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.

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.

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.

Cryoballoon Ablation Induced Hyperkalemia due to Possible Cold Agglutinin Disease.

Cryoballoon ablation is a well-established therapeutic tool for paroxysmal atrial fibrillation (PAF). We herein report a rare case of a 69-year-old man with PAF undergoing hemodialysis due to chronic kidney disease who developed hyperkalemia caused by possible cold agglutinin disease during cryoballoon ablation therapy. During the procedure, his electrocardiogram showed wide QRS when we finished cryoablation therapy. We detected hyperkalemia and performed urgent hemodialysis. We should bear in mind that cold agglutinin disease can occur during cryoballoon ablation.

The Use of Bromocriptine for Peripartum Cardiomyopathy after Twin Delivery via Oocyte Donation.

Peripartum cardiomyopathy (PPCM) is rare but life-threatening. We herein report the case of a 48-year-old woman with PPCM after oocyte donation and delivery of twins. Two weeks after delivery, she suffered from severe symptoms of heart failure [orthopnea, New York Heart Association (NYHA) class IV, pulmonary edema and a reduced left ventricular ejection fraction of 18%]. Although standard heart failure therapy was effective for diminishing the congestion, it was not sufficient to improve her symptoms or left ventricular systolic dysfunction. During admission, we added bromocriptine. A year later after the onset, she was in a good state with an improved left ventricular systolic function.

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.

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.

Role of Macrophage Socs3 in the Pathogenesis of Aortic Dissection.

BACKGROUND: Aortic dissection (AD) is a life-threatening medical emergency caused by the abrupt destruction of the intimomedial layer of the aortic walls. Given that previous studies have reported the involvement of proinflammatory cytokine interleukin-6 in AD pathogenesis, we investigated the role of signal transduction and activator of transcription 3 signaling, a downstream pathway of interleukin-6 in macrophages in pathogenesis of AD. METHODS AND RESULTS: We characterized the pathological and molecular events triggered by aortic stress, which can lead to AD. Aortic stress on the suprarenal aorta because of infrarenal aorta stiffening and angiotensin II infusion for 1 week caused focal medial rupture at the branching point of the celiac trunk and superior mesenteric artery. This focal medial rupture healed in 6 weeks in wild-type (WT) mice, but progressed to AD in mice with macrophage-specific deletion of Socs3 gene (mSocs3-KO). mSocs3-KO mice showed premature activation of cell proliferation, an inflammatory response, and skewed differentiation of macrophages toward the tissue-destructive phenotype. Concomitantly, they showed aberrant phenotypic modulation of smooth muscle cells and transforming growth factor beta signaling, which are likely to participate in tissue repair. Human AD samples revealed signal transduction and activator of transcription 3 activation in adventitial macrophages adjacent to the site of tissue destruction. CONCLUSIONS: These findings suggest that AD development is preceded by focal medial rupture, in which macrophage Socs3 maintains proper inflammatory response and differentiation of SMCs, thus promoting fibrotic healing to prevent tissue destruction and AD development. Understanding the sequence of the pathological and molecular events preceding AD development will help predict and prevent AD development and progression.

The role of IL-6 in pathogenesis of abdominal aortic aneurysm in mice.

Although the pathogenesis of abdominal aortic aneurysm (AAA) remains unclear, evidence is accumulating to support a central role for inflammation. Inflammatory responses are coordinated by various soluble cytokines of which IL-6 is one of the major proinflammatory cytokines. In this study we examined the role of IL-6 in the pathogenesis of experimental AAA induced by a periaortic exposure to CaCl2 in mice. We now report that the administration of MR16-1, a neutralizing monoclonal antibody specific for the mouse IL-6 receptor, mildly suppressed the development of AAA. The inhibition of IL-6 signaling provoked by MR16-1 also resulted in a suppression of Stat3 activity. Conversely, no significant changes in either NFκB activity, Jnk activity or the expression of matrix metalloproteinases (Mmp) -2 and -9 were identified. Transcriptome analyses revealed that MR16-1-sensitive genes encode chemokines and their receptors, as well as factors that regulate vascular permeability and cell migration. Imaging cytometric analyses then consistently demonstrated reduced cellular infiltration for MR16-1-treated AAA. These results suggest that IL-6 plays an important but limited role in AAA pathogenesis, and primarily regulates cell migration and infiltration. These data would also suggest that IL-6 activity may play an important role in scenarios of continuous cellular infiltration, possibly including human AAA.

Unstable Angina Pectoris in a 22-year-old Female Patient.

Because of the protective effect of estrogen for atherosclerosis, the prevalence of acute coronary syndrome in women before menopause is low. We report a rare case of unstable angina in a young Japanese female who had a history of cigarette smoking and contraceptive use. Her coronary stenosis was successfully treated by percutaneous coronary intervention.

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.

Hepatocyte growth factor promotes an anti-inflammatory cytokine profile in human abdominal aortic aneurysm tissue.

Abdominal aortic aneurysm (AAA) is characterized by the destruction of tissue architecture due to chronic inflammation of unknown etiology. Recent studies have indicated that control of inflammation is a promising therapeutic strategy; however, no established pharmacological intervention is currently available for AAA. We found that hepatocyte growth factor (HGF) was expressed in aneurysmal tissue, and colocalized with von Willebrand factor, the endothelial cell marker, in the most damaged part of the aneurysmal walls. In ex vivo cultures of human AAA tissue, exogenously added HGF in the presence of tumor necrosis factor-alpha (TNF-α) enhanced the secretion of anti-inflammatory cytokine interleukin-10 (IL-10) and suppressed the secretion of proinflammatory monocyte/macrophage chemotactic protein-1 (MCP-1). The angiotensin converting enzyme (ACE) inhibitors, imidaprilat and perindoprilat, enhanced the secretion of endogenous HGF, augmented the TNF-α-induced IL-10 secretion and suppressed MCP-1 secretion from AAA tissue. The ACE inhibitors also augmented the expression of HGF in the presence of bradykinin in human aortic endothelial cells in culture (HAECs). In contrast, HGF secretion was not affected by either an angiotensin II type 1 receptor (AT1) antagonist or angiotensin II in AAA tissue or in HAECs. These results suggested that angiotensin converting enzyme inhibitors may be useful in controlling chronic inflammation in AAA, partly due to their enhancement of HGF secretion.