Vascular Macrophages Research Articles

Hsp90 S-nitrosylation at Cys521, as a conformational switch, modulates cycling of Hsp90-AHA1-CDC37 chaperone machine to aggravate atherosclerosis

Endothelial dysfunction is the initial process of atherosclerosis. Heat shock protein 90 (Hsp90), as a molecular chaperone, plays a crucial role in various cardiovascular diseases. Hsp90 function is regulated by S-nitrosylation (SNO). However, the precise role of SNO-Hsp90 in endothelial dysfunction during atherosclerosis remains unclear. We here identified Hsp90 as a highly S-nitrosylated target in endothelial cells (ECs) by biotin switch assay combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS). The elevation of SNO-Hsp90 was observed in atherosclerotic human and rodent aortas as well as in oxidized LDL (oxLDL)-treated ECs. Inhibition of inducible nitric oxide synthase (iNOS) or transfection with Hsp90 cysteine 521 (Cys521) mutation plasmid decreased the level of SNO-Hsp90 in oxLDL-cultured ECs. Coimmunoprecipitation and proximity ligation assay demonstrated that SNO-Hsp90 at Cys521 suppressed the interaction between Hsp90 and activator of Hsp90 ATPase activity 1 (AHA1), but promoted the association of Hsp90 and cell division cycle 37 (CDC37). Hsp90 Cys521 mutation increased endothelial nitric oxide synthase (eNOS) activity and inhibited nuclear factor kappa-B (NF-κB) signaling, thereby increasing nitric oxide (NO) bioavailability and alleviating endothelial adhesion, inflammation and oxidative stress in oxLDL-treated ECs. Also, administration of endothelial-specific adeno-associated viruses of Cys521-mutated Hsp90 significantly mitigated vascular oxidative stress, macrophage infiltration and atherosclerosis lesion areas in high fat diet-fed ApoE-/- mice. In conclusion, SNO-Hsp90 at Cys521, that serves as a conformational switch, disrupts Hsp90/AHA1 interaction but promotes recruitment of CDC37 to exacerbate atherosclerosis.

Odorant receptors in macrophages: potential targets for atherosclerosis

In a recent report, Orecchioni et al. identify a role for the olfactory receptor (OR) Olfr2 and its human ortholog OR6A2 in atherosclerosis. Vascular macrophage Olfr2 binds octanal, a product of lipid peroxidation, activating the NLRP3 inflammasome and IL-1β secretion, and driving atherosclerosis pathology. Thus, OR6A2 inhibitors may represent a promising therapy for atherosclerosis.

Melatonin alleviates PM2.5-triggered macrophage M1 polarization and atherosclerosis via regulating NOX2-mediated oxidative stress homeostasis

It is reported that oxidative stress homeostasis was involved in PM2.5-induced foam cell formation and progression of atherosclerosis, but the exact molecular mechanism is still unclear. Melatonin is an effective antioxidant that could reverse the cardiopulmonary injury. The main purpose of this study is to investigate the latent mechanism of PM2.5-triggered atherosclerosis development and the protective role of melatonin administration. Vascular Doppler ultrasound showed that PM2.5 exposure reduced aortic elasticity in ApoE-/- mice. Meanwhile, blood biochemical and pathological analysis demonstrated that PM2.5 exposure caused dyslipidemia, elicited oxidative damage of aorta and was accompanied by an increase in atherosclerotic plaque area; while the melatonin administration could effectively alleviate PM2.5-induced macrophage M1 polarization and atherosclerosis in mice. Further investigation verified that NADPH oxidase 2 (NOX2) and mitochondria are two prominent sources of PM2.5-induced ROS production in vascular macrophages. Whereas, the combined use of two ROS-specific inhibitors and adopted with melatonin markedly rescued PM2.5-triggered macrophage M1 polarization and foam cell formation by inhibiting NOX2-mediated crosstalk of Keap1/Nrf2/NF-κB and TLR4/TRAF6/NF-κB signaling pathways. Our results demonstrated that NOX2-mediated oxidative stress homeostasis is critical for PM2.5-induced atherosclerosis and melatonin might be a potential treatment for air pollution-related cardiovascular diseases.

