Chronic Vascular Inflammation Research Articles

Quinic acid regulated TMA/TMAO-related lipid metabolism and vascular endothelial function through gut microbiota to inhibit atherosclerotic

BackgroundQuinic acid (QA) and its derivatives have good lipid-lowering and hepatoprotective functions, but their role in atherosclerosis remains unknown. This study attempted to investigate the mechanism of QA on atherogenesis in Apoe−/− mice induced by HFD.MethodsHE staining and oil red O staining were used to observe the pathology. The PCSK9, Mac-3 and SM22a expressions were detected by IHC. Cholesterol, HMGB1, TIMP-1 and CXCL13 levels were measured by biochemical and ELISA. Lipid metabolism and the HMGB1-SREBP2-SR-BI pathway were detected by PCR and WB. 16 S and metabolomics were used to detect gut microbiota and serum metabolites.ResultsQA or low-frequency ABX inhibited weight gain and aortic tissue atherogenesis in HFD-induced Apoe−/− mice. QA inhibited the increase of cholesterol, TMA, TMAO, CXCL13, TIMP-1 and HMGB1 levels in peripheral blood of Apoe−/− mice induced by HFD. Meanwhile, QA or low-frequency ABX treatment inhibited the expression of CAV-1, ABCA1, Mac-3 and SM22α, and promoted the expression of SREBP-1 and LXR in the vascular tissues of HFD-induced Apoe−/− mice. QA reduced Streptococcus_danieliae abundance, and promoted Lactobacillus_intestinalis and Ileibacterium_valens abundance in HFD-induced Apoe−/− mice. QA altered serum galactose metabolism, promoted SREBP-2 and LDLR, inhibited IDOL, FMO3 and PCSK9 expression in liver of HFD-induced Apoe−/− mice. The combined treatment of QA and low-frequency ABX regulated microbe-related Glycoursodeoxycholic acid and GLYCOCHENODEOXYCHOLATE metabolism in HFD-induced Apoe−/− mice. QA inhibited TMAO or LDL-induced HCAECs damage and HMGB1/SREBP2 axis dysfunction, which was reversed by HMGB1 overexpression.ConclusionsQA regulated the gut-liver lipid metabolism and chronic vascular inflammation of TMA/TMAO through gut microbiota to inhibit the atherogenesis in Apoe−/− mice, and the mechanism may be related to the HMGB1/SREBP2 pathway.

Vitamin D Deficiency As A Contributor To Atherosclerosis Development – A Review

Vitamin D, obtained from food or synthesized in the skin through sun exposure, plays a vital role in various physiological processes. This review focuses on cholecalciferol (vitamin D3), specifically its production from 7-dehydrocholesterol in the skin. The aim is to evaluate the impact of vitamin D on the development of atherosclerosis and other pathological conditions. Atherosclerosis, a chronic vascular inflammation caused by innate immunity, is of particular interest. Understanding the role of vitamin D in reducing inflammation and oxidative stress holds significant implications for effective treatment strategies. Deficiency of vitamin D has been observed in individuals with cardiovascular disease, ischemic stroke, and myocardial infarction. Hypovitaminosis D is also suspected to contribute to vascular calcification, a factor closely associated with cardiovascular morbidity and mortality. Investigating the multifaceted effects of vitamin D on various pathophysiological processes is thus crucial.

Black Soybean Seed Coat Extract Improves Endothelial Function and Upregulates Oxidative Stress Marker Expression in Healthy Volunteers by Stimulating Nitric Oxide Production in Endothelial Cells.

