The polyol pathway is an evolutionarily conserved system for sensing glucose uptake.

Cells must adjust the expression levels of metabolic enzymes in response to fluctuating nutrient supply. For glucose, such metabolic remodeling is highly dependent on a master transcription factor ChREBP/MondoA. However, it remains elusive how glucose fluctuations are sensed by ChREBP/MondoA despite the stability of major glycolytic pathways. Here, we show that in both flies and mice, ChREBP/MondoA activation in response to glucose ingestion involves an evolutionarily conserved glucose-metabolizing pathway: the polyol pathway. The polyol pathway converts glucose to fructose via sorbitol. It has been believed that this pathway is almost silent, and its activation in hyperglycemic conditions has deleterious effects on human health. We show that the polyol pathway regulates the glucose-responsive nuclear translocation of Mondo, a Drosophila homologue of ChREBP/MondoA, which directs gene expression for organismal growth and metabolism. Likewise, inhibition of the polyol pathway in mice impairs ChREBP's nuclear localization and reduces glucose tolerance. We propose that the polyol pathway is an evolutionarily conserved sensing system for glucose uptake that allows metabolic remodeling.

Multidisciplinary Team-Based Palliative Care for Heart Failure and Food Intake at the End of Life.

Traditionally, patients with end-stage heart failure (HF) have rarely been involved in end-of-life care (EOLC) discussions in Japan. The purpose of this study was to examine the impact of HF-specific palliative care team (HF-PCT) activities on EOLC discussions with patients, HF therapy and care, and food intake at the end of life. We retrospectively analyzed 52 consecutive patients with HF (mean age, 70 ± 15 years; 42% female) who died at our hospital between May 2013 and July 2020 and divided them into two groups: before (Era 1, n = 19) and after (Era 2, n = 33) the initiation of HF-PCT activities in June 2015. Compared to Era 1, Era 2 showed a decrease in invasive procedures, an increase in opioid and non-intubating sedative use for symptom relief, improved quality of meals at the end of life, and an increase in participation in EOLC discussions. The administration of artificial nutrition in the final three days was associated with non-ischemic cardiomyopathy etiology, the number of previous hospitalizations for HF, and multidisciplinary EOLC discussion support. HF-PCT activities may provide an opportunity to discuss EOLC with patients, reduce the burden of physical and psychological symptoms, and shift the goals of end-of-life nutritional intake to ensure comfort and quality of life.

Aß Influx into the Blood Evoked by Different Blood Aß Removal Systems: A Potential Therapy for Alzheimer's Disease.

PURPOSE: Amyloid-ß (Aß) is a brain protein that causes Alzheimer's disease. We have revealed that extracorporeal blood Aß-removal systems evoked a large Aß influx into the blood. This study investigated the system that is more effective in evoking Aß influx. METHODS: Aß removal activities were compared between hexadecyl-alkylated cellulose beads (HexDC) and fragments of polysulfone hollow fibers (PSf-HFs) in mini-columns to eliminate the filtration effect. Then, adsorptive filtration systems were adapted for PSf hemodialyzers to enhance Aß adsorption on micropores in the wall of hollow fibers. Plasma Aß concentrations of patients with renal failure were analyzed during treatment with PSf hemodialyzers alone for 8 h or tandemly connected HexDC and PSf hemodialyzers for 4 h. RESULTS: In the in vitro study, Aß removal efficiency for HexDC was approximately 100% during the 60 min treatment, whereas the removal efficiency for PSf-HF fragments gradually decreased. However, PSf hemodialyzer in adsorptive filtration systems removed Aßs comparably or more than HexDC. Aß influx into the blood increases time-dependently. Concomitant use of HexDC and PSf hemodialyzer evoked a larger Aß1-40 influx than that of PSf hemodialyzer alone. However, Aß1-42 influx by PSf hemodialyzer alone was similar to or a little larger than influx by the combined system. Both systems evoked almost doubled Aß influx than estimated Aßs existing in the normal brain during the 4 h treatment. CONCLUSION: PSf hemodialyzer alone for a longer period and concomitant use of HexDC and PSf hemodialyzer for a shorter time effectively evoked a larger Aß influx. To evoke Aß1-42 influx, PSf hemodialyzer alone was effective enough. These findings of devices and treatment time may lead to optimal clinical settings for therapy and prevention of Alzheimer's disease.

Prevention of postoperative intrapericardial adhesion by dextrin hydrogel.

