Surgical strategy for inflammatory thoracic aortic aneurysms in the endovascular surgery era.

OBJECTIVE: Inflammatory thoracic aortic aneurysms (TAAs) are very rare aortic conditions. Resection and replacement of the inflammatory aorta is the first-line treatment, and thoracic endovascular aortic repair (TEVAR) has recently been reported as a less invasive alternative even for this aortic cohort. In the present study, we reviewed our experience with inflammatory TAAs and assessed the preoperative management, surgical procedures, and outcomes. METHODS: From 2006 to 2019, 21 surgeries were performed for inflammatory TAAs in 17 of 2583 patients (0.7%) who had undergone cardiovascular surgery at our institution. The etiologies were Takayasu's arteritis in 13 patients, giant cell arteritis in 2, antineutrophil cytoplasmic antibody-associated vasculitis in 1, and unknown in 1. The mean follow-up period was 66.2 ± 50.2 months (range, 19-186 months). RESULTS: Three patients had undergone multiple surgeries. The aorta was replaced in 14 patients (ascending aorta in 9, aortic arch in 4, and thoracoabdominal aorta in 1). Three isolated TEVARs were performed in two patients and single-stage hybrid aortic repair (ascending aorta and partial arch replacement combined with zone 0 TEVAR) in four patients for extended arch and descending thoracic aortic aneurysms. Stent grafts were deployed on the native aorta in five of the seven TEVARs. The perioperative inflammation was well-controlled with prednisolone (mean dose, 7.4 ± 9.4 mg) in all patients except for one who had required two surgeries under inflammation-uncontrolled situations. No aorta-related complications, including anastomotic aneurysms and TEVAR-related aortic dissection, developed during the follow-up period, and the 5-year freedom from all-cause death was 92.9%. CONCLUSIONS: The mid-term outcomes of surgery for inflammatory TAAs were acceptable. Although replacement remains the standard procedure for inflammatory TAAs, TEVAR is a less invasive acceptable alternative when the inflammation is properly managed.

TNFα induces endothelial dysfunction in rheumatoid arthritis via LOX-1 and arginase 2: reversal by monoclonal TNFα antibodies.

AIMS: Rheumatoid arthritis (RA) is a chronic inflammatory disease affecting joints and blood vessels. Despite low levels of low-density lipoprotein cholesterol (LDL-C), RA patients exhibit endothelial dysfunction and are at increased risk of death from cardiovascular complications, but the molecular mechanism of action is unknown. We aimed in the present study to identify the molecular mechanism of endothelial dysfunction in a mouse model of RA and in patients with RA. METHODS AND RESULTS: Endothelium-dependent relaxations to acetylcholine were reduced in aortae of two tumour necrosis factor alpha (TNFα) transgenic mouse lines with either mild (Tg3647) or severe (Tg197) forms of RA in a time- and severity-dependent fashion as assessed by organ chamber myograph. In Tg197, TNFα plasma levels were associated with severe endothelial dysfunction. LOX-1 receptor was markedly up-regulated leading to increased vascular oxLDL uptake and NFκB-mediated enhanced Arg2 expression via direct binding to its promoter resulting in reduced NO bioavailability and vascular cGMP levels as shown by ELISA and chromatin immunoprecipitation. Anti-TNFα treatment with infliximab normalized endothelial function together with LOX-1 and Arg2 serum levels in mice. In RA patients, soluble LOX-1 serum levels were also markedly increased and closely related to serum levels of C-reactive protein. Similarly, ARG2 serum levels were increased. Similarly, anti-TNFα treatment restored LOX-1 and ARG2 serum levels in RA patients. CONCLUSIONS: Increased TNFα levels not only contribute to RA, but also to endothelial dysfunction by increasing vascular oxLDL content and activation of the LOX-1/NFκB/Arg2 pathway leading to reduced NO bioavailability and decreased cGMP levels. Anti-TNFα treatment improved both articular symptoms and endothelial function by reducing LOX-1, vascular oxLDL, and Arg2 levels.

Thymus-Derived CD4+CD8+ Cells Reside in Mediastinal Adipose Tissue and the Aortic Arch.