Black soybean seed coat extract (BE) contains multiple bioactive polyphenols, including flavan-3-ols and anthocyanins. BE improves endothelial function; however, it is unclear whether BE protects endothelial cells from senescence. In this study, we examined the effects of BE on endothelial cell senescence and vascular function in healthy individuals. High concentrations of glucose were used to induce senescence in bovine aortic endothelial cells incubated with BE. Senescence, vascular function, and oxidative stress markers were measured. Incubation with BE remarkably inhibited senescence-associated β-galactosidase and lactate dehydrogenase activities and dose dependently reduced intracellular reactive oxygen species levels in bovine aortic endothelial cells. BE treatment increased the levels of endothelial nitric oxide synthase (eNOS) mRNA and endothelial nitric oxide (NO) metabolites and increased the mRNA expression of klotho, a gene associated with an antiaging phenotype. To examine the effects of BE in humans, we conducted a clinical study using the second derivative of the fingertip photoplethysmogram to investigate vascular function and aging in 24 healthy volunteers. The participants consumed BE supplements (100 mg/day) or a placebo for 2 weeks. When compared with the placebo group, the BE group showed considerably improved vascular function, NO metabolite levels, and oxidative stress. These results suggest that BE supplementation improves endothelial function, possibly through antioxidant activity and NO production, and may consequently reduce the cardiovascular risk associated with aging. BE supplementation may be an effective and safe approach to reduce the risk of atherosclerosis and cardiovascular disease; however, additional studies investigating chronic vascular inflammation are needed.

Mitochondrial Dysfunction: A Roadmap for Understanding and Tackling Cardiovascular Aging.

Cardiovascular aging is a progressive remodeling process constituting a variety of cellular and molecular alterations that are closely linked to mitochondrial dysfunction. Therefore, gaining a deeper understanding of the changes in mitochondrial function during cardiovascular aging is crucial for preventing cardiovascular diseases. Cardiac aging is accompanied by fibrosis, cardiomyocyte hypertrophy, metabolic changes, and infiltration of immune cells, collectively contributing to the overall remodeling of the heart. Similarly, during vascular aging, there is a profound remodeling of blood vessel structure. These remodeling present damage to endothelial cells, increased vascular stiffness, impaired formation of new blood vessels (angiogenesis), the development of arteriosclerosis, and chronic vascular inflammation. This review underscores the role of mitochondrial dysfunction in cardiac aging, exploring its impact on fibrosis and myocardial alterations, metabolic remodeling, immune response remodeling, as well as in vascular aging in the heart. Additionally, we emphasize the significance of mitochondria-targeted therapies in preventing cardiovascular diseases in the elderly.

Dietary Salt Can Be Crucial for Food-Induced Vascular Inflammation.

Salt enhances the taste as well as the nutritional value of food. Besides, several reports are available on the incidence and epidemiology of various illnesses in relation to salt intake. Excessive salt consumption has been found to be linked with high blood pressure, renal disease, and other cardiovascular disorders due to the result of vascular inflammation. Nevertheless, studies aimed at elucidating the molecular processes that produce vascular inflammation have yet to reach their conclusions. This article emphasizes the significance of investigating the mechanisms underlying both acute and chronic vascular inflammation induced by salt. It also explores the logical inferences behind cellular oxidative stress and the role of endothelial dysfunction as the potential initiator of the inflammatory segments that remain poorly understood. It is therefore hypothesized that salt is one of the causes of chronic vascular inflammation such as atherosclerosis. The hypothesis's secrets, when revealed, can help assure cardiovascular health by proactive efforts and the development of appropriate preventative measures, in combination with medication, dietary and lifestyle adjustments.

Andrographolide protect against lipopolysacharides induced vascular endothelium dysfunction by abrogation of oxidative stress and chronic inflammation in Sprague-Dawley rats.

