Superoxide anion production and phagocytosis of crystals by cultured endothelial cells

Falasca, Gerald F.; Ramachandrula, Anand; Kelley, Kathleen A.; O’Connor, Carolyn R.; Reginato, Antonio J.

doi:10.1002/art.1780360118

Cited by 45 publications

(20 citation statements)

References 46 publications

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“…Transmission electron microscopy of macrophages treated with BCP crystals for 20 hours showed vacuoles containing structures similar in appearance to previously published images of hydoxyapatite within cells 31,32 ( Figure 1). Furthermore, X-ray elemental microanalysis of macrophages that had been cultured with BCP and then washed showed the presence of a new calcium peak, consistent with internalized crystals (online Figure I).…”

Section: Inflammatory Cytokine Secretion By Bcp-treated Macrophagessupporting

confidence: 53%

Proinflammatory Activation of Macrophages by Basic Calcium Phosphate Crystals via Protein Kinase C and MAP Kinase Pathways

Nadra

Mason²,

Philippidis³

et al. 2005

Circulation Research

338

214

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Abstract-Basic calcium phosphate (BCP) crystal deposition underlies the development of arterial calcification.Inflammatory macrophages colocalize with BCP deposits in developing atherosclerotic lesions and in vitro can promote calcification through the release of TNF alpha. Here we have investigated whether BCP crystals can elicit a proinflammatory response from monocyte-macrophages. BCP microcrystals were internalized into vacuoles of human monocyte-derived macrophages in vitro. This was associated with secretion of proinflammatory cytokines (TNF␣, IL-1␤ and IL-8) capable of activating cultured endothelial cells and promoting capture of flowing leukocytes under shear flow. Critical roles for PKC, ERK1/2, JNK, but not p38 intracellular signaling pathways were identified in the secretion of TNF alpha, with activation of ERK1/2 but not JNK being dependent on upstream activation of PKC. Using confocal microscopy and adenoviral transfection approaches, we determined a specific role for the PKC-alpha isozyme. The response of macrophages to BCP crystals suggests that pathological calcification is not merely a passive consequence of chronic inflammatory disease but may lead to a positive feed-back loop of calcification and inflammation driving disease progression. Key Words: atherosclerosis pathophysiology Ⅲ cell biology Ⅲ calcification Ⅲ inflammation Ⅲ macrophage C oronary artery calcification occurs as part of the atherosclerotic process, and is due to the deposition in the arterial intima of basic calcium phosphate (BCP) crystals, consisting mainly of calcium hydroyapatite (Ca 10 (PO 4 ) 6 (OH) 2 ) and similar to those that mineralize bone. [1][2][3][4][5][6] Using electron beam computed tomography, the amount of vessel calcification has been shown to closely correlate with the extent of plaque burden and may predict future coronary events. [7][8][9][10] However, although arterial calcification is now accepted to be an active and highly regulated process similar to that of bone ossification, [11][12][13][14] it has tended to be seen merely as a surrogate marker for the burden of atherosclerotic disease rather than a contributor to disease progression.Growing evidence from the study of degenerative arthritis, in which BCP crystals can be found in the majority of affected joints and closely correlate with the extent of joint destruction, suggests a pathogenic role in driving disease. 15,16 Thus, BCP crystals have been shown to activate synovial fibroblasts, inducing cellular proliferation and matrix metalloproteinase (MMP) secretion through a variety of intracellular signaling pathways, including protein kinase C (PKC), ERK1/2 MAP kinase, NFB, and AP-1. [17][18][19] Limited studies using murine cells have also demonstrated the ability of macrophages to interact with BCP crystals in vitro, resulting in DNA synthesis and cytokine production. 20,21 Cells of the monocyte/macrophage lineage form an important part of the innate immune system and play a key role in atherogenesis. 22 Inflammatory mediators derived from monocy...

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Section: Inflammatory Cytokine Secretion By Bcp-treated Macrophagessupporting

confidence: 53%

Proinflammatory Activation of Macrophages by Basic Calcium Phosphate Crystals via Protein Kinase C and MAP Kinase Pathways

Nadra

Mason²,

Philippidis³

et al. 2005

Circulation Research

338

214

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“…[54][55][56][57] Here we show that HMEC-1 cells as well as HUVECs engulf necrotic and apoptotic endothelial material. Under physiologic conditions engulfment of apoptotic cells by healthy endothelium may be of minor importance because this task is performed by macrophages and granulocytes.…”

Section: Discussionmentioning

confidence: 99%

Engulfment of apoptotic cells by microvascular endothelial cells induces proinflammatory responses