Double-positive CD4+CD8αß+ (DP) cells are thought to reside as T cell progenitors exclusively within the thymus. We recently discovered an unexpected CD4+ and CD8αß+ immune cell population in healthy and atherosclerotic mice by single-cell RNA sequencing. Transcriptomically, these cells resembled thymic DPs. Flow cytometry and three-dimensional whole-mount imaging confirmed DPs in thymus, mediastinal adipose tissue, and aortic adventitia, but nowhere else. Deep transcriptional profiling revealed differences between DP cells isolated from the three locations. All DPs were dependent on RAG2 expression and the presence of the thymus. Mediastinal adipose tissue DPs resided in close vicinity to invariant NKT cells, which they could activate in vitro. Thymus transplantation failed to reconstitute extrathymic DPs, and frequencies of extrathymic DPs were unaltered by pharmacologic inhibition of S1P1, suggesting that their migration may be locally confined. Our results define two new, transcriptionally distinct subsets of extrathymic DPs that may play a role in aortic vascular homeostasis.

Mycophenolate mediated remodeling of gut microbiota and improvement of gut-brain axis in spontaneously hypertensive rats.

Microbiota has a role in the host blood pressure (BP) regulation. The immunosuppressive drug mofetil mycophenolate (MMF) ameliorates hypertension. The present study analyzes whether MMF improves dysbiosis in a genetic model of hypertension. Twenty weeks old male spontaneously hypertensive rats (SHR) and Wistar Kyoto rats (WKY) were randomly divided into three groups: untreated WKY, untreated SHR, and SHR treated with MMF for 5 weeks. MMF treatment restored gut bacteria from the phyla Firmicutes and Bacteroidetes, and acetate- and lactate-producing bacteria to levels similar to those found in WKY, increasing butyrate-producing bacteria. MMF increased the percentage of anaerobic bacteria in the gut. The improvement of gut dysbiosis was associated with an enhanced colonic integrity and a decreased sympathetic drive in the gut. MMF inhibited neuroinflammation in the paraventricular nuclei in the hypothalamus. MMF increased the lower regulatory T cells proportion in mesenteric lymph nodes and Th17 and Th1 infiltration in aorta, improved aortic endothelial function and reduced systolic BP. This study demonstrates for the first time that MMF reduces gut dysbiosis in SHR. This effect could be related to its capability to improve gut integrity due to reduced sympathetic drive in the gut associated to the reduced brain neuroinflammation.

CXCR4-Binding Positron Emission Tomography Tracers Link Monocyte Recruitment and Endothelial Injury in Murine Atherosclerosis.

OBJECTIVE: vMIP-II (viral macrophage inflammatory protein 2)/vCCL2 (viral chemotactic cytokine ligand 2) binds to multiple chemokine receptors, and vMIP-II-based positron emission tomography tracer (64Cu-DOTA-vMIP-II: vMIP-II tracer) accumulates at atherosclerotic lesions in mice. Given that it would be expected to react with multiple chemokine receptors on monocytes and macrophages, we wondered if its accumulation in atherosclerosis lesion-bearing mice might correlate with overall macrophage burden or, alternatively, the pace of monocyte recruitment. Approach and Results: We employed a mouse model of atherosclerosis regression involving adenoassociated virus 8 vector encoding murine Apoe (AAV-mApoE) treatment of Apoe-/- mice where the pace of monocyte recruitment slows before macrophage burden subsequently declines. Accumulation of 64Cu-DOTA-vMIP-II at Apoe-/- plaque sites was strong but declined with AAV-mApoE-induced decline in monocyte recruitment, before macrophage burden reduced. Monocyte depletion indicated that monocytes and macrophages themselves were not the only target of the 64Cu-DOTA-vMIP-II tracer. Using fluorescence-tagged vMIP-II tracer, competitive receptor blocking with CXCR4 antagonists, endothelial-specific Cre-mediated deletion of CXCR4, CXCR4-specific tracer 64Cu-DOTA-FC131, and CXCR4 staining during disease progression and regression, we show endothelial cell expression of CXCR4 is a key target of 64Cu-DOTA-vMIP-II imaging. Expression of CXCR4 was low in nonplaque areas but strongly detected on endothelium of progressing plaques, especially on proliferating endothelium, where vascular permeability was increased and monocyte recruitment was the strongest. CONCLUSIONS: Endothelial injury status of plaques is marked by CXCR4 expression and this injury correlates with the tendency of such plaques to recruit monocytes. Furthermore, our findings suggest positron emission tomography tracers that mark CXCR4 can be used translationally to monitor the state of plaque injury and monocyte recruitment.