The development of heart disease involves interconnected factors such as oxidative stress, inflammation, and vascular dysfunction. Andrographolide (AG), known for its potent antioxidant and anti-inflammatory properties, has the potential to counteract lipopolysaccharides (LPS)-induced endothelial dysfunction by reducing oxidative stress and inflammation. Our research aimed to investigate the effects of AG on alleviating vascular endothelium dysfunction, oxidative stress, and inflammation in an experimental model induced by LPS. To create chronic vascular endothelium dysfunction, inflammation, and oxidative stress, rats received weekly injections of LPS via their tail vein over a 6-week period. The study evaluated the therapeutic effects of orally administered AG (50 mg/kg/day) on diseased conditions. We conducted aortic histology and measured nitric oxide (NO) thresholds, superoxide dismutase (SOD) activity, constitutive nitric oxide (cNOS) activity, and inducible nitric oxide (iNOS) levels, alongside several inflammatory biomarkers. To evaluate endothelial dysfunction, we assessed endothelium-dependent and endothelium-independent vasorelaxation in aortas through histopathological and various immunoassays examinations. Vascular Endothelial inflammatory activity was consequently enhanced in LPS groups animals when compared to normal control, also endothelial performance were dependently improved by AG therapy. IL-1β and tumors necrosis factor levels in the aorta decreased in a dose-dependent manner after exogenous AG delivery to LPS-treated rats. However, in current research work aortic SOD activity, NO levels, and cNOS activity increased, whereas aortic malondialdehyde levels and iNOS activity decreased after the AG treatment. These findings suggest that long-term AG therapy could be considered as a potential therapy to avoid vascular endothelial dysfunction and major nonobstructive coronary artery disease.

ILC2-mediated immune crosstalk in chronic (vascular) inflammation.

Crosstalk between innate and adaptive immunity is pivotal for an efficient immune response and to maintain immune homeostasis under steady state conditions. As part of the innate immune system, type 2 innate lymphoid cells (ILC2s) have emerged as new important regulators of tissue homeostasis and repair by fine-tuning innate-adaptive immune cell crosstalk. ILC2s mediate either pro- or anti-inflammatory immune responses in a context dependent manner. Inflammation has proven to be a key driver of atherosclerosis, resembling the key underlying pathophysiology of cardiovascular disease (CVD). Notably, numerous studies point towards an atheroprotective role of ILC2s e.g., by mediating secretion of type-II cytokines (IL-5, IL-13, IL-9). Boosting these protective responses may be suitable for promising future therapy, although these protective cues are currently incompletely understood. Additionally, little is known about the mechanisms by which chemokine/chemokine receptor signaling shapes ILC2 functions in vascular inflammation and atherosclerosis. Hence, this review will focus on the latest findings regarding the protective and chemokine/chemokine receptor guided interplay between ILC2s and other immune cells like T and B cells, dendritic cells and macrophages in atherosclerosis. Further, we will elaborate on potential therapeutic implications which result or could be distilled from the dialogue of ILC2s with cells of the immune system in cardiovascular diseases.

Not just fibrotic: endothelial-derived TGFβ maintains contractile function and lymphatic muscle phenotype during homeostasis.

Cell-cell communication within the lymphatic vasculature during homeostasis is incompletely detailed. Although many discoveries highlight the pathological roles of transforming growth factor-beta (TGFβ) in chronic vascular inflammation and associated fibrosis, only a small amount is known surrounding the role of TGFβ-signaling in homeostatic lymphatic function. Here, we discovered that pharmacological blockade of TGFβ receptor 1 (TGFβR1) negatively impacts rat mesenteric lymphatic vessel pumping, significantly reducing vessel contractility and surrounding lymphatic muscle coverage. We have identified mesenteric lymphatic endothelial cells themselves as a source of endogenous vascular TGFβ and that TGFβ production is significantly increased in these cells via activation of a number of functional pattern recognition receptors they express. We show that a continuous supply of TGFβ is essential to maintain the contractile phenotype of neighboring lymphatic muscle cells and support this conclusion through in vitro analysis of primary isolated lymphatic muscle cells that undergo synthetic differentiation during 2-D cell culture, a phenomenon that could be effectively rescued by supplementation with recombinant TGFβ. Finally, we demonstrate that lymphatic endothelial production of TGFβ is regulated, in part, by nitric oxide in a manner we propose is essential to counteract the pathological over-production of TGFβ. Taken together, these data highlight the essential role of homeostatic TGFβ signaling in the maintenance of lymphatic vascular function and highlight possible deleterious consequences of its inhibition.NEW & NOTEWORTHY The growth factor TGFβ is commonly associated with its pathological overproduction during tissue fibrosis rather than its homeostatic functions. We expose the lymphatic endothelium as a source of endogenous TGFβ, the impact of its production on the maintenance of surrounding lymphatic muscle cell phenotype, and internally regulated mechanisms of its production. Overall, these results highlight the intricate balance of TGFβ-signaling as an essential component of maintaining lymphatic contractile function.