OBJECTIVE: Postoperative intrapericardial adhesion increases the risk of complications in patients undergoing reoperation. We investigated the effect of a bioabsorbable dextrin hydrogel (DHG) on the formation of intrapericardial adhesions. METHODS: Intrapericardial adhesion was surgically induced in Japanese white rabbits with DHG treatment (Adh + DHG) or without DHG treatment (Adh). The sham group was not treated with DHG and intrapericardial adhesion was not induced. The extent of intrapericardial adhesion was assessed by adhesion scoring and crystal violet staining of the pericardial cavity. Bromodeoxyuridine (BrdU) uptake assay was performed to assess the proliferative response to the injury in the tissue beneath the intrapericardial adhesion. RESULTS: The Adh + DHG group showed looser intrapericardial adhesions compared to the Adh group. The adhesion area of the Adh + DHG group was 4.6 ± 2.2%, whereas that of the Adh group was 32.6 ± 6.4% at the end of the 28-day observation period (p < 0.01). The induction of intrapericardial adhesion resulted in a proliferative response mainly in the cardiac tissue just beneath the adhesion. There were 48.6 ± 10.7 cells/0.1 mm2 BrdU-positive cells in the Adh + DHG group and 135.7 ± 23.8 cells/0.1 mm2 BrdU-positive cells in the Adh group on day 28 (p < 0.05). CONCLUSION: These findings indicate that DHG effectively prevented intrapericardial adhesion in this model.

Ying and Yang of Stat3 in pathogenesis of aortic dissection.

Aortic dissection (AD) is a medical emergency, in which acute destruction of aortic wall occurs with unknown etiology. Recent studies have uncovered the critical role of inteleukin-6 (IL-6) and inflammatory cells including macrophages in the disease mechanism of AD. IL-6 activates janus kinase and signal transducer and activator of transcription 3 (STAT3) to alter the gene expression program in many cell types, thus regulating various aspects of inflammatory response. We found that in human AD tissue, STAT3 was activated in infiltrating macrophages and in medial smooth muscle cells (SMCs), suggesting that STAT3 may regulate the response of these cell types. However, it is unknown how Stat3 regulates the cell type-specific response in pathogenesis of AD. The role of STAT3 was examined in genetically modified mice in which STAT3 sensitivity was enhanced specifically in macrophages or in SMCs by tissue-specific deletion of suppressor of cytokine signaling 3 (Socs3), a negative regulator of STAT3. Macrophage-specific deletion of Socs3 caused acute enhancement of STAT3 activation, M1-dominant differentiation of macrophages, suppression of tissue repair response of SMCs, and exaggerated AD. In contrast, SMC-specific deletion of Socs3 caused chronic STAT3 activation and low-grade inflammatory response in aortic walls, activation of fibroblasts, M2-dominant differentiation of macrophages, increase in adventitial collagen deposition, resulting in the protection of aorta from AD by reinforcing the tensile strength of the aortic walls. Therefore, STAT3 regulates the balance between the destruction and the reinforcement of the aortic tissue, depending on the cell types and the time course of STAT3 activation, which ultimately regulates the development of AD. Elucidating such a dynamic mechanism to regulate the aortic tissue integrity would be essential to decipher the molecular pathogenesis of AD.

The Roles of Tenascins in Cardiovascular, Inflammatory, and Heritable Connective Tissue Diseases.

Tenascins are a family of multifunctional extracellular matrix (ECM) glycoproteins with time- and tissue specific expression patterns during development, tissue homeostasis, and diseases. There are four family members (tenascin-C, -R, -X, -W) in vertebrates. Among them, tenascin-X (TNX) and tenascin-C (TNC) play important roles in human pathologies. TNX is expressed widely in loose connective tissues. TNX contributes to the stability and maintenance of the collagen network, and its absence causes classical-like Ehlers-Danlos syndrome (clEDS), a heritable connective tissue disorder. In contrast, TNC is specifically and transiently expressed upon pathological conditions such as inflammation, fibrosis, and cancer. There is growing evidence that TNC is involved in inflammatory processes with proinflammatory or anti-inflammatory activity in a context-dependent manner. In this review, we summarize the roles of these two tenascins, TNX and TNC, in cardiovascular and inflammatory diseases and in clEDS, and we discuss the functional consequences of the expression of these tenascins for tissue homeostasis.

A Novel Hybrid Drug Delivery System for Treatment of Aortic Aneurysms.

