Familial hypercholesterolemia and elevated lipoprotein(a): double heritable risk and new therapeutic opportunities.

There is compelling evidence that the elevated plasma lipoprotein(a) [Lp(a)] levels increase the risk of atherosclerotic cardiovascular disease (ASCVD) in the general population. Like low-density lipoprotein (LDL) particles, Lp(a) particles contain cholesterol and promote atherosclerosis. In addition, Lp(a) particles contain strongly proinflammatory oxidized phospholipids and a unique apoprotein, apo(a), which promotes the growth of an arterial thrombus. At least one in 250 individuals worldwide suffer from the heterozygous form of familial hypercholesterolemia (HeFH), a condition in which LDL-cholesterol (LDL-C) is significantly elevated since birth. FH-causing mutations in the LDL receptor gene demonstrate a clear gene-dosage effect on Lp(a) plasma concentrations and elevated Lp(a) levels are present in 30-50% of patients with HeFH. The cumulative burden of two genetically determined pro-atherogenic lipoproteins, LDL and Lp(a), is a potent driver of ASCVD in HeFH patients. Statins are the cornerstone of treatment of HeFH, but they do not lower the plasma concentrations of Lp(a). Emerging therapies effectively lower Lp(a) by as much as 90% using RNA-based approaches that target the transcriptional product of the LPA gene. We are now approaching the dawn of an era, in which permanent and significant lowering of the high cholesterol burden of HeFH patients can be achieved. If outcome trials of novel Lp(a)-lowering therapies prove to be safe and cost-effective, they will provide additional risk reduction needed to effectively treat HeFH and potentially lower the CVD risk in these high-risk patients even more than currently achieved with LDL-C lowering alone.

Intravenous but not intrathecal central nervous system-directed chemotherapy improves survival in patients with testicular diffuse large B-cell lymphoma.

BACKGROUND: Testicular lymphoma is a rare malignancy affecting mainly elderly men, the majority representing diffuse large B-cell lymphoma (DLBCL). Its relapse rate is higher than that of nodal DLBCL, often affecting the central nervous system (CNS) with dismal prognosis. PATIENTS AND METHODS: We searched for patients with testicular DLBCL (T-DLBCL) involvement from the pathology databases of Southern Finland University Hospitals and the Danish Lymphoma Registry. Clinical information was collected, and outcomes between treatment modalities were evaluated. Progression-free survival (PFS), disease-specific survival (DSS) and overall survival (OS) were assessed using Kaplan-Meier and Cox proportional hazards methods. RESULTS: We identified 235 patients; of whom, 192 were treated with curative anthracycline-based chemotherapy. Full survival data were available for 189 patients. In univariate analysis, intravenous CNS-directed chemotherapy, and irradiation or orchiectomy of the contralateral testis translated into favourable PFS, DSS and OS, particularly among the elderly patients (each p ≤ 0.023). Intrathecal chemotherapy had no impact outcome. In multivariate analyses, the advantage of intravenous CNS-directed chemotherapy (hazard ration [HR] for OS, 0.419; 95% confidence interval [CI], 0.256-0.686; p = 0.001) and prophylactic treatment of contralateral testis (HR for OS, 0.514; 95% CI, 0.338-0.782; p = 0.002) was maintained. Rituximab improved survival only among high-risk patients (International Prognostic Index≥3, p = 0.019). The cumulative risk of CNS progression was 8.4% and did not differ between treatment modalities. CONCLUSION: The results support the use of CNS-directed chemotherapy and prophylactic treatment of the contralateral testis in patients with T-DLBCL involvement. Survival benefit appears resulting from better control of systemic disease rather than prevention of CNS progression.

Defective WNT signaling associates with bone marrow fibrosis-a cross-sectional cohort study in a family with WNT1 osteoporosis.