Lemon extract supported green synthesis of bimetallic CuO/Ag nanoporous materials for sensitive detection of vitamin D3

In modern era, deficiency of Vitamin D3 is predominantly due to limited exposure to sunlight and UV radiation resulting from indoor lifestyles. Several studies have revealed that vitamin D deficiency can lead to chronic vascular inflammation, diabetes mellitus, hypertension, congestive left ventricular hypertrophy, and heart failure. This study introduces a green synthesis of novel bimetallic nanoporous composite, CuO/Ag using lemon extract. The synthesized nanoporous material, CuO/Ag@lemon extract was characterized using several analytical techniques, including X-ray diffraction (XRD), transmission electron microscopy (TEM), scanning electron microscopy (SEM), and energy-dispersive X-ray spectroscopy (EDX). The CuO/Ag@lemon extract nanoparticles were immobilized on glassy carbon electrode (GCE) to prepare modified CuO/Ag@lemon extract–GCE interface. The electrocatalytic and electrochemical properties investigation was carried out on the modified electrode. using cyclic voltammetry (CV), differential pulse voltammetry (DPV), and amperometry for detecting of Vitamin D3. The DPV method displayed a linear response range of 0.02–22.5 µM with a detection limit of 2.62 nM, while the amperometric method showed a broader linear range of 0.25–23.25 µM with a detection limit of 2.70 nM with 82% modified electrode stability. The designed electrode exhibited a positive response to the inclusion of Vitamin D3 with electro-oxidation, reaching steady-state within 3.4 s, with 87% reproducibility within a day. The proposed method offers a rapid and sensitive platform for detection of Vitamin D3 with minimal interference from other molecules. The early diagnosis of Vitamin D3 deficiency using modified electrodes allows for early treatment, thereby preventing severe health complications.

Therapeutic targeting of chronic kidney disease-associated DAMPs differentially contributing to vascular pathology.

Chronic Kidney Disease (CKD) is associated with markedly increased cardiovascular (CV) morbidity and mortality. Chronic inflammation, a hallmark of both CKD and CV diseases (CVD), is believed to drive this association. Pro-inflammatory endogenous TLR agonists, Damage-Associated Molecular Patterns (DAMPs), have been found elevated in CKD patients' plasma and suggested to promote CVD, however, confirmation of their involvement, the underlying mechanism(s), the extent to which individual DAMPs contribute to vascular pathology in CKD and the evaluation of potential therapeutic strategies, have remained largely undescribed. A multi-TLR inhibitor, soluble TLR2, abrogated chronic vascular inflammatory responses and the increased aortic atherosclerosis-associated gene expression observed in nephropathic mice, without compromising infection clearance. Mechanistically, we confirmed elevation of 4 TLR DAMPs in CKD patients' plasma, namely Hsp70, Hyaluronic acid, HMGB-1 and Calprotectin, which displayed different abilities to promote key cellular responses associated with vascular inflammation and progression of atherosclerosis in a TLR-dependent manner. These included loss of trans-endothelial resistance, enhanced monocyte migration, increased cytokine production, and foam cell formation by macrophages, the latter via cholesterol efflux inhibition. Calprotectin and Hsp70 most consistently affected these functions. Calprotectin was further elevated in CVD-diagnosed CKD patients and strongly correlated with the predictor of CV events CRP. In nephropathic mice, Calprotectin blockade robustly reduced vascular chronic inflammatory responses and pro-atherosclerotic gene expression in the blood and aorta. Taken together, these findings demonstrated the critical extent to which the DAMP-TLR pathway contributes to vascular inflammatory and atherogenic responses in CKD, revealed the mechanistic contribution of specific DAMPs and described two alternatives therapeutic approaches to reduce chronic vascular inflammation and lower CV pathology in CKD.