The pathology of Kawasaki disease aortitis: a study of 37 cases.

BACKGROUND: Kawasaki disease (KD) is a systemic vasculitis syndrome that occurs most frequently in children. Most clinical and pathological studies have focused on its coronary artery lesions. To date, no detailed studies of the aorta have been conducted. We studied KD autopsy cases with the aims of clarifying the time-course of changes in aortic lesions, the differences in the inflammatory cells and degree of inflammation at various aortic sites, and the progression of the inflammation. MATERIALS AND METHODS: The study materials were aortic specimens taken from 37 KD autopsy cases (acute phase: 19; remote phase: 18). Twenty-seven of the cases also had coronary aneurysms. We chose 3 aortic sites, i.e., the thoracic aorta, aortic root and aortic bifurcation, and we histologically observed and compared those sites in regard to the changes with time, the kinds of infiltrating cells and the number of inflammatory cells. We also observed the relationship between the vasa vasorum and inflammatory cell localization in the tunica media, and examined the progression of inflammation in the tunica media. RESULTS: Destruction of the vascular architecture was not seen in any of the 37 cases, but inflammatory cell infiltration was observed in 90% of the acute-phase cases. The inflammatory cell infiltration involved the tunica intima and tunica adventitia of the aorta on the 6th disease-day, and all layers of the aorta on the 13th disease-day; the infiltration peaked on the 18th disease-day. The infiltration gradually disappeared thereafter, and no significant infiltration was seen in the remote phase. The infiltrating inflammatory cells consisted mainly of CD163-positive macrophages. Comparison of the 3 sites of the aorta showed that the inflammatory cell infiltration was more severe in the aortic root and aortic bifurcation than in the thoracic aorta. The progression of inflammation to the aortic tunica media from the adventitia showed 2 patterns: 1 in which macrophages were aggregated around the vasa vasorum; and a second in which there was no such aggregation around the vasa vasorum, but there was diffuse inflammatory cell infiltration of the tunica media. In addition to this, there were findings of direct infiltration of cells from the tunica intima into the tunica media. CONCLUSION: Inflammation in KD occurs in the aorta. The changes with time and the kinds of infiltrating cells were the same as reported to date for coronary arteries in KD. There were differences in the degree of inflammation among the 3 aortic sites. It can be thought that the inflammation from the adventitia to the media progresses via the vas vasorum, and also, there is a possibility of spreading directly. From the intima to the media, inflammation spreads directly. However, formation of aneurysms and destruction of the vascular architecture of the aorta were absent in this study, unlike in coronary arteries.

Dose and time-dependent toxicological impact of pantoprazole on vascular endothelium and renal tissue.

Proton pump inhibitors (PPIs) have wide pleiotropic action in addition to their therapeutic potential in gastroesophageal reflux diseases. Conversely, recent reports revealed a significant incidence of toxic events of PPIs including nephritis, osteoporosis, and cardiac damage. Thus, the study was designed to reconcile the deceptive contraindications. The present investigation targeted to reveal the toxic impact of sub-acute and sub-chronic administration of pantoprazole (PPZ) with different concentrations (low dose 4 mg/kg, medium-dose 8 mg/kg and high dose 16 mg/kg once a day) on normal vascular endothelium and renal tissue of rats. Vascular endothelial dysfunction (VED) was estimated by the contractility of an isolated aortic ring, nitrite/nitrate concentration, oxidative stress, and integrity of the endothelium layer. Moreover, the renal abnormalities were further confirmed by an increased level of serum creatinine, blood urea nitrogen (BUN), the incidence of microproteinuria, and structural alteration. Sub-acute administration of PPZ treatment did not produce any toxicological impact on endothelium and renal tissue. Whereas, sub-chronic administration of PPZ treatment causes moderate VED and renal dysfunction in a dose-dependent manner. Sub-chronic treatment of PPZ also influences the mitigation of NO and elevation of oxidative stress. Collecting all the evidence, it concludes that decreased nitric oxide availability and increased levels of oxidative stress may be a possible underlying mechanism of causing VED and renal abnormalities from high-dose PPZ treatment.