Olfactory receptor 2 in vascular macrophages drives atherosclerosis by NLRP3-dependent IL-1 production.

Atherosclerosis is an inflammatory disease of the artery walls and involves immune cells such as macrophages. Olfactory receptors (OLFRs) are G protein–coupled chemoreceptors that have a central role in detecting odorants and the sense of smell. We found that mouse vascular macrophages express the olfactory receptor Olfr2 and all associated trafficking and signaling molecules. Olfr2 detects the compound octanal, which activates the NLR family pyrin domain containing 3 (NLRP3) inflammasome and induces interleukin-1β secretion in human and mouse macrophages. We found that human and mouse blood plasma contains octanal, a product of lipid peroxidation, at concentrations sufficient to activate Olfr2 and the human ortholog olfactory receptor 6A2 (OR6A2). Boosting octanal levels exacerbated atherosclerosis, whereas genetic targeting of Olfr2 in mice significantly reduced atherosclerotic plaques. Our findings suggest that inhibiting OR6A2 may provide a promising strategy to prevent and treat atherosclerosis.

The scent of atherosclerosis.

Vascular macrophages sense an odorant to induce atherosclerotic plaque formation.

C-type lectin receptor CLEC4A2 promotes tissue adaptation of macrophages and protects against atherosclerosis

Macrophages are integral to the pathogenesis of atherosclerosis, but the contribution of distinct macrophage subsets to disease remains poorly defined. Using single cell technologies and conditional ablation via a LysMCre+Clec4a2flox/DTR mouse strain, we demonstrate that the expression of the C-type lectin receptor CLEC4A2 is a distinguishing feature of vascular resident macrophages endowed with athero-protective properties. Through genetic deletion and competitive bone marrow chimera experiments, we identify CLEC4A2 as an intrinsic regulator of macrophage tissue adaptation by promoting a bias in monocyte-to-macrophage in situ differentiation towards colony stimulating factor 1 (CSF1) in vascular health and disease. During atherogenesis, CLEC4A2 deficiency results in loss of resident vascular macrophages and their homeostatic properties causing dysfunctional cholesterol metabolism and enhanced toll-like receptor triggering, exacerbating disease. Our study demonstrates that CLEC4A2 licenses monocytes to join the vascular resident macrophage pool, and that CLEC4A2-mediated macrophage homeostasis is critical to combat cardiovascular disease.

COVID Coagulopathy and Thrombosis: A Systematic Review

Introduction: Since the onset of the SARS-CoV-2 pandemic, haematological laboratory abnormalities and thrombotic complications have been observed among infected patients. We aimed to highlight key pathophysiological mechanisms of COVID-19-associated coagulopathy and to summarize incidence rates of venous and arterial thrombotic events, comorbidities conferring risk, and current treatment guidelines including data from ongoing clinical trials. Methods: A systematic review was performed according to PRISMA recommendations of case–control studies, cohort studies, observational studies and randomized clinical trials (RCTs) published between 1 December 2019 and 30 September 2021 within PubMed and Web of Science. Inclusion criteria were English language, adult patients and at least one coagulation parameter described. Results: 2,554 records were screened, from which 59 studies were included. Abnormalities in several laboratory parameters were associated with worse clinical outcomes including elevations in prothrombin time, activated partial thromboplastin time, D-dimer, fibrinogen, von Willebrand factor antigen/activity and lupus anticoagulant antibodies. Rates of venous and arterial thromboembolism varied significantly among studies performed early in the pandemic and across different nations. Pathophysiological mechanisms included vascular endotheliopathy, increased inflammation and macrophage activation, neutrophil extracellular traps, antiphospholipid antibody production and obesity/adipose tissue signalling. Current recommendations for management of COVID coagulopathy from various societies include the use and dosing of systemic anticoagulation to prevent thrombotic sequelae in the outpatient, inpatient and critical care settings. The optimal anticoagulant dose for thromboprophylaxis in the inpatient and critical care settings is currently not well established. Conclusions: SARS-CoV-2 infection can cause a distinct form of coagulopathy, with thromboembolic complications leading to significant morbidity and mortality. The optimal treatment requires further refinement pending the results from key ongoing RCTs

CGAS-STING Pathway Performance in the Vulnerable Atherosclerotic Plaque.