This study explores bone marrow function in patients with defective WNT1 signaling. Bone marrow samples showed increased reticulin and altered granulopoiesis while overall hematopoiesis was normal. Findings did not associate with severity of osteoporosis. These observations provide new insight into the role of WNT signaling in bone marrow homeostasis. INTRODUCTION: WNT signaling regulates bone homeostasis and survival and self-renewal of hematopoietic stem cells. Aberrant activation may lead to osteoporosis and bone marrow pathology. We aimed to explore bone marrow findings in a large family with early-onset osteoporosis due to a heterozygous WNT1 mutation. METHODS: We analyzed peripheral blood samples, and bone marrow aspirates and biopsies from 10 subjects with WNT1 mutation p.C218G. One subject was previously diagnosed with idiopathic myelofibrosis and others had no previously diagnosed hematologic disorders. The findings were correlated with the skeletal phenotype, as evaluated by number of peripheral and spinal fractures and bone mineral density. RESULTS: Peripheral blood samples showed no abnormalities in cell counts, morphology or distributions but mild increase in platelet count. Bone marrow aspirates (from 8/10 subjects) showed mild decrease in bone marrow iron storages in 6 and variation in cell distributions in 5 subjects. Bone marrow biopsies (from 6/10 subjects) showed increased bone marrow reticulin (grade MF-2 in the myelofibrosis subject and grade MF-1 in 4 others), and an increase in overall, and a shift towards early-phase, granulopoiesis. The bone marrow findings did not associate with the severity of skeletal phenotype. CONCLUSIONS: Defective WNT signaling associates with a mild increase in bone marrow reticulin and may predispose to myelofibrosis, while overall hematopoiesis and peripheral blood values are unaltered in individuals with a WNT1 mutation. In this family with WNT1 osteoporosis, bone marrow findings were not related to the severity of osteoporosis.

Prompt impact of first prospective statin mega-trials on postoperative lipid management of CABG patients: a 20-year follow-up in a single hospital.

BACKGROUND: The long-term success of coronary artery bypass grafting (CABG) depends on secondary prevention. Vast evidence provided by the results of cholesterol mega-trials over two decades has shown that effective reduction of LDL cholesterol improves the prognosis of patients with coronary heart disease. However, the implementation of these results into the clinical practice has turned out to be challenging. We analysed how the information derived from clinical statin trials and international recommendations affected the local treatment practices of dyslipidaemia of CABG patients during a 20-year time period. METHODS: The cohort includes all CABG patients (n = 953) treated in Kanta-Häme Central Hospital during the time period 1990-2009. At the postoperative visits in the cardiology outpatient clinic, each patient's statin prescription was recorded, and blood lipids were determined. RESULTS: During 1990-1994, 12.0 % of patients were on statins and during the following 5-year time periods the proportion was 57.2, 82.2 and 96.8 %, respectively. During the 20-year observation period (1990-2009), the effective statin dose increased progressively during these 5-year periods up to 36-fold, while the mean concentration of LDL cholesterol decreased from 3.7 to 2.1 mmol/l and that of apolipoprotein B from 1.3 to 0.8 g/l. In the very last year of follow-up, the mean concentrations of LDL-C and apoB were 1.83 mmol/l and 0.78 g/l, respectively. The most prominent increase in statin use and dosage took place during 1994-1996 and 2003-2005, respectively. CONCLUSIONS: Among CABG patients the lipid-lowering efficacy of statin therapy improved dramatically since 1994. This progress was accompanied by significant and favourable changes of lipid and apolipoprotein-B values. This study shows that it is possible to effectively improve lipid treatment policy once the results of relevant trials are available, and that this may happen even before international or national guidelines have been updated.

Deregulated hepsin protease activity confers oncogenicity by concomitantly augmenting HGF/MET signalling and disrupting epithelial cohesion.

Hepsin belongs to a family of cell-surface serine proteases, which have sparked interest as therapeutic targets because of the accessibility of extracellular protease domain for inhibitors. Hepsin is frequently amplified and/or overexpressed in epithelial cancers, but it is not clear how enhanced hepsin expression confers a potential for oncogenicity. We show that hepsin is consistently overexpressed in more than 40% of examined breast cancers, including all major biological subtypes. The effects of doxycycline-induced hepsin overexpression were examined in mammary epithelial organoids, and we found that induced hepsin acutely downmodulates its cognate inhibitor, hepatocyte growth factor (HGF) activator inhibitor type 1 (HAI-1). Hepsin-induced depletion of cellular HAI-1 led to a sharp increase in pericellular serine protease activity. The derepressed hepsin proteolytically activated downstream serine proteases, augmented HGF/MET signalling and caused deterioration of desmosomes and hemidesmosomes; structures important for cell cohesion and cell-basement membrane interaction. Moreover, chronic induction of hepsin considerably shortened the latency of Myc-dependent tumourigenesis in the mouse mammary gland. The serine protease and uPA system inhibitor WX-UK1, identified as a micromolar range hepsin inhibitor, prevented hepsin from augmenting HGF/MET signalling and disrupting desmosomes and hemidesmosomes. The findings suggest that the oncogenic activity of hepsin arises not only from elevated expression level but also from depletion of HAI-1, events which together trigger gain-of-function activity impacting HGF/MET signalling and epithelial cohesion. Thus, hepsin overexpression is a major oncogenic conferrer to a serine protease activity involved in breast cancer dissemination.