Empagliflozin ameliorates endothelial dysfunction and suppresses atherogenesis in diabetic apolipoprotein E-deficient mice.

Recent studies reported cardioprotective effects of sodium glucose co-transporter 2 (SGLT2) inhibitors; however, the underlying mechanisms are still obscure. Here, we investigated whether empagliflozin attenuates atherogenesis and endothelial dysfunction in diabetic apolipoprotein E-deficient (ApoE-/-) mice. Male streptozotocin (STZ) - induced diabetic ApoE-/- mice were treated with empagliflozin for 12 or 8 weeks. Empagliflozin lowered blood glucose (P < 0.001) and lipid levels in diabetic ApoE-/- mice. Empagliflozin treatment for 12 weeks significantly decreased atherosclerotic lesion size in the aortic arch (P < 0.01) along with reduction of lipid deposition (P < 0.05), macrophage accumulation (P < 0.001), and inflammatory molecule expression in plaques compared with the untreated group. Empagliflozin treatment for 8 weeks significantly ameliorated diabetes-induced endothelial dysfunction as determined by the vascular response to acetylcholine (P < 0.001). Empagliflozin reduced RNA expression of a macrophage marker, CD68, and inflammatory molecules such as MCP-1 (P < 0.05) and NADPH oxidase subunits in the aorta compared with the untreated group. Empagliflozin also reduced plasma levels of vasoconstrictive eicosanoids, prostaglandin E2 and thromboxane B2 (P < 0.001), which were elevated in diabetic condition. Furthermore, empagliflozin attenuated RNA expression of inflammatory molecules in perivascular adipose tissue (PVAT), suggesting the reduction of inflammation in PVAT. In in vitro studies, methylglyoxal (MGO), a precursor of AGEs, significantly increased the expression of inflammatory molecules such as MCP-1 and TNF-α in a murine macrophage cell line, RAW264.7. Our results indicated that empagliflozin attenuated endothelial dysfunction and atherogenesis in diabetic ApoE-/- mice. Reduction of vasoconstrictive eicosanoids and inflammation in the vasculature and PVAT may have a role as underlying mechanisms at least partially.

Immunoglobulin G Subclass 4-Related Lymphoplasmacytic Thoracic Aortitis in a Patient with Acute Type A Aortic Dissection.

Immunoglobulin G subclass 4-related disease (IgG4-RD) is a recently recognized systemic inflammatory disease characterized by an elevated serum IgG4 level and an IgG4-positive lymphocyte infiltrate mainly in exocrine tissues. Previous reports documented IgG4-RD in several cardiovascular disorders. We present a case of type A aortic dissection associated with IgG4-RD. A 52-year-old man diagnosed with a type A aortic dissection was referred for surgical treatment. He underwent emergency hemiarch reconstruction with a prosthetic graft. His postoperative recovery was uncomplicated. Histopathologic examination of his aortic tissue showed marked adventitial thickening with fibrosis and an IgG4-positive plasma cell infiltrate. He was diagnosed with type A aortic dissection incidentally complicated by IgG4-RD. The relationship between IgG4-RD and the pathogenesis of aortic dissection remains unknown and requires further investigation.

Clinical characteristics and outcomes of 61 patients with chronic periaortitis including IgG4-related and non-IgG4-related cases.

AIM: Chronic periaortitis (CP) is a disease characterized by a fibro-inflammatory periaortic cuff and adventitia-predominant fibrosis. CP encompasses idiopathic retroperitoneal fibrosis and inflammatory abdominal aortic aneurysm (AAA), and recent studies have documented overlap between CP and immunoglobulin G4-related disease (IgG4-RD). This study aimed to investigate clinical characteristics and treatment outcomes of patients with CP. METHOD: CP patients were identified by retrospective review of 1245 patients with International Classification of Diseases 10th edition code of aortitis or aortic disease. Patients were further classified into IgG4-related and non-IgG4-related CP according to the criteria proposed by a Japanese study. RESULTS: A total of 61 CP patients were identified. Patients showed a male predominance (70%) with median age of 61 at diagnosis. The abdominal aorta was most commonly involved (84%), while the thoracic aorta was affected in 46% of patients. Twenty-three (38%) patients had accompanying aortic aneurysm. Approximately 60% of patients achieved remission without further relapse during the course. Ten patients were classified as IgG4-related and 25 as non-IgG4-related. There was no significant difference in clinical features and outcomes between groups, with the exception of older age and greater pancreas involvement in IgG4-related patients. CONCLUSION: We documented 61 CP patients including 10 IgG4-related cases. CP involved the abdominal aorta in most patients and the thoracic aorta in approximately 50% of patients. IgG4-related CP patients were older and had greater pancreas involvement, but disease outcomes appeared to be similar between IgG4-related and non-IgG4-related CP.