The important role of Ca2+ in pathogenic store-operated calcium entry (SOCE) is well-established. Among the proteins involved in the calcium signaling pathway, Stromal interacting molecule 1 (STIM1) is a critical endoplasmic reticulum transmembrane protein. STIM1 is activated by the depletion of calcium stores and then binds to another calcium protein, Orai1, to form a channel through which the extracellular Ca2+ can enter the cytoplasm to replenish the calcium store. Multiple studies have shown that increased STIM1 facilitates the aberrant proliferation and apoptosis of vascular smooth cells (VSMC) and macrophages which can promote the formation of rupture-prone plaque. Together with regulating the cytosolic Ca2+ concentration, STIM1 also activates STING through altered intracellular Ca2+ concentration, a critical pro-inflammatory molecule. The cGAS-STING pathway is linked with cellular proliferation and phenotypic conversion of VSMC and enhances the progression of atherosclerosis plaque. In summary, we conclude that STIM1/cGAS-STING is involved in the progression of AS and plaque vulnerability.

Heterogeneous Population of Immune cells Associated with Early Thrombosis in Arteriovenous Fistula.

End-Stage Renal Disease (ESRD) is a growing cause of morbidity and mortality in the practice of modern medicine. Advances in medicine have elongated the average life span and subsequently made chronic diseases prevalent. Hemodialysis is the main treatment that is used to treat ESRD and is a clinical procedure that is being re-imagined with novel approaches to improve patient and clinic practicality and effectiveness. Arteriovenous Fistulas (AVF) are now used in place of catheters due to their higher success and lower co-morbidities. The main drawback of AVF is the time gap that is needed from the surgical creation of AVF to its use. During this time, the AVF is susceptible to thrombosis and occlusion rendering the fistula ineffective for treatment. Immune cells play a major role in vascular pathologies and macrophages, dendritic cells, and T-regulatory cells are the main cells seen during the inflammatory and anti-inflammatory phases. However, the role of immune response and immune cells in AVF maturation is poorly understood. This study aimed to investigate the immune response and immune cell expression in femoral vessels after AVF creation in a miniswine model of AVF using immunohistochemistry and qRT-PCR. The results of this study revealed an increased expression of immune cells in AVF vessels and suggest an association of immune response with AVF creation and maturation.

Engineering pro-angiogenic biomaterials via chemoselective extracellular vesicle immobilization

Nanoscale extracellular vesicles (EVs) represent a unique cellular derivative that reflect the therapeutic potential of mesenchymal stem cells (MSCs) toward tissue engineering and injury repair without the logistical and safety concerns of utilizing living cells. However, upon systemic administration in vivo,EVs undergo rapid clearance and typically lack controlled targeted delivery, thus reducing their effectiveness in therapeutic regenerative therapies. Here, we describe a strategy that enables long-term in vivo spatial EV retention by chemoselective immobilization of metabolically incoporated azido ligand-bearing EVs (azido-EVs) within a dibenzocyclooctyne-modified collagen hydrogel. MSC-derived azido-EVs exhibit comparable morphological and functional properties as their non-labeled EV counterparts and, when immobilized within collagen hydrogel implants via click chemistry, they elicited more robust host cell infiltration, angiogenic and immunoregulatory responses including vascular ingrowth and macrophage recruitment compared to ten times the higher dose required by non-immobilized EVs. We envision this technology will enable a wide range of applications to spatially promote vascularization and host integration relevant to tissue engineering and regenerative medicine applications.