Ongoing aortic wall degeneration and subsequent aneurysm exclusion failure are major concerns after an endovascular aneurysm repair with a stent-graft. An ideal solution would be a drug therapy that targets the aortic wall and inhibits wall degeneration. Here, we described a novel drug delivery system, which allowed repetitively charging a graft with therapeutic drugs and releasing them to the aortic wall in vivo. The system was composed of a targeted graft, which was labeled with a small target molecule, and the target-recognizing nanocarrier, which contained suitable drugs. We developed the targeted graft by decorating a biotinylated polyester graft with neutravidin. We created the target-recognizing nanocarrier by conjugating drug-containing liposomes with biotinylated bio-nanocapsules. We successfully demonstrated that the target-recognizing nanocarriers could bind to the targeted graft, both in vitro and in blood vessels of live mice. Moreover, the drug released from our drug delivery system reduced the expression of matrix metalloproteinase-9 in mouse aortas. Thus, this hybrid system represents a first step toward an adjuvant therapy that might improve the long-term outcome of endovascular aneurysm repair.

The Role of Syk in Inflammatory Response of Human Abdominal Aortic Aneurysm Tissue.

Objective: Inflammatory response is central to pathogenesis of abdominal aortic aneurysm (AAA). Recently, we reported that Syk, a signaling molecule in inflammatory cells, promotes AAA development in a mouse model. In this study, we aimed to investigate the role of Syk in human AAA pathogenesis. Materials and Methods: We obtained human AAA wall samples during open surgical aortic repair at Kurume University Hospital. Immunohistochemical analyses of AAA samples were performed for Syk activation and cell type markers. Ex vivo culture of human AAA tissue was utilized to evaluate the effect of P505-15, a Syk inhibitor, on secretions of interleukin-6 (IL-6) and matrix metalloproteinases (MMPs). Results: Immunohistochemical analysis showed infiltration of B cells, T cells, and macrophages in AAA samples. Syk activation was localized mainly in B cells and part of macrophages. AAA tissue in culture secreted IL-6, MMP-9, and MMP-2 without any stimulation. The unstimulated secretions of IL-6, MMP-9, and MMP-2 were insensitive to P505-15. Secretions of IL-6 and MMP-9 were enhanced by exogenous normal human immunoglobulin G (IgG), which was suppressed by P505-15, whereas secretion of MMP-2 was insensitive to IgG or P505-15. Conclusion: These results demonstrate an important role of Syk for IgG-dependent inflammatory response in human AAA.

Therapeutic Effect of Rapamycin on Aortic Dissection in Mice.

Aortic dissection (AD) is a serious clinical condition that is unpredictable and frequently results in fatal outcome. Although rapamycin, an inhibitor of mechanistic target of rapamycin (mTOR), has been reported to be effective in preventing aortopathies in mouse models, its mode of action has yet to be clarified. A mouse AD model that was created by the simultaneous administration of ß-aminopropionitrile (BAPN) and angiotensin II (AngII) for 14 days. Rapamycin treatment was started either at day 1 or at day 7 of BAPN+AngII challenge, and continued throughout the observational period. Rapamycin was effective both in preventing AD development and in suppressing AD progression. On the other hand, gefitinib, an inhibitor of growth factor signaling, did not show such a beneficial effect, even though both rapamycin and gefitinib suppressed cell cycle activation in AD. Rapamycin suppressed cell cycle-related genes and induced muscle development-related genes in an AD-related gene expression network without a major impact on inflammation-related genes. Rapamycin augmented the activation of Akt1, Akt2, and Stat3, and maintained the contractile phenotype of aortic smooth muscle cells. These findings indicate that rapamycin was effective both in preventing the development and in suppressing the progression of AD, indicating the importance of the mTOR pathway in AD pathogenesis.

Interleukin-22 Directly Activates Myocardial STAT3 (Signal Transducer and Activator of Transcription-3) Signaling Pathway and Prevents Myocardial Ischemia Reperfusion Injury.