Effects of long-term active immunization with the second extracellular loop of human ß1- or ß3-adrenoceptors in thoracic aorta and mesenteric arteries in Lewis rats.

OBJECTIVE: To evaluate whether active immunization producing ß1- or ß3-antibodies (ß1-ABs and ß3-ABs) detected in sera of patients with dilated cardiomyopathies has deleterious effects on vascular reactivity in Lewis rat thoracic aorta (TA) and small mesenteric arteries (SMA). DESIGN AND METHOD: Lewis rats were immunized for 6months with peptidic sequences corresponding to the second extracellular loop of ß1- and ß3-adrenoceptors (ARs). During the immunization, systolic blood pressure (SBP) was monitored using the tail cuff method. The vascular reactivity of immunized rats was assessed by ex vivo studies on SMA and TA using various ß-AR agonists, phenylephrine and KCl. RESULTS: The immunizations producing functional ß1-ABs and ß3-ABs did not affect the SBP. However, in TA from ß1-AR-immunized rats, the relaxations mediated by dobutamine and salbutamol were significantly impaired in comparison with adjuvant rats whereas nebivolol-induced relaxation was not modified. Moreover, phenylephrine and KCl-mediated contractions were enhanced in these rats. In contrast, immunization with ß3-AR peptide led to the increase of relaxations induced by dobutamine in TA but did not change those induced by salbutamol and nebivolol. Surprisingly, in SMA from both rats immunized with ß1- or ß3-peptides, relaxations induced by the various ß-agonists were not changed whereas phenylephrine and KCl-mediated contractions were impaired. CONCLUSIONS: Our study shows that ß1- and ß3-ABs can affect vascular reactivity. ß1-ABs would have a pathogenic action whereas ß3-ABs would have a beneficial effect on aorta reactivity.

Interleukin-19 induces angiogenesis in the absence of hypoxia by direct and indirect immune mechanisms.

Neovascularization and inflammation are independent biological processes but are linked in response to injury. The role of inflammation-dampening cytokines in the regulation of angiogenesis remains to be clarified. The purpose of this work was to test the hypothesis that IL-19 can induce angiogenesis in the absence of tissue hypoxia and to identify potential mechanisms. Using the aortic ring model of angiogenesis, we found significantly reduced sprouting capacity in aortic rings from IL-19(-/-) compared with wild-type mice. Using an in vivo assay, we found that IL-19(-/-) mice respond to vascular endothelial growth factor (VEGF) significantly less than wild-type mice and demonstrate decreased capillary formation in Matrigel plugs. IL-19 signals through the IL-20 receptor complex, and IL-19 induces IL-20 receptor subunit expression in aortic rings and cultured human vascular smooth muscle cells, but not endothelial cells, in a peroxisome proliferator-activated receptor-γ-dependent mechanism. IL-19 activates STAT3, and IL-19 angiogenic activity in aortic rings is STAT3-dependent. Using a quantitative RT-PCR screening assay, we determined that IL-19 has direct proangiogenic effects on aortic rings by inducing angiogenic gene expression. M2 macrophages participate in angiogenesis, and IL-19 has indirect angiogenic effects, as IL-19-stimulated bone marrow-derived macrophages secrete proangiogenic factors that induce greater sprouting of aortic rings than unstimulated controls. Using a quantitative RT-PCR screen, we determined that IL-19 induces expression of angiogenic cytokines in bone marrow-derived macrophages. Together, these data suggest that IL-19 can promote angiogenesis in the absence of hypoxia by at least two distinct mechanisms: 1) direct effects on vascular cells and 2) indirect effects by stimulation of macrophages.

Clopidogrel significantly lowers the development of atherosclerosis in ApoE-deficient mice in vivo.

