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.

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.

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.

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.

Genetic Ablation of MicroRNA-33 Attenuates Inflammation and Abdominal Aortic Aneurysm Formation via Several Anti-Inflammatory Pathways.

OBJECTIVE: Abdominal aortic aneurysm (AAA) is an increasingly prevalent and ultimately fatal disease with no effective pharmacological treatment. Because matrix degradation induced by vascular inflammation is the major pathophysiology of AAA, attenuation of this inflammation may improve its outcome. Previous studies suggested that miR-33 (microRNA-33) inhibition and genetic ablation of miR-33 increased serum high-density lipoprotein cholesterol and attenuated atherosclerosis. APPROACH AND RESULTS: MiR-33a-5p expression in central zone of human AAA was higher than marginal zone. MiR-33 deletion attenuated AAA formation in both mouse models of angiotensin II- and calcium chloride-induced AAA. Reduced macrophage accumulation and monocyte chemotactic protein-1 expression were observed in calcium chloride-induced AAA walls in miR-33-/- mice. In vitro experiments revealed that peritoneal macrophages from miR-33-/- mice showed reduced matrix metalloproteinase 9 expression levels via c-Jun N-terminal kinase inactivation. Primary aortic vascular smooth muscle cells from miR-33-/- mice showed reduced monocyte chemotactic protein-1 expression by p38 mitogen-activated protein kinase attenuation. Both of the inactivation of c-Jun N-terminal kinase and p38 mitogen-activated protein kinase were possibly because of the increase of ATP-binding cassette transporter A1 that is a well-known target of miR-33. Moreover, high-density lipoprotein cholesterol derived from miR-33-/- mice reduced expression of matrix metalloproteinase 9 in macrophages and monocyte chemotactic protein-1 in vascular smooth muscle cells. Bone marrow transplantation experiments indicated that miR-33-deficient bone marrow cells ameliorated AAA formation in wild-type recipients. MiR-33 deficiency in recipient mice was also shown to contribute the inhibition of AAA formation. CONCLUSIONS: These data strongly suggest that inhibition of miR-33 will be effective as a novel strategy for treating AAA.

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.

Loss of MURC/Cavin-4 induces JNK and MMP-9 activity enhancement in vascular smooth muscle cells and exacerbates abdominal aortic aneurysm.

Abdominal aortic aneurysm (AAA) is relatively common in elderly patients with atherosclerosis. MURC (muscle-restricted coiled-coil protein)/Cavin-4 modulating the caveolae function of muscle cells is expressed in cardiomyocytes, skeletal muscle cells and smooth muscle cells. Here, we show a novel functional role of MURC/Cavin-4 in vascular smooth muscle cells (VSMCs) and AAA development. Both wild-type (WT) and MURC/Cavin-4 knockout (MURC-/-) mice subjected to periaortic application of CaCl2 developed AAAs. Six weeks after CaCl2 treatment, internal and external aortic diameters were significantly increased in MURC-/- AAAs compared with WT AAAs, which were accompanied by advanced fibrosis in the tunica media of MURC-/- AAAs. The activity of JNK and matrix metalloproteinase (MMP) -2 and -9 were increased in MURC-/- AAAs compared with WT AAAs at 5 days after CaCl2 treatment. At 6 weeks after CaCl2 treatment, MURC-/- AAAs exhibited attenuated JNK activity compared with WT AAAs. There was no difference in the activity of MMP-2 or -9 between saline and CaCl2 treatments. In MURC/Cavin-4-knockdown VSMCs, TNFα-induced activity of JNK and MMP-9 was enhanced compared with control VSMCs. Furthermore, WT, MURC-/-, apolipoprotein E-/- (ApoE-/-), and MURC/Cavin-4 and ApoE double-knockout (MURC-/-ApoE-/-) mice were subjected to angiotensin II (Ang II) infusion. In both ApoE-/- and MURC-/-ApoE-/- mice infused for 4 weeks with Ang II, AAAs were promoted. The internal aortic diameter was significantly increased in Ang II-infused MURC-/-ApoE-/- mice compared with Ang II-infused ApoE-/- mice. In MURC/Cavin-4-knockdown VSMCs, Ang II-induced activity of JNK and MMP-9 was enhanced compared with control VSMCs. Our results suggest that MURC/Cavin-4 in VSMCs modulates AAA progression at the early stage via the activation of JNK and MMP-9. MURC/Cavin-4 is a potential therapeutic target against AAA progression.

Inflammasome activation by mitochondrial oxidative stress in macrophages leads to the development of angiotensin II-induced aortic aneurysm.