BACKGROUND Interleukin (IL)-22, a member of the IL-10 cytokine family, is the only known cytokine that is secreted by immune cells but does not target immune cells; it mainly targets epithelial cells. In this study, we aimed to determine whether IL-22 administration could activate the myocardial STAT3 (signal transducer and activator of transcription-3) signaling pathway, and thus prevent myocardial injury, in a mouse model of ischemia reperfusion injury. METHODS AND RESULTS We evaluated the STAT3 activation after IL-22 injection by Western blot analysis and immunostaining for phosphorylated STAT3 in the heart and found that STAT3 activation in heart tissue rapidly peaked after IL-22 injection. Coimmunostaining of phosphorylated STAT3 and α-actinin revealed that STAT3 activation occurred in cardiomyocytes after IL-22 administration. In heart tissue from intact mice, real-time PCR demonstrated significant expression of IL-22 receptor subunit 1, and coimmunostaining of IL-22 receptor subunit 1 and α-actinin showed IL-22 receptor subunit 1 expression in cardiomyocytes. In cultured cardiomyocytes, IL-22 activated STAT3, and we detected IL-22 receptor subunit 1 expression. Overall, these results indicated that IL-22 directly activated the myocardial IL-22-receptor subunit 1-STAT3 signaling pathway. Following ischemia reperfusion, compared with PBS-treated mice, IL-22-treated mice exhibited a significantly reduced infarct size, significantly reduced myocardial apoptosis, and significantly enhanced phosphorylated STAT3 expression. Moreover, heart tissue from IL-22-treated mice exhibited a significantly reduced expression ratio of phosphorylated p53 to p53. CONCLUSIONS Our present findings suggest that IL-22 directly activated the myocardial STAT3 signaling pathway and acted as a cardioprotective cytokine to ameliorate acute myocardial infarction after ischemia reperfusion.

MRTF-A promotes angiotensin II-induced inflammatory response and aortic dissection in mice.

Aortic dissection (AD) is a major cause of acute aortic syndrome with high mortality due to the destruction of aortic walls. Although recent studies indicate the critical role of inflammation in the disease mechanism of AD, it is unclear how inflammatory response is initiated. Here, we demonstrate that myocardin-related transcription factor A (MRTF-A), a signal transducer of humoral and mechanical stress, plays an important role in pathogenesis of AD in a mouse model. A mouse model of AD was created by continuous infusion of angiotensin II (AngII) that induced MRTF-A expression and caused AD in 4 days. Systemic deletion of Mrtfa gene resulted in a marked suppression of AD development. Transcriptome and gene annotation enrichment analyses revealed that AngII infusion for 1 day caused pro-inflammatory and pro-apoptotic responses before AD development, which were suppressed by Mrtfa deletion. AngII infusion for 1 day induced pro-inflammatory response, as demonstrated by expressions of Il6, Tnf, and Ccl2, and apoptosis of aortic wall cells, as detected by TUNEL staining, in an MRTF-A-dependent manner. Pharmacological inhibition of MRTF-A by CCG-203971 during AngII infusion partially suppressed AD phenotype, indicating that acute suppression of MRTF-A is effective in preventing the aortic wall destruction. These results indicate that MRTF-A transduces the stress of AngII challenge to the pro-inflammatory and pro-apoptotic responses, ultimately leading to AD development. Intervening this pathway may represent a potential therapeutic strategy.

Genetic Deletion of Socs3 in Smooth Muscle Cells Ameliorates Aortic Dissection in Mice.

Aortic dissection (AD) is the acute destruction of aortic wall and is reportedly induced by inflammatory response. Here we investigated the role of smooth muscle Socs3 (a negative regulator of Janus kinases/signal transducer and activator of transcription signaling) in AD pathogenesis using a mouse model generated via ß-aminopropionitrile and angiotensin II infusion. Socs3 deletion specifically in smooth muscle cells yielded a chronic inflammatory response of the aortic wall, which was associated with increased fibroblasts, reinforced aortic tensile strength, and less-severe tissue destruction. Although an acute inflammatory response is detrimental in AD, smooth muscle-regulated inflammatory response seemed protective against AD.

High Salt Intake Worsens Aortic Dissection in Mice: Involvement of IL (Interleukin)-17A-Dependent ECM (Extracellular Matrix) Metabolism.