Electronegative LDL induces priming and inflammasome activation leading to IL-1ß release in human monocytes and macrophages.

BACKGROUND: Electronegative LDL (LDL(−)), a modified LDL fraction found in blood, induces the release of inflammatory mediators in endothelial cells and leukocytes. However, the inflammatory pathways activated by LDL(−) have not been fully defined. We aim to study whether LDL(−) induced release of the first-wave proinflammatory IL-1ß in monocytes and monocyte-derived macrophages (MDM) and the mechanisms involved. METHODS: LDL(−) was isolated from total LDL by anion exchange chromatography. Monocytes and MDM were isolated from healthy donors and stimulated with LDL(+) and LDL(−) (100 mg apoB/L). RESULTS: In monocytes, LDL(−) promoted IL-1ß release in a time-dependent manner, obtaining at 20 h-incubation the double of IL-1ß release induced by LDL(−) than by native LDL. LDL(−)-induced IL-1ß release involved activation of the CD14-TLR4 receptor complex. LDL(−) induced priming, the first step of IL-1ß release, since it increased the transcription of pro-IL-1ß (8-fold) and NLRP3 (3-fold) compared to native LDL. Several findings show that LDL(−) induced inflammasome activation, the second step necessary for IL-1ß release. Preincubation of monocytes with K+ channel inhibitors decreased LDL(−)-induced IL-1ß release. LDL(−) induced formation of the NLRP3-ASC complex. LDL(−) triggered 2-fold caspase-1 activation compared to native LDL and IL-1ß release was strongly diminished in the presence of the caspase-1 inhibitor Z-YVAD. In MDM, LDL(−) promoted IL-1ß release, which was also associated with caspase-1 activation. CONCLUSIONS: LDL(−) promotes release of biologically active IL-1ß in monocytes and MDM by induction of the two steps involved: priming and NLRP3 inflammasome activation. SIGNIFICANCE: By IL-1ß release, LDL(−) could regulate inflammation in atherosclerosis.

Intracellular RNA recognition pathway activates strong anti-viral response in human mast cells.

Mast cells have been implicated in the first line of defence against parasites and bacteria, but less is known about their role in anti-viral responses. Allergic diseases often exacerbate during viral infection, suggesting an increased activation of mast cells in the process. In this study we investigated human mast cell response to double-stranded RNA and viral infection. Cultured human mast cells were incubated with poly(I:C), a synthetic RNA analogue and live Sendai virus as a model of RNA parainfluenza virus infection, and analysed for their anti-viral response. Mast cells responded to intracellular poly(I:C) by inducing type 1 and type 3 interferons and TNF-α. In contrast, extracellular Toll-like receptor 3 (TLR)-3-activating poly(I:C) failed to induce such response. Infection of mast cells with live Sendai virus induced an anti-viral response similar to that of intracellular poly(I:C). Type 1, but not type 3 interferons, up-regulated the expression of melanoma differentiation-associated gene 5 (MDA-5) and retinoic acid-inducible gene-1 (RIG-1), and TLR-3, demonstrating that human mast cells do not express functional receptors for type 3 interferons. Furthermore, virus infection induced the anti-viral proteins MxA and IFIT3 in human mast cells. In conclusion, our results support the notion that mast cells can recognize an invading virus through intracellular virus sensors and produce high amounts of type 1 and type 3 interferons and the anti-viral proteins human myxovirus resistance gene A (MxA) and interferon-induced protein with tetratricopeptide repeats 3 (IFIT3) in response to the virus infection.

Immune functions of serum amyloid A.