OBJECTIVE: Abdominal aortic aneurysm (AAA) is considered a chronic inflammatory disease; however, the molecular basis underlying the sterile inflammatory response involved in the process of AAA remains unclear. We previously showed that the inflammasome, which regulates the caspase-1-dependent interleukin-1ß production, mediates the sterile cardiovascular inflammatory responses. Therefore, we hypothesized that the inflammasome is a key mediator of initial inflammation in AAA formation. APPROACH AND RESULTS: Apoptosis-associated speck-like protein containing a caspase recruitment domain is highly expressed in adventitial macrophages in human and murine AAA tissues. Using an established mouse model of AAA induced by continuous infusion of angiotensin II in Apoe(-/-) mice, NLR family pyrin domain containing 3 (NLRP3), apoptosis-associated speck-like protein containing a caspase recruitment domain, and caspase-1 deficiency in Apoe(-/-) mice were shown to decrease the incidence, maximal diameter, and severity of AAA along with adventitial fibrosis and inflammatory responses significantly, such as inflammatory cell infiltration and cytokine expression in the vessel wall. NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain, and caspase-1 deficiency in Apoe(-/-) mice also reduced elastic lamina degradation and metalloproteinase activation in the early phase of AAA formation. Furthermore, angiotensin II stimulated generation of mitochondria-derived reactive oxygen species in the adventitial macrophages, and this mitochondria-derived reactive oxygen species generation was inhibited by NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain, and caspase-1 deficiency. In vitro experiments revealed that angiotensin II stimulated the NLRP3 inflammasome activation and subsequent interleukin-1ß release in macrophages, and this activation was mediated through an angiotensin type I receptor/mitochondria-derived reactive oxygen species-dependent pathway. CONCLUSIONS: Our results demonstrate the importance of the NLRP3 inflammasome in the initial inflammatory responses in AAA formation, indicating its potential as a novel therapeutic target for preventing AAA progression.

Prostaglandin E2 inhibits elastogenesis in the ductus arteriosus via EP4 signaling.

BACKGROUND: Elastic fiber formation begins in mid-gestation and increases dramatically during the last trimester in the great arteries, providing elasticity and thus preventing vascular wall structure collapse. However, the ductus arteriosus (DA), a fetal bypass artery between the aorta and pulmonary artery, exhibits lower levels of elastic fiber formation, which promotes vascular collapse and subsequent closure of the DA after birth. The molecular mechanisms for this inhibited elastogenesis in the DA, which is necessary for the establishment of adult circulation, remain largely unknown. METHODS AND RESULTS: Stimulation of the prostaglandin E2 (PGE2) receptor EP4 significantly inhibited elastogenesis and decreased lysyl oxidase (LOX) protein, which catalyzes elastin cross-links in DA smooth muscle cells (SMCs), but not in aortic SMCs. Aortic SMCs expressed much less EP4 than DASMCs. Adenovirus-mediated overexpression of LOX restored the EP4-mediated inhibition of elastogenesis in DASMCs. In EP4-knockout mice, electron microscopic examination showed that the DA acquired an elastic phenotype that was similar to the neighboring aorta. More importantly, human DA and aorta tissues from 7 patients showed a negative correlation between elastic fiber formation and EP4 expression, as well as between EP4 and LOX expression. The PGE2-EP4-c-Src-phospholipase C (PLC)γ-signaling pathway most likely promoted the lysosomal degradation of LOX. CONCLUSIONS: Our data suggest that PGE2 signaling inhibits elastogenesis in the DA, but not in the aorta, through degrading LOX protein. Elastogenesis is spatially regulated by PGE2-EP4 signaling in the DA.

BMP type I receptor inhibition attenuates endothelial dysfunction in mice with chronic kidney disease.

The molecular mechanisms of endothelial dysfunction and vascular calcification have been considered independently and potential links are currently unknown in chronic kidney disease (CKD). Bone morphogenetic protein (BMP) receptor signaling mediates calcification of atherosclerotic plaques. Here we tested whether BMP receptor signaling contributes to endothelial dysfunction, as well as to osteogenic differentiation of vascular smooth muscle cells (VSMCs), in a model of short-term CKD. In C57BL/6 mice, subtotal nephrectomy activated BMP receptor and increased phosphatase-and-tensin homolog (PTEN) protein in the endothelial cells and medial VSMCs without vascular remodeling in the aorta. In the endothelial cells, PTEN induction led to inhibition of the Akt-endothelial nitric oxide synthase (eNOS) pathway and endothelial dysfunction. In VSMCs, the PTEN increase induced early osteogenic differentiation. CKD-induced inhibition of eNOS phosphorylation and the resultant endothelial dysfunction were inhibited in mice with endothelial cell-specific PTEN ablation. Knockout of the BMP type I receptor abolished endothelial dysfunction, the inhibition of eNOS phosphorylation, and VSMC osteogenic differentiation in mice with CKD. A small molecule inhibitor of BMP type I receptor, LDN-193189, prevented endothelial dysfunction and osteogenic differentiation in CKD mice. Thus, BMP receptor activation is a mechanism for endothelial dysfunction in addition to vascular osteogenic differentiation in a short-term CKD model. PTEN may be key in linking BMP receptor activation and endothelial dysfunction in CKD.

