Inflammatory Vascular Disease Research Articles

Creation of an Atherosclerosis Model Using Palmitic Acid and Oleic Acid in the Vascular Smooth Muscle Cells of Rats.

Atherosclerosis (AS) is a chronic vascular inflammatory disease resulting from vascular endothelial injury and lipid deposition, closely linked to abnormal lipid metabolism within the body. The critical processes involved in atherosclerosis encompass lipid deposition, oxidation, metabolic disruptions, and inflammatory stimulation within the inner vessel wall. Lipid deposition emerges as a pivotal factor triggering these pathological changes, with vascular smooth muscle cells (VSMCs) playing a significant role in the development of AS. Therefore, the goal was to employ lipids, specifically palmitic acid (PA) and oleic acid (OA) solutions, to stimulate VSMCs and create an in vitro atherosclerosis model. This approach allows for the establishment of a rapid and efficient cell model for simulating atherosclerosis in vitro. Primary vascular smooth muscle cells (VSMCs) were isolated and cultured from the thoracic aorta of healthy rats using the tissue-block method. VSMCs were identified through cell climbing slices and immunofluorescence. The growth of VSMCs was observed using light microscopy. The logarithmic growth phase of VSMCs was induced and stimulated by various concentrations of palmitic acid (PA) and oleic acid (OA) ranging from 0 to 650 μmol/L, with a gradient dilution of 50 μmol/L. VSMC activity was assessed using the 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Intracellular lipid deposition was visualized through Oil Red O staining. The levels of total cholesterol (TC), triglyceride (TG), high-density lipoprotein-cholesterol (HDL-C), and low-density lipoprotein-cholesterol (LDL-C) within VSMCs were quantified using commercially available kits. The optimal conditions for VSMC proliferation were determined to be an OA concentration of 500 μmol/L, a PA concentration of 300 μmol/L, and a culture duration of 48 hours. In comparison to the control group, the presence of lipid droplets within VSMCs became significantly evident following treatment with OA or PA. Furthermore, the levels of TC, TG, and LDL-C increased, while the HDL-C content decreased after treatment with OA or PA. A research model for atherosclerosis (AS) and the early stages of cardiovascular events, specifically lipid deposition, was successfully established through the use of OA and PA solutions. This model has the potential to open up new research avenues for gaining a deeper understanding of the pathogenesis and progression of AS.

Effects of Banxia Baizhu Tianma Decoction in alleviating atherosclerosis based on the regulation of perivascular adipose

Ethnopharmacological relevanceThe occurrence and development of atherosclerosis, a common chronic inflammatory vascular disease, are closely related to cardiovascular and cerebrovascular diseases. Banxia Baizhu Tianma Decoction (BBTD) is a representative traditional Chinese medicine formula that resolves phlegm, disperses wind, invigorates the spleen and eliminates dampness and is also a commonly used clinical medication for treating vascular diseases. Aim of the studyTo explore the pharmacological mechanisms of BBTD in alleviating atherosclerosis, the present study was carried out by conducting an integrative analysis of aortic and perivascular adipose tissue (PVAT) proteomics and metabolomics. Materials and methodsEight-week-old ApoE-/- mice were randomly divided into the BBTD group and the model group, and nine age-matched C57BL/6J (C57) mice were used as the control group (n = 9). The C57 mice were fed a standard diet, while the ApoE-/- mice were fed a high-fat, high-cholesterol diet for 12 weeks. Mice in the BBTD group were transgastrically administered BBTD at a dose of 17.8 g/kg/day for 8 weeks, while the model group and control group mice received an equivalent volume of saline by gavage. Histomorphology of the aortas and PVAT was assessed by HE staining, oil red O staining, Masson staining, and α-SMA and CD68 immunohistochemical methods. An integrative analysis of aortic proteomics, PVAT proteomics and PVAT metabolomics was conducted to study the pharmacological mechanisms of BBTD. ResultsCompared to the model group, mice treated with BBTD had thicker fibrous caps, increased collagen content, less erosion of smooth muscle cells and infiltration of macrophages, as well as a relatively low inflammatory response level, suggesting that BBTD treatment reduced plaque vulnerability. Omics analysis suggested that BBTD treatment demonstrated anti-atherosclerotic effects and increased plaque stability in the aorta by activating the TGF-beta pathway. Simultaneously, BBTD inhibited PVAT inflammation levels (decreased the levels of MCP and IL-6). Proteomics and metabolomics of PVAT suggested that the targets of BBTD included upregulation of the α-linolenic acid metabolic pathway and downregulation of multiple inflammatory pathways, such as the NF-kappa B signalling pathway, primary immunodeficiency and Th17 cell differentiation in PVAT. ConclusionsBBTD reduces the vulnerability of atherosclerotic plaques and inhibits the inflammatory phenotype of perivascular adipose tissue.