The anti-platelet drug clopidogrel has been shown to modulate adhesion molecule and cytokine expression, both playing an important role in the pathogenesis of atherosclerosis. The aim of this study was to investigate the impact of clopidogrel on the development and progression of atherosclerosis. ApoE(-/-) mice fed an atherogenic diet (cholesterol: 1 %) for 6 months received a daily dose of clopidogrel (1 mg/kg) by i.p. injection. Anti-platelet treatment was started immediately in one experimental group, and in another group clopidogrel was started 2 month after beginning of the atherogenic diet. Blood was analysed at days 30, 60 and 120 to monitor the lipid profile. After 6 months the aortic arch and brachiocephalic artery were analysed by Sudan IV staining for plaque size and by morphometry for luminal occlusion. Serum levels of various adhesion molecules were investigated by ELISA and the cellular infiltrate was analysed by immunofluorescence. After daily treatment with 1 mg/kg clopidogrel mice showed a significant reduction of atherosclerotic lesions in the thoracic aorta and within cross sections of the aortic arch [plaque formation 55.2 % (clopidogrel/start) vs. 76.5 % (untreated control) n = 8, P < 0.05]. After treatment with clopidogrel P-/E-selectin levels and cytokine levels of MCP-1 and PDGFß were significantly reduced as compared to controls. The cellular infiltrate showed significantly reduced macrophage and T-cell infiltration in clopidogrel-treated animals. These results show that clopidogrel can effectively delay the development and progression of 'de-novo' atherosclerosis. However, once atherosclerotic lesions were already present, anti-platelet treatment alone did not result in reverse remodelling of these lesions.

Emu oil decreases atherogenic plaque formation in cafeteria diet-induced obese rats.

BACKGROUND: Atherosclerosis-induced coronary heart disease - caused by elevated levels of low-density lipoproteins (LDL) and inflammation - is one of the most prevalent diseases. Monounsaturated fatty acids are reported to prevent atherosclerosis; emu oil is a rich source of monounsaturated fatty acid, and we hypothesize that emu oil supplementation could lower inflammation and prevent atherosclerosis in diet-induced obese (DIO) animals. Male Wistar rats were randomly divided into five groups (n = 6), and fed with normal diet (chow pellet; ND), or with cafeteria diet (CD), or with CD along with emu oil supplementation at three different doses: ED1 (2 mL), ED2 (4 mL) and ED3 (8 mL) kg(-1) body weight (BW), respectively. RESULTS: After 12 weeks, the animals were sacrificed and serum was analysed for measuring lipid profile, C-reactive proteins, testosterone and luteinizing hormone. Histopathological studies were performed to observe atherogenic changes in thoracic aorta. Restoration of altered lipid and hormonal profiles, and inhibition of atherogenic changes in thoracic aorta, were observed with supplementation of emu oil, confirming its anti-atherosclerotic activity. CONCLUSION: The high content of oleic acid in emu oil could have orchestrated - either solely or in combination with linoleic and linolenic acids - causing the upregulation of testosterone biosynthesis and inhibition of atheromatous plaque formation in diet-induced obese animals. © 2015 Society of Chemical Industry.

SIV/SHIV Infection Triggers Vascular Inflammation, Diminished Expression of Krüppel-like Factor 2 and Endothelial Dysfunction.

BACKGROUND: Human immunodeficiency virus (HIV) infection is associated with increased risk of thromboembolic and cardiovascular comorbid conditions. Although systemic inflammation is linked to cardiovascular risk, direct evidence of vascular inflammation and endothelial dysfunction is lacking. METHODS: We examined by immunofluorescence microscopy thoracic aortas from 16 simian immunodeficiency virus (SIV)- or simian-human immunodeficiency virus (SHIV)-infected and 16 uninfected rhesus macaques. RESULTS: Focal endothelial proliferation and subendothelial inflammatory cells were found in sections of all infected animals, compared with minimal changes in sections from the 16 uninfected controls. In the infected animals, we detected increased endothelial levels of bacterial 16s ribosomal DNA as well as increased subendothelial accumulation of CD68(+) monocytes/macrophages (P< .001) and CD8(+) T lymphocytes (P< .001). Endothelial dysfunction was manifested by decreased levels of endothelial nitric oxide synthase (P< .005) and Krüppel-like factor 2 (KLF2) (P< .005). KLF2 expression was decreased in primary human aortic endothelial cells exposed to bacterial lipopolysaccharide or to oxidized low-density lipoprotein in vitro, and this could be prevented by simvastatin. CONCLUSIONS: SIV and SHIV infection lead to endothelial inflammation, dysfunction, and decreased KLF2 expression reflecting early atherosclerotic changes. Translocated bacterial components and lipid oxidation products may induce endothelial dysfunction in HIV infection that could be prevented by statin treatment.