Renal Nerve-Mediated Erythropoietin Release Confers Cardioprotection During Remote Ischemic Preconditioning.

BACKGROUND: Remote ischemic preconditioning (RIPC) induced by transient limb ischemia is a powerful innate mechanism of cardioprotection against ischemia. Several described mechanisms explain how RIPC may act through neural pathways or humoral factors; however, the mechanistic pathway linking the remote organ to the heart has not yet been fully elucidated. This study aimed to investigate the mechanisms underlying the RIPC-induced production of Janus kinase (JAK)-signal transducer and activator of the transcription (STAT)-activating cytokines and cardioprotection by using mouse and human models of RIPC. METHODS AND RESULTS: Screened circulating cardioprotective JAK-STAT-activating cytokines in mice unexpectedly revealed increased serum erythropoietin (EPO) levels after RIP induced by transient ischemia. In mice, RIPC rapidly upregulated EPO mRNA and its main transcriptional factor, hypoxia-inducible factor-1α (HIF1α), in the kidney. Laser Doppler blood flowmetry revealed a prompt reduction of renal blood flow (RBF) after RIPC. RIPC activated cardioprotective signaling pathways and the anti-apoptotic Bcl-xL pathway in the heart, and reduced infarct size. In mice, these effects were abolished by administration of an EPO-neutralizing antibody. Renal nerve denervation also abolished RIPC-induced RBF reduction, EPO production, and cardioprotection. In humans, transient limb ischemia of the upper arm reduced RBF and increased serum EPO levels. CONCLUSIONS: Based on the present data, we propose a novel RIPC mechanism in which inhibition of infarct size by RIPC is produced through the renal nerve-mediated reduction of RBF associated with activation of the HIF1α-EPO pathway.

Inhibitory effect of statins on inflammation-related pathways in human abdominal aortic aneurysm tissue.

HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase inhibitors (statins) have been suggested to attenuate abdominal aortic aneurysm (AAA) growth. However, the effects of statins in human AAA tissues are not fully elucidated. The aim of this study was to investigate the direct effects of statins on proinflammatory molecules in human AAA walls in ex vivo culture. Simvastatin strongly inhibited the activation of nuclear factor (NF)-κB induced by tumor necrosis factor (TNF)-α in human AAA walls, but showed little effect on c-jun N-terminal kinase (JNK) activation. Simvastatin, as well as pitavastatin significantly reduced the secretion of matrix metalloproteinase (MMP)-9, monocyte chemoattractant protein (MCP)-2 and epithelial neutrophil-activating peptide (CXCL5) under both basal and TNF-α-stimulated conditions. Similar to statins, the Rac1 inhibitor NSC23766 significantly inhibited the activation of NF-κB, accompanied by a decreased secretion of MMP-9, MCP-2 and CXCL5. Moreover, the effect of simvastatin and the JNK inhibitor SP600125 was additive in inhibiting the secretion of MMP-9, MCP-2 and CXCL5. These findings indicate that statins preferentially inhibit the Rac1/NF-κB pathway to suppress MMP-9 and chemokine secretion in human AAA, suggesting a mechanism for the potential effect of statins in attenuating AAA progression.

Macrophage-derived angiopoietin-like protein 2 accelerates development of abdominal aortic aneurysm.

OBJECTIVE: Recently, we reported that angiopoietin-like protein 2 (Angptl2) functions in various chronic inflammatory diseases. In the present study, we asked whether Angptl2 and its associated chronic inflammation contribute to abdominal aortic aneurysm (AAA). METHODS AND RESULTS: Immunohistochemistry revealed that Angptl2 is abundantly expressed in infiltrating macrophages within the vessel wall of patients with AAA and in a CaCl(2)-induced AAA mouse model. When Angptl2-deficient mice were used in the mouse model, they showed decreased AAA development compared with wild-type mice, as evidenced by reduction in aneurysmal size, less severe destruction of vessel structure, and lower expression of proinflammatory cytokines and matrix metalloproteinase-9. However, no difference in the number of infiltrating macrophages within the aortic aneurysmal vessel wall was observed between genotypes. AAA development was also significantly suppressed in wild-type mice that underwent Angptl2-deficient bone marrow transplantation. Expression levels of proinflammatory cytokines and metalloproteinase-9 in Angptl2-deficient macrophages were significantly decreased, and those decreases were rescued by treatment of Angptl2 deficient macrophages with exogenous Angptl2. CONCLUSIONS: Macrophage-derived Angptl2 contributes to AAA development by inducing inflammation and degradation of extracellular matrix in the vessel wall, suggesting that targeting the Angptl2-induced inflammatory axis in macrophages could represent a new strategy for AAA therapy.