Non-Psychoactive Phytocannabinoids Inhibit Inflammation-Related Changes of Human Coronary Artery Smooth Muscle and Endothelial Cells.

Atherosclerosis is associated with vascular smooth muscle cell proliferation, chronic vascular inflammation, and leukocyte adhesion. In view of the cardioprotective effects of cannabinoids described in recent years, the present study investigated the impact of the non-psychoactive phytocannabinoids cannabidiol (CBD) and tetrahydrocannabivarin (THCV) on proliferation and migration of human coronary artery smooth muscle cells (HCASMC) and on inflammatory markers in human coronary artery endothelial cells (HCAEC). In HCASMC, CBD and THCV at nontoxic concentrations exhibited inhibitory effects on platelet-derived growth factor-triggered proliferation (CBD) and migration (CBD, THCV). When interleukin (IL)-1β- and lipopolysaccharide (LPS)-stimulated HCAEC were examined, both cannabinoids showed a concentration-dependent decrease in the expression of vascular cell adhesion molecule-1 (VCAM-1), which was mediated independently of classical cannabinoid receptors and was not accompanied by a comparable inhibition of intercellular adhesion molecule-1. Further inhibitor experiments demonstrated that reactive oxygen species, p38 mitogen-activated protein kinase activation, histone deacetylase, and nuclear factor κB (NF-κB) underlie IL-1β- and LPS-induced expression of VCAM-1. In this context, CBD and THCV were shown to inhibit phosphorylation of NF-κB regulators in LPS- but not IL-1β-stimulated HCAEC. Stimulation of HCAEC with IL-1β and LPS was associated with increased adhesion of monocytes, which, however, could not be significantly abolished by CBD and THCV. In summary, the results highlight the potential of the non-psychoactive cannabinoids CBD and THCV to regulate inflammation-related changes in HCASMC and HCAEC. Considering their effect on both cell types studied, further preclinical studies could address the use of CBD and THCV in drug-eluting stents for coronary interventions.

GV1001 Inhibits the Severity of the Ligature-Induced Periodontitis and the Vascular Lipid Deposition Associated with the Periodontitis in Mice.

GV1001, a 16 amino acid peptide derived from the catalytic segment of human telomerase reverse transcriptase, was developed as an anti-cancer vaccine. Subsequently, it was found to exhibit anti-inflammatory and anti-Alzheimer's disease properties. Periodontitis is a risk factor for a variety of systemic diseases, including atherosclerosis, a process in which chronic systemic and vascular inflammation results in the formation of plaques containing lipids, macrophages, foam cells, and tissue debris on the vascular intima. Thus, we investigated the effect of GV1001 on the severity of ligature-induced periodontitis, vascular inflammation, and arterial lipid deposition in mice. GV1001 notably reduced the severity of ligature-induced periodontitis by inhibiting gingival and systemic inflammation, alveolar bone loss, and vascular inflammation in wild-type mice. It also significantly lowered the amount of lipid deposition in the arterial wall in ApoE-deficient mice receiving ligature placement without changing the serum lipid profile. In vitro, we found that GV1001 inhibited the Receptor Activator of NF-κB ligand (RANKL)-induced osteoclast formation and tumor necrosis factor-α (TNF-α)-induced phenotypic changes in endothelial cells. In conclusion, our study suggests that GV1001 prevents the exacerbation of periodontitis and atherosclerosis associated with periodontitis partly by inhibiting local, systemic, and vascular inflammation and phenotypic changes of vascular endothelial cells.