Thermoneutral Housing Accelerates Metabolic Inflammation to Potentiate Atherosclerosis but Not Insulin Resistance.

Chronic, low-grade inflammation triggered by excess intake of dietary lipids has been proposed to contribute to the pathogenesis of metabolic disorders, such as obesity, insulin resistance, type 2 diabetes, and atherosclerosis. Although considerable evidence supports a causal association between inflammation and metabolic diseases, most tests of this link have been performed in cold-stressed mice that are housed below their thermoneutral zone. We report here that thermoneutral housing of mice has a profound effect on the development of metabolic inflammation, insulin resistance, and atherosclerosis. Mice housed at thermoneutrality develop metabolic inflammation in adipose tissue and in the vasculature at an accelerated rate. Unexpectedly, this increased inflammatory response contributes to the progression of atherosclerosis but not insulin resistance. These findings not only suggest that metabolic inflammation can be uncoupled from obesity-associated insulin resistance, but also point to how thermal stress might limit our ability to faithfully model human diseases in mice.

Deletion of Periostin Protects Against Atherosclerosis in Mice by Altering Inflammation and Extracellular Matrix Remodeling.

OBJECTIVE: Periostin is a secreted protein that can alter extracellular matrix remodeling in response to tissue injury. However, the functional role of periostin in the development of atherosclerotic plaques has yet to be described despite its observed induction in diseased vessels and presence in the serum. APPROACH AND RESULTS: Hyperlipidemic, apolipoprotein E-null mice (ApoE(-/) (-)) were crossed with periostin (Postn(-/-)) gene-deleted mice and placed on a high-fat diet for 6 or 14 weeks to induce atherosclerosis. En face analysis of aortas showed significantly decreased lesion areas of ApoE(-/-) Postn(-/-) mice compared with ApoE(-/-) mice, as well as a reduced inflammatory response with less macrophage content. Moreover, diseased aortas from ApoE(-/-) Postn(-/-) mice displayed a disorganized extracellular matrix with less collagen cross linking and smaller fibrotic caps, as well as increased matrix metalloproteinase-2, metalloproteinase-13, and procollagen-lysine, 2-oxoglutarate 5-dioxygenase-1 mRNA expression. Furthermore, the loss of periostin was associated with a switch in vascular smooth muscle cells toward a more proliferative and synthetic phenotype. Mechanistically, the loss of periostin reduced macrophage recruitment by transforming growth factor-ß in cellular migration assays. CONCLUSIONS: These are the first genetic data detailing the function of periostin as a regulator of atherosclerotic lesion formation and progression. The data suggest that periostin could be a therapeutic target for atherosclerotic plaque formation through modulation of the immune response and extracellular matrix remodeling.

Mechanism of agonistic angiotensin II type I receptor autoantibody-amplified contractile response to Ang II in the isolated rat thoracic aorta.

Agonistic autoantibody to the angiotensin II type I receptor (AT1-AA) is highly associated with preeclampsia by increasing the sensitivity of Ang II during pregnancy in rats, thus leading to a preeclampsia-like syndrome. However, the mechanism underlying this phenomenon remains unclear. The purpose of this study was to observe AT1-AA amplification of Ang II-induced vasoconstriction in rat thoracic aortic rings. It was found that exposure to low concentrations of AT1-AA (0.4 nM) caused a contraction of <5% of the maximal response to 60 mM KCl. In addition, the Ang II-induced contractile response was amplified in the presence of a threshold contraction to AT1-AA, as manifested by a leftward shift of the midpoint of the concentration-response curve with no change in the maximal response. These results showed that preincubation with low AT1-AA could amplify the Ang II dose-response curve, and this amplification could be attenuated markedly by 0.1 µM heptapeptide AFHYESQ. In calcium-free Krebs solution, 10 µM of 2-aminoethoxydiphenyl borate (an IP3 receptor inhibitor) both blocked the AT1-AA base contraction and completely abolished the amplification. Both 5 µM of U-73122 (a phospholipase C inhibitor) and 10 µM of εV1-2 (an εPKC inhibitor) could partially inhibit the Ang II-induced contractile response. εV1-2, but not U-73122, could completely inhibit the amplification response of AT1-AA to Ang II. These results suggest that AT1-AA is able to cause amplification response to Ang II probably via the calcium-independent protein kinase C pathway, which may provide a new therapy strategy for preeclampsia.