Evaluation of Uric Acid to Albumin Ratio as a Marker of Coronary Artery Disease Severity in Acute Coronary Syndrome: A Cross-Sectional Study.

Coronary artery disease (CAD) is a widespread cause of morbidity and mortality. Serum uric acid, a mediator of endothelial dysfunction and inflammation in vascular disease, can increase the risk of atherosclerosis, contributing to CAD. As serum albumin inhibits platelet activation and aggregation, low levels of it can contribute to platelet-induced coronary artery stenosis. Limited studies have been conducted worldwide in evaluating the role of uric acid to albumin ratio (UAR) in predicting severity or poor outcomes in acute coronary syndrome (ACS) patients. This study was undertaken to assess the role of UAR as a predictor of CAD severity, which can facilitate the identification of high-risk patients. A hospital-based analytical cross-sectional study was conducted in an urban tertiary healthcare center for a period of two months between June and August of 2022. A total of 100 ACS patients were included in the study. The study population included patients above the age of 18 years diagnosed with ACS who underwent a coronary angiography. Coronary angiograms were used to diagnose the presence of CAD, and its severity was assessed using Synergy between Percutaneous Coronary Intervention with Taxus and Cardiac Surgery (SYNTAX) scores (SS). The correlation of UAR with CAD severity using SS was studied and compared between three varieties of ACS: ST-elevation myocardial infarction (STEMI), non-ST-elevation myocardial infarction (NSTEMI), and unstable angina (UA). Chi-squared tests were used to determine statistical significance for qualitative data.Independent t-tests were used to identify the mean difference between two quantitative variables. Receiver operating characteristic (ROC) curves were constructed for UAR and high SS. A comparison between UAR and neutrophil to lymphocyte ratio (NLR) as a predictor of disease severity was done.ROC and optimal cutoff points were chosen to calculate sensitivity, specificity, and positive and negative predictive values. Microsoft Excel (Microsoft, Redmond, WA, USA) and SPSS V22.0(IBM Corp., Armonk, NY, USA) were used to analyze the data. A total of 100 ACS patients were included in the study and divided into two groups on the basis of SS, with 74% showing low severity and 26% showing intermediate-high severity. There was a statistically significant difference found between older age and SS (p=0.017). Our study showed 74% (n=74) of the patients were male and 26% (n=26) were female. It also revealed that 75.7% (n=56) of the male patients were in the low-severity group, and 24.3% (n=18) of males were in the intermediate-high severity group. 69.2% (n=18) of the female patients were in the low-severity group, and 30.8% (n=8) were in the intermediate-high severity group. Of the 100 patients, 55% were diagnosed with STEMI, of which 69.1% were in the low-severity group, and 30.9% were in the intermediate-high severity group. Among all the patients 33% of the patients were diagnosed as NSTEMI, of which 72.7% were in the low-severity group, and 27.3% were in the intermediate-high severity group. Twelve percent of the patients were diagnosed with UA, and 100% of these patients were in the low-severity group. The mean UAR was 1.40 ± 0.38 in the low-severity group and 1.29 ± 0.46 in the intermediate-high severity group (p=0.22). Our study yielded no statistically significant difference in UAR among varying severities of CAD.

Knowledge Mapping of Global Status and Trends for Thromboangiitis Obliterans: A Bibliometrics and Visual Analysis.

Thromboangiitis obliterans (TAO) is a segmental nonatherosclerotic inflammatory vascular disease characterized by recurrent progressive inflammatory reactions and thrombosis in the small and medium-sized arteries and veins of the extremities. However, there are few bibliometric studies on TAO. Therefore, this study was employed to generalize the research status, hotspots and development trends of TAO-related research. The data from 1999 to 2022 were collected from the Web of Science core collection database, and analyzed through bibliometrics software. VOSviewer was utilized to carry out academic collaboration between different countries/regions, institutions, and authors, visualization map of co-cited authors, journals, reference, and co-occurring keywords. CiteSpace was used to analyze the dual-map of journals, keyword bursts, and timeline of keywords. Bar and pie charts in this study were statistically analyzed and graphed through Microsoft Excel 2021. Scimago Graphica was applied to map the academic collaboration between different countries/regions. A total of 553 literatures were involved in this study. Japan at the leading global position not only in the number of publications, but also total citations, average citations and H-index. Institution with the major contribution to TAO research is Mashhad University of Medical Sciences, and Nagoya University. Annals of Vascular Surgery, Angiology, Journal of Vascular Surgery are the main publication channel for articles related to TAO. Fazeli, B., Iwai, T., and Kihara, Y. are major contributors in this field. The studies on TAO keywords could be grouped into four clusters: Etiology, Mechanism, Cell therapy and Clinical therapy. Although the number of TAO publications has fluctuated over the past 20 years, it has generally shown a steady upward trend. Etiology and treatment research on TAO and some keywords such as trail, therapy, outcome, management, stem cells, angioplasty, and activation will become a hot spot in the future.