OBJECTIVE: Aortic dissection (AD) is a fatal disease that occurs suddenly without preceding clinical signs or symptoms. Although high salt intake is a proposed risk factor for cardiovascular diseases, the relationship between AD and high salt intake has not been clarified. We examined the effect of high-salt challenge on a mouse AD model. Approach and Results: AD was induced in male mice by continuous infusion of ß-aminopropionitrile and Ang II (angiotensin II). High-salt challenge exacerbated aortic wall destruction in AD. Deletion of Il17a (IL-17KO [IL (interleukin)-17A knockout]) did not affect the AD phenotype at baseline, but it abolished the high salt-induced worsening of the aortic destruction. Unexpectedly, aortas of IL-17KO mice exhibited global changes in ECM (extracellular matrix)-related genes without alteration of proinflammatory genes, altered architecture of collagen fibers, and reduced stiffness before AD induction. The aortas of IL-17KO mice were less sensitive to AD-inducing stimuli, as shown by the induction of phenotypic modulation markers SMemb and vimentin, suggesting a reduced stress response. The aortas of IL-17KO mice had a higher population of smooth muscle cells with nuclear-localized phosphorylated Smad2, indicative of TGFß (transforming growth factor-beta) signal activation. Consistently, pretreatment of smooth muscle cells in culture with IL-17A blunted the activation of Smad2 by TGFß1. CONCLUSIONS: These findings indicate that high salt intake has a worsening effect on AD in the context of high aortic wall stiffness, which is under the control of IL-17A through ECM metabolism. Therefore, salt restriction may represent a low-cost and practical way to reduce AD risk.

Indomethacin reduces rates of aortic dissection and rupture of the abdominal aorta by inhibiting monocyte/macrophage accumulation in a murine model.

Aortic dissection is a life-threatening condition, which is characterised by separation of the constituent layers of the aortic wall. We have recently shown that monocyte/macrophage infiltration into the aortic wall is a pathogenic mechanism of the condition. In the present study, we investigated whether the anti-inflammatory agent, indomethacin, could inhibit monocyte/macrophage accumulation in the aortic wall and ensuing dissection. Indomethacin was administered (from 3 days prior with daily oral administration) to mice in which aortic dissection was induced using beta-aminopropionitrile (BAPN) and angiotensin II (Ang II) infusion (2 weeks). Indomethacin prevented death from abdominal aortic dissection and decreased incidence of aortic dissection by as high as 40%. Histological and flow cytometry analyses showed that indomethacin administration resulted in inhibition of monocyte transendothelial migration and monocyte/macrophage accumulation in the aortic wall. These results indicate that indomethacin administration reduces rate of onset of aortic dissection in a murine model of the condition.

STAT3 Activation Correlates with Adventitial Neutrophil Infiltration in Human Aortic Dissection.

Objective: Aortic dissection (AD) is a fatal disease that is caused by the rapid destruction of the aortic wall. Although recent studies in animal models indicate an important relationship between inflammation and tissue destruction, activation status of inflammatory signaling and its relation to the inflammatory cell infiltration are poorly characterized in human AD. Materials and Methods: We examined the activation of inflammatory signaling molecules NFκB and STAT3, and neutrophil infiltration in AD tissue samples that were obtained during the surgical repair within 24 h after AD onset. Results: Activation of NFκB was observed mainly in the intima both in AD samples and in aortic samples without AD. Activation of STAT3 was observed in AD samples, but not in the aortic sample without AD. Neutrophil infiltration was observed predominantly in the adventitial layer of AD samples. Histological analysis revealed that STAT3 was activated in cells other than neutrophils. Notably, STAT3 activation and neutrophil infiltration showed positive correlation in adventitial layer of AD tissue. Conclusion: These findings demonstrated that adventitial STAT3 activation was associated with neutrophil infiltration, suggesting their importance in AD pathogenesis.

Activation of the AKT Pathway in the Ascending Aorta With Bicuspid Aortic Valve.

BACKGROUND: Dilatation of the ascending aorta affects those patients with bicuspid aortic valve (BAV), even after valvular surgery, possibly due to tissue fragility. The goal of the study was the molecular characterization of aorta with BAV compared to that with normal tricuspid aortic valve (TAV). Methods and Results: The subjects were patients who underwent surgery for aortic valve stenosis in 2013 and 2014. Nine patients with BAV and 13 with TAV were examined. There was no difference in the clinical characteristics or grade of aortic valve stenosis, but the diameters of the ascending aorta were significantly higher in the BAV group. The ascending aortic specimens were subjected to transcriptome analyses, which revealed the changes in receptor tyrosine kinase (RTK) pathway-related genes between TAV and BAV samples. Immunohistochemical study revealed higher staining of phosphorylated AKT (pAKT) in the media of the ascending aorta in the BAV group, regardless of the size of ascending aorta, whereas total AKT did not show such a difference. Immunofluorescence staining revealed the AKT activation was mainly in the medial vascular smooth muscle cells. CONCLUSIONS: The results showed that the RTK-AKT pathway in the medial layer of the ascending aorta is activated in aortae with BAV. Activation of this pathway may be associated with fragility and dilatation of the ascending aorta with BAV.