IL-9 aggravates the development of atherosclerosis in ApoE-/- mice.

AIMS: Recently, interleukin (IL)-9 was found to be involved in the pathogenesis of many inflammatory diseases. Here, we tested whether IL-9 was related to atherosclerosis and investigated the underlying mechanisms. METHODS AND RESULTS: IL-9R was expressed in mouse aortic endothelial cells (MAECs) and aortic tissues, and IL-9 levels were elevated in plasma and aortic arches in Apolipoprotein E-deficient (ApoE-/-) mice. ApoE-/- mice fed a western diet for 10 weeks were administered recombinant mouse IL-9 (rIL-9) or anti-IL-9 neutralizing monoclonal antibody (mAb). Mice treated with rIL-9 developed markedly larger plaques in both the aorta and aortic root. Immunohistochemical studies demonstrated increases in both vascular endothelial adhesion molecule-1 (VCAM-1) expression and the infiltration of inflammatory cells, including T cells and macrophages, in plaques. However, treatment with the anti-IL-9 mAb caused the opposite effect. The administration of rIL-9 did not affect the splenic T cell or peripheral monocyte subsets. Meanwhile, IL-9 induced VCAM-1 expression in MAECs mainly via a STAT3-dependent pathway, consequently increasing monocyte-endothelial adhesion. Moreover, treatment with anti-VCAM-1 mAb partially abrogated the IL-9-induced increase in plaque area. In addition, CD4(+)IL-9(+) T cells and IL-9 were increased in patients with acute coronary syndrome, and the levels of IL-9 in culture supernatants and soluble VCAM-1 (sVCAM-1) in plasma were significantly positively correlated in the enrolled patients. CONCLUSION: Our results demonstrated that IL-9 exerted pro-atherosclerotic effects in ApoE-/- mice at least partially by inducing VCAM-1 expression, which mediated inflammatory cell infiltration into atherosclerotic lesions.

Bone marrow-specific caspase-1/11 deficiency inhibits atherosclerosis development in Ldlr(-/-) mice.

Recent investigations have suggested that inflammasome activation plays an important role during atherosclerosis. Upon activation, the inflammasome induces processing and release of pro-inflammatory cytokines interleukin 1ß (IL-1ß) and interleukin 18 (IL-18) via activation of caspase-1/11. Previously, it was shown that complete caspase-1 deficiency is protective against atherosclerosis development. However, while macrophages are the main inflammatory cells involved in atherosclerosis, the exact role of macrophage-specific caspase-1/11 activation during development of cardiovascular disease has never been investigated. We hypothesized that hematopoietic caspase-1/11 deficiency leads to reduced atherosclerosis development. To investigate the specific contribution of hematopoietic caspase-1/11 activation to atherosclerosis development, Ldlr(-/-) mice received a transplant (tp) of wild-type (WT) or caspase-1/11(-/-) bone marrow, to create WT-tp mice and caspase-1/11(-/-) -tp mice, and fed a high-fat, high-cholesterol diet for 12 weeks. Our results showed an increase in anti-inflammatory blood leukocytes in caspase-1/11(-/-) -tp mice compared with WT-tp mice, as indicated by a decreased level of Ly6C(high) monocytes and an increased level of Ly6C(low) monocytes. In line with our hypothesis, hematopoietic deletion of caspase-1/11 resulted in a strong reduction in atherosclerotic plaque size. Furthermore, necrotic core content was dramatically decreased in caspase-1/11(-/-) -tp mice. Our data indicate that hematopoietic caspase-1/11 activation is involved in vascular inflammation and atherosclerosis, and plays an important role in cardiovascular disease progression.