Exploring the mechanism of atherosclerosis and the intervention of traditional Chinese medicine combined with mesenchymal stem cells based on inflammatory targets

Atherosclerosis (AS) is a chronic inflammatory vascular disease, which is the common pathological basis of cardiovascular and cerebrovascular diseases. The immune inflammatory response throughout the course of AS has been evidenced by studies, in which a large number of immune cells and inflammatory factors play a crucial role in the pathogenesis of AS. The inflammation related to AS is mainly mediated by inflammatory cytokines (IL-1β, IL-6, IL-18, TNF-α, hs-CRP, SAA), inflammatory enzymes (Lp-PLA2, sPLA2-IIA, MMPs), and inflammatory signaling pathways (P38 MAPK signaling pathway, NF-κB signaling pathway, TLR2/4 signaling pathway). It is involved in the pathophysiological process of AS, and the degree of inflammation measured by it can be used to evaluate the risk of progression of AS plaque instability. In recent years, traditional Chinese medicine (TCM) has shown the advantage of minimal side effects in immune regulation and has made some progress in the prevention and treatment of AS. Mesenchymal stem cells (MSCs), as self-renewal, highly differentiated, and pluripotent stem cells with anti-inflammatory properties and immune regulation, have been widely used for AS treatment. They also play an important inflammation-immune regulatory function in AS. Notably, in terms of regulating immune cells and inflammatory factors, compared with TCM and its compound, the combination therapy has obvious anti-inflammatory advantages over the use of MSCs alone. It is an important means to further improve the efficacy of AS and provides a new way for the prevention and treatment of AS.

Airborne magnetite nanoparticles induced early vascular pathologies by disrupting lipid metabolism under high-fat dietary patterns.

Magnetite nanoparticles (MNPs) have been extensively detected in the atmospheric environment and implicated as a prominent threat to atherosclerosis, a chronic vascular inflammatory disease. Due to globalization and economic development, the dramatic shift in diet from traditional to high-fat dietary patterns aggravated atherosclerosis progression induced by environmental factors. However, limited knowledge is available regarding vascular risks and underlying mechanisms of airborne MNPs in high-risk populations with high-fat dietary habits. Herein, we demonstrated that MNPs exerted a proatherogenic effect under high-fat dietary patterns, leading to aortic wall thickening, elastic fiber disorganization, macrophage infiltration, and local inflammation. Based on the correlation analysis between MNPs and PM group, we identified that MNPs might be a key PM component in atherogenic toxicity. MNPs exposure disturbed the dynamic process of lipid metabolism, manifested as aortic lipid accumulation, dyslipidemia, and hepatic lipid metabolism disorder, which was modulated by the JAK-STAT pathway. Overall, these findings provide new insight into understanding the cardiovascular risks and mechanisms of MNPs among high-risk populations.

Current modalities for the diagnostic and management approach of buerger’s disease: a case report and comprehensive review

Background: Thromboangiitis obliterans (TAO or Buerger’s disease) is a non-atherosclerotic inflammatory vascular disease usually related to smoking. Until now, there is no consensus establishing the diagnosis and standard treatment. Case Illustration: A 74-year-old smoker woman complained of blackening and painful fingertips in both upper limbs. On upper-extremities examination, we found necrotic gangrene at the 3rd fingertips of the right hand, and the 2nd and 4th fingertips of the left hand, with limitation of the movement at the affected finger due to the pain. On laboratory findings, there was a leukocytosis, mild Anemia, no coagulopathy, and normal autoimmune screening. Doppler Ultrasonography showed vascular incompetence of the left palmar arch artery, with no deep or superficial vein thrombosis. Arteriography revealed multiple stenosis of the Left Radial artery and Right Ulnar artery with collateral corkscrew-shaped. The patient was diagnosed with peripheral Critical Limb Threatening Ischemia caused by TAO, which underwent conservative management for 10 days and Percutaneous Trans Angioplasty (PTA) ballooning. Discussion: Buerger disease commonly affects smoker men between 40-45 years old. Several clinical criteria were used to establish TAO, including Shinoya and Olin's criteria. There are still no specific management guidelines for TAO, and smoking cessation is the only accepted effective treatment to prevent the progression of the disease and avoid amputation, followed by conservative and interventional management for patients with Critical Limb Ischemia. Conclusions: Awareness of the entity and familiarity with the clinical, angiographic, and pathologic features are the keys to a prompt and correct diagnosis of TAO. Although still controversial, endovascular intervention is regarded as a potentially efficacious approach in TAO with critical limb ischemia management.