MAVS signaling is required for preventing persistent chikungunya heart infection and chronic vascular tissue inflammation

Chikungunya virus (CHIKV) infection has been associated with severe cardiac manifestations, yet, how CHIKV infection leads to heart disease remains unknown. Here, we leveraged both mouse models and human primary cardiac cells to define the mechanisms of CHIKV heart infection. Using an immunocompetent mouse model of CHIKV infection as well as human primary cardiac cells, we demonstrate that CHIKV directly infects and actively replicates in cardiac fibroblasts. In immunocompetent mice, CHIKV is cleared from cardiac tissue without significant damage through the induction of a local type I interferon response from both infected and non-infected cardiac cells. Using mice deficient in major innate immunity signaling components, we found that signaling through the mitochondrial antiviral-signaling protein (MAVS) is required for viral clearance from the heart. In the absence of MAVS signaling, persistent infection leads to focal myocarditis and vasculitis of the large vessels attached to the base of the heart. Large vessel vasculitis was observed for up to 60 days post infection, suggesting CHIKV can lead to vascular inflammation and potential long-lasting cardiovascular complications. This study provides a model of CHIKV cardiac infection and mechanistic insight into CHIKV-induced heart disease, underscoring the importance of monitoring cardiac function in patients with CHIKV infections.

Escin ameliorates inflammation via inhibiting mechanical stretch and chemically induced Piezo1 activation in vascular endothelial cells

Escin is an active ingredient used in the treatment of phlebitis. However, the pharmacological mechanism of escin remains largely unclear. Here, we aimed to determine the molecular basis for the therapeutic effect of escin. Human umbilical vein endothelial cells (HUVECs) were subjected to shear-stress assays with or without escin. Intracellular Ca2+ levels, inflammatory factors and the activity of NF-κB were measured in endothelial cells (ECs) after mechanical-stretch or Yoda1 activation. Isometric tensions in aortic rings were identified. In addition, murine liver endothelial cells (MLECs) isolated from Piezo1 endothelial specific knockout mice (Piezo1△ EC) were used to explore the role of Piezo1. Our results showed that escin inhibited inflammatory factors, intracellular Ca2+ levels and Yoda1-evoked relaxation of thoracic aorta rings. Cell alignment induced by shear stress was inhibited by escin in HUVECs, and Piezo1 siRNA was used to show that this effect was dependent on Piezo1 channels. Moreover, escin reduced the inflammation and inhibited the activity of NF-κB in ECs with mechanical-stretch, which were insensitive to Piezo1 deletion. SN50, an NF-κB antagonist, significantly inhibited the mechanical stretch-induced inflammatory response. In addition, escin reduced inflammation in ECs subjected to mechanical-stretch, which was insensitive after using NF-κB antagonist. Collectively, our results demonstrate that escin inhibits the mechanical stretch-induced inflammatory response via a Piezo1-mediated NF-κB pathway. This study improves our understanding of a molecular target of escin that mediates its effect on chronic vascular inflammation.

Endothelial Gata6 deletion reduces monocyte recruitment and proinflammatory macrophage formation and attenuates atherosclerosis through Cmpk2-Nlrp3 pathways

Endothelial dysfunction results in chronic vascular inflammation, which is critical for the development of atherosclerotic diseases. Transcription factor Gata6 has been reported to regulate vascular endothelial cell activation and inflammation in vitro. Here, we aimed to explore the roles and mechanisms of endothelial Gata6 in atherogenesis.Endothelial cell (EC) specific Gata6 deletion was generated in the ApoeKO hyperlipidemic atherosclerosis mouse model. Atherosclerotic lesion formation, endothelial inflammatory signaling, and endothelial-macrophage interaction were examined in vivo and in vitro by using cellular and molecular biological approaches. EC-GATA6 deletion mice exhibited a significant decrease in monocyte infiltration and atherosclerotic lesion compared to littermate control mice. Cytosine monophosphate kinase 2 (Cmpk2) was identified as a direct target gene of GATA6 and EC-GATA6 deletion decreased monocyte adherence, migration and pro-inflammatory macrophage foam cell formation through regulation of the CMPK2-Nlrp3 pathway. Endothelial target delivery of Cmpk2-shRNA by intercellular adhesion molecule 2 (Icam-2) promoter-driven AAV9 carrying the shRNA reversed the Gata6 upregulation mediated elevated Cmpk2 expression and further Nlrp3 activation and thus attenuated atherosclerosis. In addition, C–C motif chemokine ligand 5 (Ccl5) was also identified as a direct target gene of Gata6 to regulate monocyte adherence and migration influencing atherogenesis.This study provides direct in vivo evidence of EC-GATA6 involvement in the regulation of Cmpk2-Nlrp3, as well as Ccl5, on monocyte adherence and migration in atherosclerosis development and advances our understanding of the in vivo mechanisms of atherosclerotic lesion development, and meanwhile provides opportunities for future therapeutic interventions.