Serum amyloid A (SAA) is a highly conserved, acute-phase protein synthesized predominantly by the liver. After secretion into the circulation, it associates with high-density lipoprotein (HDL) particles. During acute inflammation, serum SAA levels may rise up to 1000-fold, and under these conditions, SAA displaces apolipoprotein A-I from HDL, thus becoming the major apolipoprotein of circulating HDL3. SAA exhibits significant immunological activity by, for example, inducing the synthesis of several cytokines and by being chemotactic for neutrophils and mast cells. It exerts many of its immunological activities by binding and activating cell-surface receptors, including Toll-like receptor (TLR) 2 and TLR4, formyl peptide receptor-like 1 (FPRL1), class B scavenger receptor CD36, and the ATP receptor P2X7. SAA also recently has been shown to activate the inflammasome cascade, which has a key role in immune activation, thus further stressing the unique role of SAA in immunomodulation. Traditionally, SAA has been considered to have a key role in the pathogenesis of amyloid A-type amyloidosis, but we now understand that it may also participate in the pathogenesis of chronic inflammatory diseases, such as rheumatoid arthritis and atherosclerosis. Thus, SAA is one potential target in the treatment of diseases associated with chronic inflammation. The purpose of this review is to shed light on SAA as an immunologically active protein. We also focus on the recent findings implicating SAA in the regulation of the inflammasome cascade.

Imatinib mesylate alleviates diarrhea in a mouse model of intestinal allergy.

BACKGROUND: When sensitized epicutaneously and challenged orally with ovalbumin, Balb/c mice develop allergen-induced diarrhea. As mast cells play important roles in diarrhea, we studied whether allergic diarrhea could be alleviated with imatinib mesylate. METHODS: Balb/c mice were sensitized and challenged with ovalbumin and treated orally with imatinib. Cytokine mRNA expressions were determined with quantitative RT-PCR and numbers of small intestinal mast cells determined by staining for chloroacetate esterase and mucosal mast cell protease-1. Immunofluorescence staining was used to assess the intestinal CCL1 expression. KEY RESULTS: Ovalbumin-sensitized and challenged Balb/c mice developed diarrhea, which was associated with increased number of mast cells and expression of interleukin (IL)-4 and -13, and chemokines CCL1 and CCL17 in the small intestine. Treatment with imatinib reduced the incidence of diarrhea, inhibited the development of mastocytosis and jejunal mRNA expression of IL-13, CCL1, CCL17 and CCL22. Mast cell-deficient W/W(-V) mice, and surprisingly, also their mast cell-competent control (+/+) littermates failed to develop diarrhea as a response to ovalbumin. This strain-dependent difference was associated with the inability of +/+ and W/W(-V) mice to increase the number of intestinal mast cells and expression of IL-4, IL-13, CCL1 and CCL17 after ovalbumin challenge. CONCLUSIONS & INFERENCES: Development of allergic diarrhea is associated with the ability of mice to develop intestinal mastocytosis. Imatinib inhibited the development of intestinal mastocytosis, reduced the incidence of diarrhea, and reduced the expression of IL-13, CCL1, and CCL17. Targeting intestinal mast cells could be a feasible approach to treat allergic diarrhea.

Lysophosphatidic acid and sphingosine-1-phosphate promote morphogenesis and block invasion of prostate cancer cells in three-dimensional organotypic models.

Normal prostate and some malignant prostate cancer (PrCa) cell lines undergo acinar differentiation and form spheroids in three-dimensional (3-D) organotypic culture. Acini formed by PC-3 and PC-3M, less pronounced also in other PrCa cell lines, spontaneously undergo an invasive switch, leading to the disintegration of epithelial structures and the basal lamina, and formation of invadopodia. This demonstrates the highly dynamic nature of epithelial plasticity, balancing epithelial-to-mesenchymal transition against metastable acinar differentiation. This study assessed the role of lipid metabolites on epithelial maturation. PC-3 cells completely failed to form acinar structures in delipidated serum. Adding back lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P) rescued acinar morphogenesis and repressed invasion effectively. Blocking LPA receptor 1 (LPAR1) functions by siRNA (small interference RNA) or the specific LPAR1 inhibitor Ki16425 promoted invasion, while silencing of other G-protein-coupled receptors responsive to LPA or S1P mainly caused growth arrest or had no effects. The G-proteins Gα(12/13) and Gα(i) were identified as key mediators of LPA signalling via stimulation of RhoA and Rho kinases ROCK1 and 2, activating Rac1, while inhibition of adenylate cyclase and accumulation of cAMP may be secondary. Interfering with these pathways specifically impeded epithelial polarization in transformed cells. In contrast, blocking the same pathways in non-transformed, normal cells promoted differentiation. We conclude that LPA and LPAR1 effectively promote epithelial maturation and block invasion of PrCa cells in 3-D culture. The analysis of clinical transcriptome data confirmed reduced expression of LPAR1 in a subset of PrCa's. Our study demonstrates a metastasis-suppressor function for LPAR1 and Gα(12/13) signalling, regulating cell motility and invasion versus epithelial maturation.