Senescent CD153+ T Lymphocytes Increase in the Peripheral Blood of Patients with Thromboangiitis Obliterans.

Buerger's disease, also known as Thromboangiitis Obliterans (TAO), is a progressive, inflammatory vascular disease with unknown etiology. To address the degree of T cell immunosenescence in this inflammatory disease, the frequency of senescent T cells expressing CD57 and/or CD153 (CD30L) in patients with TAO. In this study, nine male cigarette smoker patients with TAO, nine male healthy cigarette smokers, and nine male healthy non-smoker blood donors were enrolled. PBMCs were extracted from the blood of all participants and stored in liquid nitrogen before use. The percentages of senescent T cells were detected by flow cytometry. The results were analyzed using non-parametric statistical tests. The frequencies of senescent CD3+CD4+CD57+CD153+ and CD3+CD4+CD57-CD153+ T cells significantly increased in patients compared with the non-smoker controls (p=0.01 and p=0.04, respectively). The frequency of senescent CD3+CD4-CD57-CD153+ T cells was higher in patients compared with the smoker controls (p=0.02). In patients with TAO, CD57+CD153- cells were more frequent in CD3hiCD4- and CD3hiCD4+ T cells compared with the CD3loCD4- and CD3loCD4+ T cells (p=0.008 and p=0.0002, respectively). Conversely, the frequency of CD57-CD153+ T cells was significantly higher in CD3loCD4- T cells compared with the CD3hiCD4- T cells (p=0.004). The percentage of CD3+CD4+CD57+CD153- T cells correlated negatively with smoking level in smoker controls (p=0.02, Spearman r=-0.80). Elevated frequencies of senescent CD4+CD57+CD153+ and CD4+CD57-CD153+ T cells in patients compared with non-smoker and smoker controls suggest the contribution of immunosenescence in TAO.

The Roles of Periodontal Bacteria in Atherosclerosis.

Atherosclerosis (AS) is an inflammatory vascular disease that constitutes a major underlying cause of cardiovascular diseases (CVD) and stroke. Infection is a contributing risk factor for AS. Epidemiological evidence has implicated individuals afflicted by periodontitis displaying an increased susceptibility to AS and CVD. This review concisely outlines several prevalent periodontal pathogens identified within atherosclerotic plaques, including Porphyromonas gingivalis, Aggregatibacter actinomycetemcomitans, and Fusobacterium nucleatum. We review the existing epidemiological evidence elucidating the association between these pathogens and AS-related diseases, and the diverse mechanisms for which these pathogens may engage in AS, such as endothelial barrier disruption, immune system activation, facilitation of monocyte adhesion and aggregation, and promotion of foam cell formation, all of which contribute to the progression and destabilization of atherosclerotic plaques. Notably, the intricate interplay among bacteria underscores the complex impact of periodontitis on AS. In conclusion, advancing our understanding of the relationship between periodontal pathogens and AS will undoubtedly offer invaluable insights and potential therapeutic avenues for the prevention and management of AS.

Biomimetic nanoparticles targeting atherosclerosis for diagnosis and therapy

AbstractAtherosclerosis is a typical chronic inflammatory vascular disease that seriously endangers human health. At present, oral lipid‐lowering or anti‐inflammatory drugs are clinically used to inhibit the development of atherosclerosis. However, traditional oral drug treatments have problems such as low utilization, slow response, and serious side effects. Traditional nanodrug delivery systems are difficult to interactively recognize by normal biological organisms, and it is difficult to target the delivery of drugs to target lesions. Therefore, building a biomimetic nanodrug delivery system with targeted drug delivery based on the pathological characteristics of atherosclerosis is the key to achieving efficient and safe treatment of atherosclerosis. In this review, various nanodrug delivery systems that can target atherosclerosis are summarized and discussed. In addition, the future prospects and challenges of its clinical translation are also discussed.