Inhibition of eNOS phosphorylation mediates endothelial dysfunction in renal failure: new effect of asymmetric dimethylarginine.

Patients with chronic kidney disease have elevated circulating asymmetric dimethylarginine (ADMA). Recent studies have suggested that ADMA impairs endothelial nitric oxide synthase (eNOS) by effects other than competition with the substrate L-arginine. Here, we sought to identify the molecular mechanism by which increased ADMA causes endothelial dysfunction in a chronic kidney disease model. In wild-type mice with remnant kidney disease, blood urea nitrogen, serum creatinine, and ADMA were increased by 2.5-, 2-, and 1.2-fold, respectively, without any change in blood pressure. Nephrectomy reduced endothelium-dependent relaxation and eNOS phosphorylation at Ser1177 in isolated aortic rings. In transgenic mice overexpressing dimethylarginine dimethylaminohydrolase-1, the enzyme that metabolizes ADMA, circulating ADMA was not increased by nephrectomy and was decreased to half that of wild-type mice. These mice did not exhibit the nephrectomy-induced inhibition of both endothelium-dependent relaxation and eNOS phosphorylation. In cultured human endothelial cells, agonist-induced eNOS phosphorylation and nitric oxide production were decreased by ADMA at concentrations less than that of L-arginine in the media. Thus, elevated circulating ADMA may be a cause, not an epiphenomenon, of endothelial dysfunction in chronic kidney disease. This effect may be attributable to inhibition of eNOS phosphorylation.

Regression of abdominal aortic aneurysm by inhibition of c-Jun N-terminal kinase.

Abdominal aortic aneurysm (AAA) is a common disease among elderly people that, when surgical treatment is inapplicable, results in progressive expansion and rupture of the aorta with high mortality. Although nonsurgical treatment for AAA is much awaited, few options are available because its molecular pathogenesis remains elusive. Here, we identify JNK as a proximal signaling molecule in the pathogenesis of AAA. Human AAA tissue showed a high level of phosphorylated JNK. We show that JNK programs a gene expression pattern in different cell types that cooperatively enhances the degradation of the extracellular matrix while suppressing biosynthetic enzymes of the extracellular matrix. Selective inhibition of JNK in vivo not only prevented the development of AAA but also caused regression of established AAA in two mouse models. Thus, JNK promotes abnormal extracellular matrix metabolism in the tissue of AAA and may represent a therapeutic target.

RhoH plays critical roles in Fc epsilon RI-dependent signal transduction in mast cells.

RhoH is an atypical small G protein with defective GTPase activity that is specifically expressed in hematopoietic lineage cells. RhoH has been implicated in regulation of several physiological processes including hematopoiesis, integrin activation, and T cell differentiation and activation. In the present study, we investigated the role of RhoH in mast cells by generating RhoH knockout mice. Despite observing normal development of mast cells in vivo, passive systemic anaphylaxis and histamine release were impaired in these mice. We also observed defective degranulation and cytokine production upon FcepsilonRI ligation in RhoH-deficient bone marrow-derived mast cells. Furthermore, FcepsilonRI-dependent activation of Syk and phosphorylation of its downstream targets, including LAT, SLP76, PLCgamma1, and PLCgamma2 were impaired, however phosphorylation of the gamma-subunit of FcepsilonRI remained intact. We also found RhoH-Syk association that was greatly enhanced by active Fyn. Our results indicate that RhoH regulates FcepsilonRI signaling in mast cells by facilitating Syk activation, possibly as an adaptor molecule for Syk.

Tenascin-C is expressed in abdominal aortic aneurysm tissue with an active degradation process.

Abdominal aortic aneurysm (AAA) is a common disease caused by segmental weakening of the aortic walls and progressive aortic dilation leading to the eventual rupture of the aorta. Currently no biomarkers have been established to indicate the disease status of AAA. Tenascin-C (TN-C) is a matricellular protein that is synthesized under pathological conditions. In the current study, we related TN-C expression to the clinical course and the histopathology of AAA to investigate whether the pattern of TN-C expression could indicate the status of AAA. We found that TN-C and matrix metalloproteinase (MMP)-9 were highly expressed in human AAA. In individual human AAA TN-C deposition associated with the tissue destruction, overlapped mainly with the smooth muscle actin-positive cells, and showed a pattern distinct from macrophages and MMP-9. In the mouse model of AAA high TN-C expression was associated with rapid expansion of the AAA diameter. Histological analysis revealed that TN-C was produced mainly by vascular smooth muscle cells and was deposited in the medial layer of the aorta during tissue inflammation and excessive destructive activities. Our findings suggest that TN-C may be a useful biomarker for indicating the pathological status of smooth muscle cells and interstitial cells in AAA.

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.