Mast cells generated from patients with atopic eczema have enhanced levels of granule mediators and an impaired Dectin-1 expression.

BACKGROUND: The disrupted skin barrier of patients with atopic eczema (AE) might facilitate contact between mast cells (MCs) in the skin and environmental triggers of the disease. One such trigger is the skin-colonizing yeast Malassezia sympodialis (M. sympodialis). In this study, we investigated the interaction of MC with M. sympodialis. METHODS: Mast cells were generated from peripheral blood CD34(+) progenitor cells of healthy controls (HC) and M. sympodialis-sensitized AE patients. Biopsy specimens were taken from HC and lesional AE skin for immunohistological stainings. RESULTS: The progenitor-derived MCs expressed the macrophage-inducible C-type lectin receptor Mincle, and exposure of these cells to M. sympodialis induced up-regulation of the mRNA expression of Mincle. Furthermore, we demonstrate that, when compared to HC, the progenitor-derived MCs from AE patients (i) contain more intrinsic granule mediators such as histamine, (ii) exhibit enhanced IL-6 release in response to M. sympodialis exposure, and (iii) have an impaired up-regulation of the fungal recognition receptor Dectin-1. In addition, analysis of skin sections from HC and AE patients revealed MCs as the predominant Dectin-1-expressing cell type in the skin. CONCLUSION: Our data indicate that progenitor-derived MCs from AE patients differ from those from HC. Further investigations with skin-derived MCs are necessary to confirm the observed differences which could provide new insights into the pathogenic mechanisms underlying AE.

The anti-allergic compound tranilast attenuates inflammation and inhibits bone destruction in collagen-induced arthritis in mice.

BACKGROUND AND PURPOSE: Recent findings suggest the importance of mast cells in the pathogenesis of rheumatoid arthritis and their potential as a therapeutic target. Tranilast is an anti-allergic compound with a potent membrane-stabilizing effect on mast cells and a wide range of anti-inflammatory effects, thus may be advantageous in the treatment of arthritis. Here, we have evaluated the effects of tranilast on the progression of collagen-induced arthritis in mice. EXPERIMENTAL APPROACH: Tranilast (400 mg.kg(-1).day(-1)) was orally administered for 8 weeks to mice with established collagen-induced arthritis. Arthritis was assessed by clinical signs and X-ray scores. In paw tissue, the numbers of mast cells and osteoclasts were measured by histological analysis, and several inflammatory factors were assessed by RT-PCR and Western blot analysis.* KEY RESULTS: TNF-alpha-positive mast cells were present extensively throughout the inflamed synovium of vehicle-treated arthritic mice, with some mast cells in close proximity to osteoclasts in areas of marked bone and cartilage destruction. Tranilast significantly reduced clinical and X-ray scores of arthritis and decreased numbers of TNF-alpha-positive mast cells and mRNA levels of TNF-alpha, chymase (mouse mast cell protease 4), tryptase (mouse mast cell protease 6), stem cell factor, interleukin-6, cathepsin-K, receptor activator of nuclear factor-kappaB, and of receptor activator of nuclear factor-kappaB-ligand, but increased interleukin-10 mRNA level in paws of arthritic mice. Osteoclast numbers were decreased by treatment with tranilast. CONCLUSIONS AND IMPLICATIONS: Tranilast possesses significant anti-rheumatic efficacy and, probably, this therapeutic effect is partly mediated by inhibition of mast cell activation and osteoclastogenesis.

Ethanol induces apoptosis in human mast cells.

AIMS: Alcohol abuse is associated with increased frequency of infections attributed to ethanol-induced immune suppression. The precise mechanism of immune suppression is however not known. Mast cells (MC) belong to the innate immune system and they have been implicated in the first line of immune defence against bacteria and parasites. Therefore we studied the effects of ethanol and its first metabolite acetaldehyde on mast cell viability, proliferation and apoptosis. MAIN METHODS: Human mast cell line (HMC)-1 cells, mouse bone marrow derived mast cells (mBMMC) and human peripheral blood derived mast cells (HuMC) were used. Effects of ethanol and acetaldehyde on mast cell proliferation were determined by assessing incorporation of [(3)H]thymidine into cellular DNA and by trypan blue exclusion. Apoptosis was assessed by measuring apoptotic nucleosomes and caspase-3, -8 and -9 activities using ELISA and by using Tunel assay. The expression of anti- and proapoptotic proteins Bcl-2 and Bax was analyzed by RT-PCR and western blot, respectively. KEY FINDINGS: Ethanol, but not acetaldehyde inhibited dose-dependently the proliferation and viability HMC-1 and mBMMC cells. The decreased viability was caused by apoptotic cell death of the MC. Significant apoptosis of HMC-1 cells was observed in the presence of 43mM (2.5 per thousand) ethanol. Induction of apoptosis was associated with clearly increased caspase-3 activity and moderately increased caspase-8 and 9 activities. Ethanol also shifted the Bcl-2/Bax balance towards apoptosis. SIGNIFICANCE: The ethanol-induced reduction of MC viability could contribute to immunosuppression associated with ethanol abuse.