Injectable liposomal docosahexaenoic acid alleviates atherosclerosis progression and enhances plaque stability

Atherosclerosis is a chronic inflammatory vascular disease that is characterized by the accumulation of lipids and immune cells in plaques built up inside artery walls. Docosahexaenoic acid (DHA, 22:6n-3), an omega-3 polyunsaturated fatty acid (PUFA), which exerts anti-inflammatory and antioxidant properties, has long been purported to be of therapeutic benefit to atherosclerosis patients. However, large clinical trials have yielded inconsistent data, likely due to variations in the formulation, dosage, and bioavailability of DHA following oral intake. To fully exploit its potential therapeutic effects, we have developed an injectable liposomal DHA formulation intended for intravenous administration as a plaque-targeted nanomedicine. The liposomal formulation protects DHA against chemical degradation and increases its local concentration within atherosclerotic lesions. Mechanistically, DHA liposomes are readily phagocytosed by activated macrophages, exert potent anti-inflammatory and antioxidant effects, and inhibit foam cell formation. Upon intravenous administration, DHA liposomes accumulate preferentially in atherosclerotic lesional macrophages and promote polarization of macrophages towards an anti-inflammatory M2 phenotype, resulting in attenuation of atherosclerosis progression in both ApoE−/− and Ldlr−/− experimental models. Plaque composition analysis demonstrates that liposomal DHA inhibits macrophage infiltration, reduces lipid deposition, and increases collagen content, thus improving the stability of atherosclerotic plaques against rupture. Matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) further reveals that DHA liposomes can partly restore the complex lipid profile of the plaques to that of early-stage plaques. In conclusion, DHA liposomes offer a promising approach for applying DHA to stabilize atherosclerotic plaques and attenuate atherosclerosis progression, thereby preventing atherosclerosis-related cardiovascular events.

The S100B Protein: A Multifaceted Pathogenic Factor More Than a Biomarker.

S100B is a calcium-binding protein mainly concentrated in astrocytes in the nervous system. Its levels in biological fluids are recognized as a reliable biomarker of active neural distress, and more recently, mounting evidence points to S100B as a Damage-Associated Molecular Pattern molecule, which, at high concentration, triggers tissue reactions to damage. S100B levels and/or distribution in the nervous tissue of patients and/or experimental models of different neural disorders, for which the protein is used as a biomarker, are directly related to the progress of the disease. In addition, in experimental models of diseases such as Alzheimer's and Parkinson's diseases, amyotrophic lateral sclerosis, multiple sclerosis, traumatic and vascular acute neural injury, epilepsy, and inflammatory bowel disease, alteration of S100B levels correlates with the occurrence of clinical and/or toxic parameters. In general, overexpression/administration of S100B worsens the clinical presentation, whereas deletion/inactivation of the protein contributes to the amelioration of the symptoms. Thus, the S100B protein may be proposed as a common pathogenic factor in different disorders, sharing different symptoms and etiologies but appearing to share some common pathogenic processes reasonably attributable to neuroinflammation.

Pro-inflammatory cytokines mediating senescence of vascular endothelial cells in atherosclerosis.

Atherosclerosis (AS) is a chronic inflammatory vascular disease, and aging is a major risk factor. The accumulation of senescent vascular endothelial cells (VECs) often leads to chronic inflammation and oxidative stress and induces endothelial dysfunction, contributing to the occurrence and development of AS. Senescent cells can secrete a variety of pro-inflammatory cytokines to induce the senescence of adjacent cells in a paracrine manner, leading to the transmission of signaling of cellular senescence to neighboring cells and the accumulation of senescent cells. Recent studies have demonstrated that several pro-inflammatory cytokines, including IL-17, TNF-α, and IFN-γ, can induce the senescence of VECs. This review summarizes and focuses on the pro-inflammatory cytokines that often induce the senescence of VECs and the molecular mechanisms of these pro-inflammatory cytokines inducing senescence of VECs. Targeting the senescence of VECs induced by pro-inflammatory cytokines may provide a potential and novel strategy for the prevention and treatment of AS.

Hydrogen sulfide attenuates TMAO‑induced macrophage inflammation through increased SIRT1 sulfhydration.