Cytokine Profile of Human Abdominal Aortic Aneurysm: Involvement of JAK/STAT Pathway.

Objective: Abdominal aortic aneurysm (AAA) is characterized by inflammation and destruction of normal tissue architecture. The present study aimed to evaluate the inflammatory signaling cascade by analyzing the cytokines of AAA tissue. Materials and Methods: We analyzed the comprehensive cytokine secretion profiles of 52 cytokines from human AAA in four patients with AAA using fluorescent beads-based multiplex assay. Further, the effect of janus kinase (JAK) inhibition by pyridone 6 on cytokine profiles was also evaluated. Results: Cytokine secretion profiles were found to be similar among the four patients. A high level of JAK/signal transducers and activator of transcription (STAT) pathway activity in AAA tissue in culture was maintained, which may be attributed to the secretion of endogenous JAK-activating cytokines. Inhibition of JAK by pyridone 6 resulted in the suppression of STAT3 phosphorylation and secretion of a subset of chemokines and JAK-activating cytokines. However, the inhibition of JAK had no effect on the secretion of matrix metalloproteinase (MMP)-2, MMP-9, or TGF-ß family that is responsible for the metabolism of extracellular matrix. Conclusion: The findings of the present study suggested that AAA tissue exhibits a stereotypical profile of cytokine secretion, where JAK/STAT pathway may play a role in regulating a subset of cytokines. Identification of such a cytokine profile may reveal potential diagnostic markers and therapeutic targets for AAA.

Characterization of SMAD2 Activation in Human Thoracic Aortic Aneurysm.

Objective: Thoracic aortic aneurysm (TAA) reflects the local expansion of the thoracic aorta; the underlying causal molecular mechanism of TAA is not well understood. Recent studies have shown the importance of transforming growth factor beta (TGFß) signaling in Marfan and Loeys-Dietz syndromes; however, its role in non-familial, non-syndromic TAA remains unclear. Materials and Methods: We performed histochemical and immunohistochemical analyses for activated (phosphorylated) SMAD2 (P-SMAD2) as an indicator of TGFß signaling activities in the ascending TAA tissue as well as in the ascending aortic tissue with a normal diameter obtained from 7 patients without any clinical findings suggesting familial or syndromic TAA. Results: TAA samples showed a higher P-SMAD2-positive area than samples with a normal diameter. P-SMAD2 signal was higher in the outer zone of the aortic and TAA walls. Within the TAA tissue, P-SMAD2 staining showed the following two distinct patterns: layer-like staining at the border of the medial layer and the thickened intima and a spot-like staining within the medial layer surrounding the microvessels. Conclusion: These findings suggested that TGFß signaling is activated in several distinct histopathological contexts in TAA, suggesting a complex role of TGFß.

Involvement of B Cells, Immunoglobulins, and Syk in the Pathogenesis of Abdominal Aortic Aneurysm.

BACKGROUND: Abdominal aortic aneurysm (AAA) is a potentially life-threatening disease that is common in older individuals. Currently, therapeutic options are limited to surgical interventions. Although it has long been known that AAA tissue is enriched in B cells and immunoglobulins, their involvement in AAA pathogenesis remains controversial. METHODS AND RESULTS: We investigated the role of B cells and immunoglobulins in a murine model of AAA, induced with a periaortic application of CaCl2, and in human AAA. Both human and mouse AAA tissue showed B-cell infiltration. Mouse AAA tissue showed deposition of IgG and activation of Syk, a key molecule in B-cell activation and immunoglobulin function, which were localized to infiltrating cells including B cells and macrophages. B-cell-deficient muMT mice showed suppression of AAA development that was associated with reduced activation of Syk and less expression of matrix metalloproteinase-9. Administration of exogenous immunoglobulins restored the blunted Syk activation and AAA development in muMT mice. Additionally, exogenous immunoglobulins induced interleukin-6 and metalloproteinase-9 secretions in human AAA tissue cultures. Furthermore, administration of R788, a specific Syk inhibitor, suppressed AAA expansion, reduced inflammatory response, and reduced immunoglobulin deposition in AAA tissue. CONCLUSIONS: From these results, we concluded that B cells and immunoglobulins participated in AAA pathogenesis by promoting inflammatory and tissue-destructive activities. Finally, we identified Syk as a potential therapeutic target.