Clonal expansion of T/NK-cells during tyrosine kinase inhibitor dasatinib therapy.

Dasatinib, a broad-spectrum tyrosine kinase inhibitor (TKI), predominantly targets BCR-ABL and SRC oncoproteins and also inhibits off-target kinases, which may result in unexpected drug responses. We identified 22 patients with marked lymphoproliferation in blood while on dasatinib therapy. Clonality and immunophenotype were analyzed and related clinical information was collected. An abrupt lymphocytosis (peak count range 4-20 x 10(9)/l) with large granular lymphocyte (LGL) morphology was observed after a median of 3 months from the start of therapy and it persisted throughout the therapy. Fifteen patients had a cytotoxic T-cell and seven patients had an NK-cell phenotype. All T-cell expansions were clonal. Adverse effects, such as colitis and pleuritis, were common (18 of 22 patients) and were preceded by LGL lymphocytosis. Accumulation of identical cytotoxic T cells was also detected in pleural effusion and colon biopsy samples. Responses to dasatinib were good and included complete, unexpectedly long-lasting remissions in patients with advanced leukemia. In a phase II clinical study on 46 Philadelphia chromosome-positive acute lymphoblastic leukemia, patients with lymphocytosis had superior survival compared with patients without lymphocytosis. By inhibiting immunoregulatory kinases, dasatinib may induce a reversible state of aberrant immune reactivity associated with good clinical responses and a distinct adverse effect profile.

Leukocyte cathepsin S is a potent regulator of both cell and matrix turnover in advanced atherosclerosis.

OBJECTIVE: A dysbalance of proteases and their inhibitors is instrumental in remodeling of atherosclerotic plaques. One of the proteases implicated in matrix degradation is cathepsin-S (CatS). To address its role in advanced lesion composition, we generated chimeric LDLr(-/-) mice deficient in leukocyte CatS by transplantation with CatS(-/-)xLDLr(-/-) or with LDLr(-/-) bone marrow and administered a high-fat diet. METHODS AND RESULTS: No difference in aortic root lesion size could be detected between CatS(+/+) and CatS(-/-) chimeras. However, leukocyte CatS deficiency markedly changed plaque morphology and led to a dramatic reduction in necrotic core area by 77% and an abundance of large foam cells. Plaques of CatS(-/-) chimeras contained 17% more macrophages, 62% less SMCs, and 33% less intimal collagen. The latter two could be explained by a reduced number of elastic lamina fractures. Moreover, macrophage apoptosis was reduced by 60% with CatS deficiency. In vitro, CatS was found to be involved in cholesterol metabolism and in macrophage apoptosis in a collagen and fibronectin matrix. CONCLUSIONS: Leukocyte CatS deficiency results in considerably altered plaque morphology, with smaller necrotic cores, reduced apoptosis, and decreased SMC content and collagen deposition and may thus be critical in plaque stability.

Mast cells associate with T-cells and neointimal microvessels in giant cell arteritis.

OBJECTIVE: Mast cells (MCs) are known to be involved in the neovascularization and regulation of T cell responses. However, the presence of MCs in giant cell arteritis (GCA) is unknown. This prompted us to study the presence and phenotype of MCs in GCA. METHODS: Human GCA specimens collected for diagnostic purposes were examined with immunohistochemistry. Double immunostainings of MC tryptase with cathepsin G, vascular endothelial cell growth factor (VEGF), CD3, and CD31/D34 were performed. RESULTS: Double immunostainings showed that activated tryptase-, cathepsin G- and VEGF-expressing MCs associate with CD3+ T cells and CD31/CD34+ neointimal neovessels in the GCA lesions. CONCLUSIONS: The results suggest that MCs may contribute to the pathogenesis of GCA putatively by regulating the functions of other inflammatory cells and resident vessel wall cells. Importantly, MCs promote neovascularization, which is considered as a prerequisite for the neointimal thickening in GCA.