The role of 14-3-3 in the progression of vascular inflammation induced by lipopolysaccharide.

To explore the role of 14-3-3 protein and the Hippo and yes-associated protein 1 (YAP) signaling pathway in lipopolysaccharide (LPS)-induced vascular inflammation. Human umbilical vein endothelial cells (HUVECs) and C57B6 mice were treated with LPS to establish cell and animal models of vascular inflammation. Lentiviral transfection, Western blot, qPCR, immunofluorescence, immunohistochemistry, co-immunoprecipitation, and enzyme-linked immunosorbent assays were used to measure inflammatory factors and expression of 14-3-3 protein and phosphorylation of YAP at S127. HUVECs and C57B6 mice were pretreated with a YAP inhibitor, Verteporfin, to observe changes in YAP expression and downstream vascular inflammation. LPS induced acute and chronic inflammatory responses in HUVECs and mice and upregulated the expression of several inflammatory factors. LPS also induced expression of 14-3-3 protein and phosphorylation of YAP at S127 in response to acute vascular inflammation and downregulated these markers in response to chronic vascular inflammation. Verteporfin reduced these LPS-induced effects on vascular inflammation. In chronic vascular inflammation, 14-3-3 protein is downregulated, which promotes inflammation by increasing Hippo/YAP nuclear translocation.

Inhibition of MAOB Ameliorated High-Fat-Diet-Induced Atherosclerosis by Inhibiting Endothelial Dysfunction and Modulating Gut Microbiota.

In this study, monoamine oxidase B (MAOB) was activated under pathological conditions, and was the novel source of cardiovascular reactive oxygen species (ROS). ROS-induced endothelial dysfunction results in sustained and chronic vascular inflammation, which is central to atherosclerotic diseases. However, whether MAOB regulates endothelial oxidative stress and its related mechanism and whether gut microbiota mediates the anti-atherosclerosis effect of MAOB inhibitor remains unclear. In our study, MAOB expressions were elevated in high-fat diet (HFD) fed mice aortas, but only in vascular endothelial cells (not in smooth muscle cells). MAOB small interfering RNA significantly attenuated the palmitic-acid (PA)-induced endothelial oxidative stress and dysfunction. Furthermore, RNA-sequencing data revealed that MAOB knockdown decreased the levels of proinflammatory and apoptotic gene induced by PA. Microarray analysis and qPCR assay showed that miR-3620-5p was significantly decreased under the HFD condition. The dual-luciferase reporter, Western blot and qPCR assay confirmed that miR-3620-5p directly regulated MAOB by binding to its mRNA 3'UTR. Moreover, inhibition of MAOB by selegiline significantly ameliorated endothelial dysfunction and reduced atherosclerotic burden in HFD-fed ApoE-/- mice. Finally, 16S rRNA sequencing showed that selegiline significantly altered the community compositional structure of gut microbiota. Specifically, selegiline treatment enriched the abundance of Faecalibaculum and Akkermansia, decreased the abundance of unclassified_f__Lachnospiraceae, Desulfovibrio, and Blautia, and these genera were significantly correlated with the serum biochemical indices. Taken together, our findings showed that MAOB controlled endothelial oxidative stress homeostasis, and revealed the anti-atherosclerotic effect of selegiline by ameliorating endothelial dysfunction and modulating the composition and function of gut microbiota.

Immunophenotyping of Monocyte Migration Markers and Therapeutic Effects of Selenium on IL-6 and IL-1β Cytokine Axes of Blood Mononuclear Cells in Preoperative and Postoperative Coronary Artery Disease Patients.