Chronic inflammation is a key factor that accelerates the progression of inflammatory vascular disease. Hydrogen sulfide (H2S) has potent anti‑inflammatory effects; however, its underlying mechanism of action has not been fully elucidated. The present study aimed to investigate the potential effect of H2S on sirtuin 1 (SIRT1) sulfhydration in trimethylamine N‑oxide (TMAO)‑induced macrophage inflammation, and its underlying mechanism. Pro‑inflammatory M1 cytokines (MCP‑1, IL‑1β, and IL‑6) and anti‑inflammatory M2 cytokines (IL‑4 and IL‑10) were detected by RT‑qPCR. CSE, p65 NF‑κB, p‑p65 NF‑κB, IL‑1β, IL‑6 and TNF‑α levels were measured by Western blot. The results revealed that cystathionine γ‑lyase protein expression was negatively associated with TMAO‑induced inflammation. Sodium hydrosulfide (a donor of H2S) increased SIRT1 expression and inhibited the expression of inflammatory cytokines in TMAO‑stimulated macrophages. Furthermore, nicotinamide, a SIRT1 inhibitor, antagonized the protective effect of H2S, which contributed to P65 NF‑κB phosphorylation and upregulated the expression of inflammatory factors in macrophages. H2S ameliorated TMAO‑induced activation of the NF‑κB signaling pathway via SIRT1 sulfhydration. Moreover, the antagonistic effect of H2S on inflammatory activation was largely eliminated by the desulfhydration reagent dithiothreitol. These results indicated that H2S may prevent TMAO‑induced macrophage inflammation by reducing P65 NF‑κB phosphorylation via the upregulation and sulfhydration of SIRT1, suggesting that H2S may be used to treat inflammatory vascular diseases.

Clinical characteristics and outcomes of children with Kawasaki disease combined with sepsis in the pediatric intensive care unit.

Kawasaki disease (KD) is a vascular inflammatory disease with unknown pathogenesis. There are few studies on KD combined with sepsis worldwide. To provide valuable data regarding clinical characteristics and outcomes related to pediatric patients with KD combined with sepsis in pediatric intensive care unit (PICU). We retrospectively analyzed the clinical data of 44 pediatric patients admitted in PICU at Hunan Children's Hospital with KD combined with sepsis between January 2018 and July 2021. Of the 44 pediatric patients (mean age, 28.18 ± 24.28 months), 29 were males and 15 were female. We further divided the 44 patients into two groups: KD combined with severe sepsis (n=19) and KD combined with non-severe sepsis (n=25). There were no significant between-group differences in leukocyte, C-reactive protein, and erythrocyte sedimentation rate. Interleukin-6, interleukin-2, interleukin-4 and procalcitonin in KD with severe sepsis group were significantly higher than those in KD with non-severe sepsis group. And the percentage of suppressor T lymphocyte and natural killer cell in severe sepsis group were significantly higher than those in non-severe group, while the CD4+/CD8+ T lymphocyte ratio was significantly lower in KD with severe sepsis group than in KD with non-severe sepsis group. All 44 children survived and were successfully treated after intravenous immune globulin (IVIG) combined with antibiotics. Children who develop with KD combined with sepsis have different degrees of inflammatory response and cellular immunosuppression, and the degree of inflammatory response and cellular immunosuppression is significantly correlated with the severity of the disease.

LncRNA PVT1 inhibits endothelial cells apoptosis in coronary heart disease through regulating MAPK1 expression via miR-532-3p

Background: Coronary atherosclerotic heart disease (CAD) is an inflammatory vascular disease caused by atherosclerosis. Long non-coding RNAs are involved in the pathophysiological process of coronary heart disease. Here we investigated the regulatory effects of lncRNA PVT1 (PVT1) in human coronary artery endothelial cells (HCAECs). Methods: qRT-PCR and western blot were performed to detect gene and protein expressions. CCK-8, flow cytometry and wound healing assays were used to determine cell viability, apoptosis and migration of HCAECs. The binding relationship among miR-532-3p, PVT1 and MAPK1 was verified by dual luciferase reporter assay. Results: Overexpression of PVT1 markedly reduced cell apoptosis and increased cell proliferation and migration. However, miR-532-3p upregulation suppressed cell proliferation and migration and promoted apoptosis of HCAECs. PVT1 suppressed the expression of miR-532-3p via directly targeting miR-532-3p. And miR-532-3p overexpression abolished the effect of PVT1 upregulation on proliferation and apoptosis in HCAECs. Furthermore, MAPK1 acted as a target gene of miR-532-3p and miR-532-3p inhibited MAPK1 expression. Conclusion: PVT1 promoted MAPK1 expression by targeting miR-532-3p, thus inhibiting HCAECs apoptosis and promoting cell proliferation, suggesting PVT1 might have great potential as a therapeutic target for CAD.