CORRELATIONS BETWEEN CD68 RECEPTOR EXPRESSION AND ACTIVITY OF MACROPHAGE POLARIZATION MARKER ENZYMES IN RAT TESTES DURING PROLONGED BLOCKADE OF LUTEINIZING HORMONE SYNTHESIS BY TRIPTORELIN

Luteinizing hormone and testosterone have a significant effect on the polarization of macrophages. Changing the polarization of macrophages can cause morphological and metabolic changes in various organs and tissues. The CD68 receptor is associated with proinflammatory polarization of macrophages. Currently, the scientific literature provides limited data on the relationship between the expression of the CD68 receptor on testicular macrophages and the activity of markers of macrophage polarization enzymes during long-term deprivation of luteinizing hormone synthesis. The aim of this study was to establish correlations between the number of CD68+ cells in the interstitial space and testicular vessels and the activity of inducible NO synthase, arginase and superoxide anion radical production after 270 and 365 days of central blockade of luteinizing hormone synthesis by triptorelin. Materials and methods. The study was performed on 15 adult male Wistar rats. Animals were randomly divided into 2 groups: control (5 animals) and experimental (10 animals). Animals of the experimental group were injected with a solution of triptorelin acetate at the rate of 0.3 mg of active substance per kg of animal weight to model the central derivation of luteinizing hormone synthesis. Animals from the experimental group were removed from the experiment on days 270 and 365 of the simulation of central derivation of luteinizing hormone synthesis. Histological examination of the testes was performed after preparation of paraffin sections. To perform immunohistochemical study of testicular macrophages for the presence of CD68 receptors we performed, after the manufacture of paraffin blocks, deparaffinization of sections was with subsequent unmasking of antigens. Inducible NO synthase activity, arginase and superoxide anion radical production were determined in 10% of testicular homogenates. Quantitative distribution of the CD68 receptor in the interstitium and testicular blood vessels was also determined. After determining the distribution of the studied parameters, a correlation analysis was performed by the Spearman method and the correlation of the ranks of the studied parameters and its statistical significance were determined. Results. The production of superoxide anion radical is directly proportionally strongly correlated with the expression of CD68 on interstitial and vascular macrophages. There were no statistically significant correlations between the prevalence of CD68 receptor in the interstitium and vascular vessels and the activity of inducible NO synthase and arginase on day 270 of central deprivation of luteinizing hormone synthesis by triptorelin. The production of superoxide anion radical, inducible NO synthase and arginase activity, and the prevalence of the CD68 receptor in the interstitium and blood vessels of testes on day 365 of central deprivation of luteinizing hormone synthesis do not have statistically significant correlations. Conclusions. Expression of the CD68 receptor on interstitial and parietal testicular macrophages leads to hyperproduction of superoxide anion radical on day 270 of central deprivation of luteinizing hormone synthesis by triptorelin. The prevalence of CD68 on day 360 of central deprivation of luteinizing hormone synthesis by triptorelin does not affect the activity of macrophage polarization marker enzymes.

Effect of FURIN SNP rs17514846 on coronary atherosclerosis in human cardiac specimens: An autopsy study of 106 cases

BackgroundCoronary artery disease (CAD), including coronary atherosclerosis (CAS), is one of the most common causes of death. The FURIN SNP rs17514846 is assumed to be a risk factor for CAD. We evaluated this relationship using autopsy specimens and autopsy data, such as the histopathological degree of CAS. Materials and methodsA total of 106 samples were genotyped from obtained blood samples. Myocardial and coronary arterial FURIN levels were quantified by ELISA. The degree of CAS was classified histopathologically according to the Stary classification, and the localization of FURIN was examined by immunostaining. The obtained data were analyzed statistically. ResultsFURIN expression was widely observed in the myocardium, vascular smooth muscle cells, endothelial cells, adipocytes, and macrophages. FURIN level in the myocardium of cases with the AA genotype at the FURIN SNP rs17514846 was higher than that in CC cases. Additionally, FURIN levels in both coronary arteries and myocardium were higher at the early stage of CAS than at the late stage microscopically. ConclusionOur study suggested that the A allele of rs17514846 is associated with higher FURIN level in the heart and that FURIN exhibits a higher level in the early stage of CAS. These findings deepen our understanding of the mechanism of CAS.