Multivessel coronary artery disease (CAD) is characterized by underlying chronic vascular inflammation and occlusion in the coronary arteries, where these patients undergo coronary artery bypass grafting (CABG). Since post-cardiotomy inflammation is a well known phenomenon after CABG, attenuation of this inflammation is required to reduce perioperative morbidity and mortality. In this study, we aimed to phenotype circulating frequencies and intensities of monocyte subsets and monocyte migration markers, respectively, and to investigate the plasma level of inflammatory cytokines and chemokines between preoperative and postoperative CAD patients and later, to intervene the inflammation with sodium selenite. We found a higher amplitude of inflammation, postoperatively, in terms of CCR1high monocytes and significantly increased pro-inflammatory cytokines, IL-6, IL-8, and IL-1RA. Further, in vitro intervention with selenium displayed mitigating effects on the IL-6/STAT-3 axis of mononuclear cells derived from postoperative CAD patients. In addition, in vitro selenium intervention significantly reduced IL-1β production as well as decreased cleaved caspase-1 (p20) activity by preoperative (when stimulated) as well as postoperative CAD mononuclear cells. Though TNF-α exhibited a positive correlation with blood troponin levels in postoperative CAD patients, there was no obvious effect of selenium on the TNF-α/NF-κB axis. In conclusion, anti-inflammatory selenium might be utilized to impede systemic inflammatory cytokine axes to circumvent aggravating atherosclerosis and further damage to the autologous bypass grafts during the post-surgical period.

Hedgehog-induced ZFYVE21 promotes chronic vascular inflammation by activating NLRP3 inflammasomes in T cells.

The zinc finger protein ZFYVE21 is involved in immune signaling. Using humanized mouse models, primary human cells, and patient samples, we identified a T cell-autonomous role for ZFYVE21 in promoting chronic vascular inflammation associated with allograft vasculopathy. Ischemia-reperfusion injury (IRI) stimulated endothelial cells to produce Hedgehog (Hh) ligands, which in turn induced the production of ZFYVE21 in a population of T memory cells with high amounts of the Hh receptor PTCH1 (PTCHhi cells, CD3+CD4+CD45RO+PTCH1hiPD-1hi), vigorous recruitment to injured endothelia, and increased effector responses in vivo. After priming by interferon-γ (IFN-γ), Hh-induced ZFYVE21 activated NLRP3 inflammasome activity in T cells, which potentiated IFN-γ responses. Hh-induced NLRP3 inflammasomes and T cell-specific ZFYVE21 augmented the vascular sequelae of chronic inflammation in mice engrafted with human endothelial cells or coronary arteries that had been subjected to IRI before engraftment. Moreover, the population of PTCHhi T cells producing high amounts of ZFYVE21 was expanded in patients with renal transplant-associated IRI, and sera from these patients expanded this population in control T cells in a manner that depended on Hh signaling. We conclude that Hh-induced ZFYVE21 activates NLRP3 inflammasomes in T cells, thereby promoting chronic inflammation.

Endothelial Dysfunction in Neurodegenerative Diseases.

The cerebral vascular system stringently regulates cerebral blood flow (CBF). The components of the blood-brain barrier (BBB) protect the brain from pathogenic infections and harmful substances, efflux waste, and exchange substances; however, diseases develop in cases of blood vessel injuries and BBB dysregulation. Vascular pathology is concurrent with the mechanisms underlying aging, Alzheimer's disease (AD), and vascular dementia (VaD), which suggests its involvement in these mechanisms. Therefore, in the present study, we reviewed the role of vascular dysfunction in aging and neurodegenerative diseases, particularly AD and VaD. During the development of the aforementioned diseases, changes occur in the cerebral blood vessel morphology and local cells, which, in turn, alter CBF, fluid dynamics, and vascular integrity. Chronic vascular inflammation and blood vessel dysregulation further exacerbate vascular dysfunction. Multitudinous pathogenic processes affect the cerebrovascular system, whose dysfunction causes cognitive impairment. Knowledge regarding the pathophysiology of vascular dysfunction in neurodegenerative diseases and the underlying molecular mechanisms may lead to the discovery of clinically relevant vascular biomarkers, which may facilitate vascular imaging for disease prevention and treatment.