IgG4 related disease: a novel association with hypertrophic osteoarthropathy

IgG4 related disease (IgG4-RD) is a recently recognized disease that has several associated clinical phenotypes including autoimmune pancreatitis, sclerosing cholangitis, major salivary gland enlargement (Mikulicz disease), orbital pseudotumor, retroperitoneal fibrosis, and inflammatory vascular disease manifesting as aortitis or coronary artery calcification. Histopathology of affected organs shows lymphoplasmacytic infiltrations with a predominance of IgG4-positive plasma cells in the affected tissue and an increased number of eosinophils. Serum IgG4 levels are elevated in two-thirds of patients, and IgE is also often elevated. We report here the first known associated case of presumed IgG4-RD with hypertrophic osteoarthropathy. Hypertrophic osteoarthropathy (HOA) is frequently a paraneoplastic disease of bone, but HOA can be associated with chronic infection, chronic pulmonary disease, cardiac shunts, and cirrhosis. HOA is a clinical diagnosis consisting of arthralgia, digital clubbing, and periostosis of tubular bones seen on imaging with or without synovial effusion. Our 35 yo male LatinX patient presented with typical clinical symptoms of HOA that were confirmed on imaging. During the negative work up for malignancy, disproportionate-for-age coronary artery calcification was identified, which prompted an evaluation for IgG4-RD. The patient also had lung disease (peribronchial thickening), atopic dermatitis, subtle clubbing, elevated IgE, elevated IgG4 (9× normal), and eosinophilia. The patient's symptoms and inflammatory markers improved on prednisone and methotrexate, but a decision to treat with rituximab was made after having to discontinue methotrexate for transaminitis. Rituximab has been used in patients with IgG4-RD with some success, and our patient continues to improve in his skin, respiratory, and bone symptoms with reduction in IgG4, inflammatory markers, and bone turnover markers (alkaline phosphatase).

Abstract 265: Coronavirus Infection Induced Interferon Signaling Promotes Atherosclerotic Plaque Vulnerability

Atherosclerosis is a chronic inflammatory vascular disease characterized by the formation of lipid-rich plaques inside arteries. The rupture of vulnerable plaques and consequent acute complications, such as myocardial infarction and stroke, are the leading causes of morbidity and mortality worldwide. It is known that pre-existing cardiovascular comorbidities pose a risk for severe outcomes in COVID-19, though the underlying pathophysiology is not fully understood. To investigate the role of coronavirus infection in established atherosclerotic plaques, we developed an atherosclerotic model of natural murine beta coronavirus infection with mouse hepatitis virus strain-A59 (MHV-A59). We fed Ldlr-/- mice a Western diet for three months prior to MHV-A59 intranasal inoculation and assessed plaque morphology at day post infection (dpi) 7 and dpi 30. Respiratory infection in mice recapitulated many aspects of COVID-19 pathophysiology. More strikingly, virus was detected in atherosclerotic aorta and induced multiple features of vulnerable plaques, a prerequisite for plaque rupture, characterized by thinner fibrous caps, less collagen content, and larger necrotic cores. The phenotype was persistent at dpi 30 when the mice were fully recovered. To further explore the underlying mechanism, we performed single-cell RNA sequencing (scRNA-seq) on infected aortas isolated at dpi 7. Our data revealed that interferon γ was exclusively upregulated in activated T cells and elicited various responses across multiple cell populations within infected aortas. The drastic responses that potentially contribute to plaque instability include activation of a more proinflammatory endothelial cell phenotype, downregulation of TGF- β mediated fibroblast to myofibroblast transition, and enhanced degradation of extracellular matrix and smooth muscle cell senescence. Moreover, macrophages in infected plaques activate inflammasomes, release IL-18, and undergo pyroptosis, thereby further contributing to the hyperinflammatory state of the atherosclerotic plaques. Taken together, our data shed light on a molecular mechanism for coronavirus infection induced plaque instability and provide a small animal model to explore future therapeutics.