Kirsch

Woywodt

Beese

et al. 2006

Blood

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IntroductionApoptosis is essential to maintain homeostasis in multicellular organisms and apoptotic cells are rapidly and effectively cleared by professional phagocytes before they undergo secondary necrosis and release their noxious cytoplasmic content into the environment. 1 Ineffective clearance of apoptotic cells contributes to disease pathogenesis. 2,3 This may be true especially for autoimmune diseases such as systemic lupus erythematosus (SLE) because apoptotic cells are thought to be a potential source of autoantigens and disturbed clearance of apoptotic corpses may initiate and drive autoimmunity. [4][5][6] This concept of acquired autoimmunity has also been confirmed in several animal models that showed disturbed engulfment of apoptotic cells. [7][8][9][10] Vascular endothelial cells (ECs) serve as a crucial barrier between tissues and the circulation. They secrete a variety of substances, regulate coagulation, and participate in the immune response. 11 Under physiologic conditions circulating ECs (CECs) are almost not traceable, whereas in a variety of vascular diseases such as myocardial infarction, small-vessel vasculitis, transplantation, or cancer high numbers of CECs are detectable in the peripheral circulation. [12][13][14][15][16][17] Consequentially, accumulation of CECs may affect the homeostasis of the vessel wall by interfering with the EC layer both in the vicinity of endothelial lesions or even distant from the site of injury.Clearance of dying cells or cellular debris has been mostly ascribed to professional phagocytes, for example, antigenpresenting macrophages, neutrophils, or dendritic cells, but it is conceivable that other cell types such as epithelial cells or ECs may also partake in this process. 18,19 ECs are not professional phagocytes although specific subpopulations, such as liver ECs or cells from high endothelial venules, are able to phagocytose apoptotic cells. 20,21 Phagocytosis of circulating endothelial debris by healthy endothelium thus appears to be an intriguing concept.The role of endothelial-or platelet-derived microparticles in the circulation is the subject of several recently published studies but few, if any, data, shed light on the impact of apoptotic endothelial corpses on the adjacent endothelium. [22][23][24][25][26][27][28][29][30][31] The aim of the present study was to establish an in vitro model to study the interaction of apoptotic or necrotic ECs with a healthy EC layer. We here demonstrate that microvascular ECs, when exposed to apoptotic cells, react with the release of proinflammatory chemotactic cytokines and that this response triggers enhanced adhesion of primary neutrophils and macrophages. Patients, materials, and methodsThe study was approved by the Hannover Medical School Ethics Committee and conducted in accordance with the Declaration of Helsinki. Written informed consent was obtained from all patients included in this study. EC cultureHuman umbilical vein endothelial cells (HUVECs) were isolated from umbilical cords by exposure of the vein...

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“…A consistent relationship has also been noted between elevated serum uric acid concentration and circulating inflammatory markers [22][23][24] . Moreover, urate could be phagocytosed by endothelial cells [25] . Further, Waring et al pointed out in an interesting review which discussed uric acid as a risk factor for cardiovascular disease [26] , that uric acid could even traverse dysfunctional endothelial cells and accumulate as crystals within atherosclerotic plaques [27] .…”

Section: Urate In Stroke Survivors 791mentioning

confidence: 99%

Urate predicts subsequent cardiac death in stroke survivors

Wong

MacWalter²,

Fraser³

et al. 2002

European Heart Journal

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Aims To test the hypothesis that urate predicts cardiac death after stroke independent of conventional risk factors of atherosclerosis, creatinine and diuretic use. Methods and ResultsSerum urate concentration was measured in an unselected cohort of 354 stroke survivors who were followed-up for a median of 2·8 years. Cardiac death was the primary end-point. Urate was associated with a statistically significant threefold increase in relative risk of cardiac death even after adjustment for other conventional risk factors. In the subgroup of patients who were not on diuretics, raised urate was associated with a 12-fold significant increase in relative risk of cardiac death after adjusting for renal function and other conventional risk factors. A urate concentration of greater than 0·31 mmol . l 1 was 78% sensitive at predicting cardiac death within 5 years after stroke, but was only 54% specific. If urate exceeded 0·38 mmol . l 1 , specificity of predicting cardiac death within 5 years after stroke was 88%.Conclusions Elevated serum urate concentration may be used to stratify risk of future cardiac death after stroke. This appeared to be true even in stroke survivors who were not on diuretic therapy.

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Superoxide anion production and phagocytosis of crystals by cultured endothelial cells

Cited by 45 publications

References 46 publications

Proinflammatory Activation of Macrophages by Basic Calcium Phosphate Crystals via Protein Kinase C and MAP Kinase Pathways

Proinflammatory Activation of Macrophages by Basic Calcium Phosphate Crystals via Protein Kinase C and MAP Kinase Pathways

Engulfment of apoptotic cells by microvascular endothelial cells induces proinflammatory responses

Urate predicts subsequent cardiac death in stroke survivors

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