Single-Cell RNA Sequencing of the Rat Carotid Arteries Uncovers Potential Cellular Targets of Neointimal Hyperplasia.

Aims: In-stent restenosis (ISR) remains an Achilles heel of drug-eluting stents despite technical advances in devices and procedural techniques. Neointimal hyperplasia (NIH) is the most important pathophysiological process of ISR. The present study mapped normal arteries and stenotic arteries to uncover potential cellular targets of neointimal hyperplasia.Methods and Results: By comparing the left (control) and right (balloon injury) carotid arteries of rats, we mapped 11 clusters in normal arteries and 11 mutual clusters in both the control and experimental groups. Different clusters were categorized into 6 cell types, including vascular smooth muscle cells (VSMCs), fibroblasts, endothelial cells (ECs), macrophages, unknown cells and others. An abnormal cell type expressing both VSMC and fibroblast markers at the same time was termed a transitional cell via pseudotime analysis. Due to the high proportion of VSMCs, we divided them into 6 clusters and analyzed their relationship with VSMC phenotype switching. Moreover, N-myristoyltransferase 1 (NMT1) was verified as a credible VSMC synthetic phenotype marker. Finally, we proposed several novel target genes by disease susceptibility gene analysis, such as Cyp7a1 and Cdk4, which should be validated in future studies.Conclusion: Maps of the heterogeneous cellular landscape in the carotid artery were defined by single-cell RNA sequencing and revealed several cell types with their internal relations in the ISR model. This study highlights the crucial role of VSMC phenotype switching in the progression of neointimal hyperplasia and provides clues regarding the underlying mechanism of NIH.

Loss of myeloid Bmal1 exacerbates hypertensive vascular remodelling through interaction with STAT6 in mice.

In addition to its involvement of inflammatory responses, limited information is available on the phenotype and behaviour of vascular macrophages during hypertensive vascular remodelling. Here, we aim at studying the contribution of BMAL1 to the pro-fibrotic macrophage phenotype in the vasculature during hypertension, which leads to enhanced vascular remodelling and promoted blood pressure increase. Wild type Bmal1f/f and myeloid cell selective Bmal1 knockout Bmal1f/f; LysMCre/+ mice were infused with AngII for 4 weeks to induce hypertension. AngII-induced blood pressure increase, vascular media thickness and vascular dysfunction were enhanced in Bmal1f/f; LysMCre/+ mice, accompanied with a pro-fibrotic M2 phenotype of the vascular macrophages. Bmal1f/f; LysMCre/+ mice also have more up-regulations of MMP9 and MMP13 expression in the vascular wall, accompanied by enhanced collagen deposition after AngII infusion. Loss of Bmal1 in bone marrow-derived macrophages enhanced STAT6 activation induced by IL4, and the subsequent MMP13 up-regulation and activity. In macrophages, loss of Bmal1 enhanced the phosphorylation and nuclear translocation of STAT6 triggered by IL4, through possibly a direct interaction between BMAL1 and STAT6. To further determine whether IL4-induced signalling in macrophage contributes to enhanced vascular remodelling in hypertensive mice, we showed that deletion of myeloid IL4Rα in Il4raf/f; LysMCre/+ mice attenuated blood pressure increase and hypertensive vascular remodelling after AngII infusion. Our results suggested a tonic effect of BMAL1 deletion on hypertensive vascular remodelling. BMAL1 might inhibit IL4-STAT6 signalling in macrophages through the interaction with STAT6 to reduce STAT6 activation and target gene transcription, especially MMP9 and MMP13, contributing to vascular remodelling.

Interferon-stimulated gene 15 pathway is a novel mediator of endothelial dysfunction and aneurysms development in angiotensin II infused mice through increased oxidative stress.