Abstract 712: IL-19 Is A Lymphokine That Induces Prox1-dependent Lymphangiogenesis And Permeability

Introduction: Atherosclerosis is a vascular inflammatory disease associated with lymphangiogenesis, but whether lymphangiogenesis contributes to disease progression or is simply a compensatory attempt at disease resolution is currently unresolved. Recent studies are revealing a role for lymphatic vessels in reverse cholesterol transport (RCT), which could attenuate atherosclerosis. We have previously reported that Interleukin-19 (IL-19), an anti-inflammatory cytokine, uniquely attenuates atherosclerotic plaque progression while also being pro-angiogenic. This drives our hypothesis that one mechanism whereby IL-19 is atheroprotective is by promoting functional lymphangiogenesis and lymphatic flux. Methods & Results: IL-19 can significantly induce human dermal lymphatic endothelial cell (hdLEC) proliferation, migration, and tube formation, to the same degree as VEGFC, a potent inducer of lymphangiogenesis. RNA sequencing analysis indicates that IL-19 induces an angiogenic transcriptional program through Prox1, a master regulator of lymphangiogenesis. Knockdown of Prox1 led to a significant decrease in IL-19-associated proliferation and migration. IL-19 also increased expression of Angpt2, an endothelial cell protein that induces permeability through regulation of tight junctions, through a Prox1-dependent mechanism. Electric Cell-substrate Impedance Sensing assays showed that IL-19 treatment increased hdLEC permeability and mitigated oxLDL-associated decreased permeability, suggestive of maintaining lymphatic barrier function during atherosclerosis. IL-19 treatment also increased dil-HDL transport across an hdLEC barrier. Preliminary in vivo data suggests injection of rmIL-19 in Il19 -/- mice increases lymphatic permeability and flux through increased lymphatic uptake of Evans blue dye. Conclusion: These data suggest that IL-19 increases lymphangiogenesis, permeability, and may increase RCT to plausibly decrease atherosclerosis. These results can influence our understanding of the association between the lymphatic system and atherosclerosis.

Complexity of Inflammation in the Trajectory of Vascular Disease: Interleukin 6 and Beyond

Takayasu's arteritis, first described by Dr. Mikito Takayasu in 1908, is a systemic vasculitis that mostly affects the aorta and its major branches. Although the etiology of the disease is yet unknown, genetic and environmental factors may both play a role. One hundred years after the discovery of Takayasu's arteritis, inflammation is finally widely recognized as a fundamental condition common to all vascular diseases, and clinical trials have proven the efficacy of molecularly targeted drugs that block each step of the NLRP3 inflammasome/interleukin (IL)-1β/IL-6 cascade in patients with atherosclerotic vascular disease and elevated C-reactive protein (CRP). Recent advances have also been made in the treatment of Takayasu's arteritis. The randomized controlled trials and subsequent open-label and post-marketing surveillance studies in Japan have demonstrated that tocilizumab, an anti-IL-6 receptor antibody, is effective in the treatment of Takayasu's arteritis and prevents relapse during tapering of prednisolone doses. IL-6 is also heavily engaged in the remodeling of large vessels after acute aortic dissection as demonstrated in animal studies. In patients with acute aortic dissection, those with markedly elevated CRP levels in the acute phase are known to have an increased risk of aorta-related events, such as rupture due to aortic diameter enlargement, in the subacute and chronic phases. We discovered that elevated CRP levels following aortic dissection are caused by IL-6, which is produced by neutrophils that infiltrate the adventitia of the dissected aorta. In a mouse model of acute aortic dissection, we showed that IL-6 produced by these neutrophils causes progressive destruction of the arterial wall structure and that blockade of IL-6 signaling can prevent post-dissection vascular remodeling and improve life outcome. Therefore, inhibiting IL-6 signaling is anticipated to be effective in the secondary prevention of myocardial infarction and suppression of vascular modeling after dissection and even as an anti-inflammatory therapy for Takayasu's arteritis; however, this approach does not solve everything. Undoubtedly, the mechanisms of inflammation in vascular disease are diverse and complex, and the cytokines and cell populations involved at each site (coronary artery vs. aorta) and in each phenotype (atherosclerosis vs. aortic aneurysm vs. aortic dissection) need to be understood for each type of inflammation. Osteopontin (OPN) is a recruiter of monocytes and macrophages, induces cellular immune responses as a Th1 cytokine, acts as a fibrosis-promoting factor, and has been shown to be deeply involved in the pathogenesis of vascular diseases. We have shown that senescent T cells, which emerge with obesity and aging, secrete significant amounts of OPN, leading to metabolic abnormalities and chronic inflammation. Neutrophil extracellular traps (NETs) released from activated neutrophils have been shown to contribute to the pathogenesis of acute coronary syndromes (ACS) by interacting with macrophages, platelets, and vascular endothelial cells and thus promoting plaque erosion and immunothrombosis. In addition to standard anticoagulant and antiplatelet therapies, the effectiveness of anti-immunothrombotic therapies targeting NETs as a new preventive and therapeutic approach for ACS will be examined in the future.