence of myocardial infarction. We therefore sought to determine whether genetic variation in the TNF receptor-1 gene (TNFR1) contributes to aging-related atherosclerosis in humans and whether Tnfr1 expression aggravates aging-related atherosclerosis in mice. With 1330 subjects from a coronary angiography database, we performed a case-control association study of coronary artery disease (CAD) with 16 TNFR1 single-nucleotide polymorphisms (SNPs). Two TNFR1 SNPs significantly associated with CAD in subjects >55 years old, and this association was supported by analysis of a set of 759 independent CAD cases. In multiple linear regression analysis, accounting for TNFR1 SNP rs4149573 significantly altered the relationship between aging and CAD index among 1811 subjects from the coronary angiography database. To confirm that TNFR1 contributes to aging-dependent atherosclerosis, we grafted carotid arteries from 18- and 2-month-old wild-type (WT) and Tnfr1(-/-) mice into congenic apolipoprotein E-deficient (Apoe(-/-)) mice and harvested grafts from 1 to 7 weeks post-operatively. Aged WT arteries developed accelerated atherosclerosis associated with enhanced TNFR1 expression, enhanced macrophage recruitment, reduced smooth muscle cell proliferation and collagen content, augmented apoptosis and plaque hemorrhage. In contrast, aged Tnfr1(-/-) arteries developed atherosclerosis that was indistinguishable from that in young Tnfr1(-/-) arteries and significantly less than that observed in aged WT arteries. We conclude that TNFR1 polymorphisms associate with aging-related CAD in humans, and TNFR1 contributes to aging-dependent atherosclerosis in mice.
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Project description:Hyperglycemia has been associated with an increased risk of cardiovascular morbidity and mortality. Although numerous studies have demonstrated that hyperglycemia is associated with the atherosis component of atherosclerosis, limited studies have addressed the independent role of hyperglycemia in the pathophysiology of sclerotic vascular disease. We hypothesized that hyperglycemia, as assessed by hemoglobin A1c (HbA1c), would be independently associated two common indices of arterial stiffness (pressure-strain elastic modulus (Ep) and Young's elastic modulus (YEM)).We examined the cross-sectional association between HbA1c and arterial stiffness using B-mode ultrasound examination of the carotid artery in 9050 participants from the community-based Atherosclerosis Risk in Communities (ARIC) study. We used multivariable linear and logistic regression models to characterize the association between HbA1c and increased Ep and YEM.Higher values of HbA1c were associated in a graded fashion with increased arterial stiffness (P-trend < 0.001 for both EP and YEM). After adjusting for traditional risk factors, increasing HbA1c deciles were significantly associated with elevated EP (OR for the highest decile of HbA1c compared to the lowest, 2.01, 95% CI: 1.30, 3.11) and YEM (OR = 1.71, 95% CI: 1.15, 2.55).Elevated HbA1c is associated with measures of increased arterial stiffness, even after accounting for arterial wall thickness. This is consistent with the hypothesis that hyperglycemia contributes to arterial stiffness beyond its effects on atherosis and suggests that hyperglycemia is associated with altered material within the arterial wall.
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