Interferon-stimulated gene 15 (ISG15) encodes a ubiquitin-like protein that induces a reversible post-translational modification (ISGylation) and can also be secreted as a free form. ISG15 plays an essential role as host-defence response to microbial infection; however, its contribution to vascular damage associated with hypertension is unknown. Bioinformatics identified ISG15 as a mediator of hypertension-associated vascular damage. ISG15 expression positively correlated with systolic and diastolic blood pressure and carotid intima-media thickness in human peripheral blood mononuclear cells. Consistently, Isg15 expression was enhanced in aorta from hypertension models and in angiotensin II (AngII)-treated vascular cells and macrophages. Proteomics revealed differential expression of proteins implicated in cardiovascular function, extracellular matrix and remodelling, and vascular redox state in aorta from AngII-infused ISG15-/- mice. Moreover, ISG15-/- mice were protected against AngII-induced hypertension, vascular stiffness, elastin remodelling, endothelial dysfunction, and expression of inflammatory and oxidative stress markers. Conversely, mice with excessive ISGylation (USP18C61A) show enhanced AngII-induced hypertension, vascular fibrosis, inflammation and reactive oxygen species (ROS) generation along with elastin breaks, aortic dilation, and rupture. Accordingly, human and murine abdominal aortic aneurysms showed augmented ISG15 expression. Mechanistically, ISG15 induces vascular ROS production, while antioxidant treatment prevented ISG15-induced endothelial dysfunction and vascular remodelling. ISG15 is a novel mediator of vascular damage in hypertension through oxidative stress and inflammation.

Enhanced Bone Remodeling After Fracture Priming.

The immune system is an active component of bone repair. Mast cells influence the recruitment of macrophages, osteoclasts and blood vessels into the repair tissue. We hypothesized that if mast cells and other immune cells are sensitized to recognize broken bone, they will mount an increased response to subsequent fractures that may be translated into enhanced healing. To test this, we created a bone defect on the left leg of anesthetized mice and 2weeks later, a second one on the right leg. Bone repair in the right legs was then compared to control mice that underwent the creation of bilateral window bone defects at the same time. Mice were euthanized at 14 and 56days. Mineralized tissue quantity and morphometric parameters were assessed using micro-CT and histology. The activity of osteoblasts, osteoclasts, vascular endothelial cells, mast cells, and macrophages was evaluated using histochemistry. Our main findings were (1) no significant differences in the amount of bone produced at 14- or 56days post-operative between groups; (2) mice exposed to subsequent fractures showed significantly better bone morphometric parameters after 56days post-operative; and (3) significant increases in the content of blood vessels, osteoclasts, and the number of macrophages in the subsequent fracture group. Our results provide strong evidence that a transient increase in the inflammatory state of a healing injury promotes faster bone remodelling and increased neo-angiogenesis. This phenomenon is also characterized by changes in mast cell and macrophage content that translate into more active recruitment of mesenchymal stromal cells.

Tissue-Engineered Carotid Artery Interposition Grafts Demonstrate High Primary Patency and Promote Vascular Tissue Regeneration in the Ovine Model.

Tissue-engineered vascular graft for the reconstruction of small arteries is still an unmet clinical need, despite the fact that a number of promising prototypes have entered preclinical development. Here we test Poly(3-hydroxybutyrate-co-3-hydroxyvalerate)Poly(ε-caprolactone) 4-mm-diameter vascular grafts equipped with vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and stromal cell-derived factor 1α (SDF-1α) and surface coated with heparin and iloprost (PHBV/PCL[VEGF-bFGF-SDF]Hep/Ilo, n = 8) in a sheep carotid artery interposition model, using biostable vascular prostheses of expanded poly(tetrafluoroethylene) (ePTFE, n = 5) as a control. Primary patency of PHBV/PCL[VEGF-bFGF-SDF]Hep/Ilo grafts was 62.5% (5/8) at 24 h postimplantation and 50% (4/8) at 18 months postimplantation, while all (5/5) ePTFE conduits were occluded within the 24 h after the surgery. At 18 months postimplantation, PHBV/PCL[VEGF-bFGF-SDF]Hep/Ilo grafts were completely resorbed and replaced by the vascular tissue. Regenerated arteries displayed a hierarchical three-layer structure similar to the native blood vessels, being fully endothelialised, highly vascularised and populated by vascular smooth muscle cells and macrophages. The most (4/5, 80%) of the regenerated arteries were free of calcifications but suffered from the aneurysmatic dilation. Therefore, biodegradable PHBV/PCL[VEGF-bFGF-SDF]Hep/Ilo grafts showed better short- and long-term results than bio-stable ePTFE analogues, although these scaffolds must be reinforced for the efficient prevention of aneurysms.

Krüppel-Like Factor 15/Interleukin 11 Axis-Mediated Adventitial Remodeling Depends on Extracellular Signal-Regulated Kinases 1 and 2 Activation in Angiotensin II-Induced Hypertension.

BackgroundAdventitial remodeling is a pathological hallmark of hypertension that results in target organ damage. Activated adventitial fibroblasts have emerged as critical regulators in this process, but the precise mechanism remains unclear.Methods and ResultsInterleukin 11 (IL‐11) knockout and wild‐type mice were subjected to angiotensin II (Ang II) infusion to establish models of hypertension‐associated vascular remodeling. IL‐11 mRNA and protein were increased especially in the adventitia in response to Ang II. Compared with wild‐type mice, Ang II–treated IL‐11 knockout mice showed amelioration of vascular hypertrophy, adventitial fibrosis, macrophage infiltration, and inflammatory factor expression. Recombination mouse IL‐11 exacerbated adventitial fibrosis in Ang II–infused wild‐type mice. Interestingly, IL‐11 neutralizing antibody attenuated adventitial fibrosis, macrophage infiltration, and inflammatory factor expression after Ang II infusion for 7 days. Mechanistically, in primary cultured adventitial fibroblasts, Krüppel‐like factor 15 negatively regulated Ang II–induced IL‐11 expression. Ang II increased extracellular signal‐regulated kinases 1 and 2 activation, especially in adventitia, and caused biphasic extracellular signal‐regulated kinases 1 and 2 activation in adventitial fibroblasts. A rapid and early activation increased IL‐11 production through decreasing Krüppel‐like factor 15 expression, which, in turn, induced the second extracellular signal‐regulated kinases 1 and 2 activation, resulting in posttranscriptional profibrotic gene expression.ConclusionsThese results demonstrate that extracellular signal‐regulated kinases 1 and 2 activation is important for Krüppel‐like factor 15–mediated IL‐11 expression in adventitial fibroblasts to promote adventitial remodeling in Ang II–induced hypertension. Therefore, targeting the Krüppel‐like factor 15/IL‐11 axis might serve as a new therapeutic strategy for vascular diseases.

Line-1 methylation in different vessels, vascular and blood cells in human atherosclerosis.

Background and Aims: Decreased LINE-1 methylation was associated with cardiovascular diseases. However, LINE-1 methylation in vascular cells is poorly investigated in atherosclerosis. Here we studied DNA methylation of LINE-1 promoter in human carotid atherosclerotic plaque, intact artery, and vein, as well as in vascular smooth muscle cells (VSMC) and macrophages (MPH) isolated from plaques, and in blood cells.

Impact of Dietary Lipids on the Reverse Cholesterol Transport: What We Learned from Animal Studies.

Reverse cholesterol transport (RCT) is a physiological mechanism protecting cells from an excessive accumulation of cholesterol. When this process begins in vascular macrophages, it acquires antiatherogenic properties, as has been widely demonstrated in animal models. Dietary lipids, despite representing a fundamental source of energy and exerting multiple biological functions, may induce detrimental effects on cardiovascular health. In the present review we summarize the current knowledge on the mechanisms of action of the most relevant classes of dietary lipids, such as fatty acids, sterols and liposoluble vitamins, with effects on different steps of RCT. We also provide a critical analysis of data obtained from experimental models which can serve as a valuable tool to clarify the effects of dietary lipids on cardiovascular disease.