Recent studies of obesity have provided new insights into the mechanisms underlying insulin resistance and metabolic dysregulation. Numerous efforts have been made to identify key regulators of obesity-linked adipose tissue inflammation and insulin resistance. We found that angiopoietin-like protein 2 (Angptl2) was secreted by adipose tissue and that its circulating level was closely related to adiposity, systemic insulin resistance, and inflammation in both mice and humans. Angptl2 activated an inflammatory cascade in endothelial cells via integrin signaling and induced chemotaxis of monocytes/macrophages. Constitutive Angptl2 activation in vivo induced inflammation of the vasculature characterized by abundant attachment of leukocytes to the vessel walls and increased permeability. Angptl2 deletion ameliorated adipose tissue inflammation and systemic insulin resistance in diet-induced obese mice. Conversely, Angptl2 overexpression in adipose tissue caused local inflammation and systemic insulin resistance in nonobese mice. Thus, Angptl2 is a key adipocyte-derived inflammatory mediator that links obesity to systemic insulin resistance.

Objective— Cardiovascular disease (CVD), the most common morbidity resulting from atherosclerosis, remains a frequent cause of death. Efforts to develop effective therapeutic strategies have focused on vascular inflammation as a critical pathology driving atherosclerosis progression. Nonetheless, molecular mechanisms underlying this activity remain unclear. Here, we ask whether angiopoietin-like protein 2 (Angptl2), a proinflammatory protein, contributes to vascular inflammation that promotes atherosclerosis progression. Approach and Results— Histological analysis revealed abundant Angptl2 expression in endothelial cells and macrophages infiltrating atheromatous plaques in patients with cardiovascular disease. Angptl2 knockout in apolipoprotein E–deficient mice ( ApoE −/− / Angptl2 −/− ) attenuated atherosclerosis progression by decreasing the number of macrophages infiltrating atheromatous plaques, reducing vascular inflammation. Bone marrow transplantation experiments showed that Angptl2 deficiency in endothelial cells attenuated atherosclerosis development. Conversely, ApoE −/− mice crossed with transgenic mice expressing Angptl2 driven by the Tie2 promoter ( ApoE −/− /Tie2- Angptl2 Tg), which drives Angptl2 expression in endothelial cells but not monocytes/macrophages, showed accelerated plaque formation and vascular inflammation because of increased numbers of infiltrated macrophages in atheromatous plaques. Tie2- Angptl2 Tg mice alone did not develop plaques but exhibited endothelium-dependent vasodilatory dysfunction, likely because of decreased production of endothelial cell–derived nitric oxide. Conversely, Angptl2 −/− mice exhibited less severe endothelial dysfunction than did wild-type mice when fed a high-fat diet. In vitro, Angptl2 activated proinflammatory nuclear factor-κB signaling in endothelial cells and increased monocyte/macrophage chemotaxis. Conclusions— Endothelial cell–derived Angptl2 accelerates vascular inflammation by activating proinflammatory signaling in endothelial cells and increasing macrophage infiltration, leading to endothelial dysfunction and atherosclerosis progression.

Objective-To elucidate whether and how the endoplasmic reticulum (ER) stress-C/EBP homologous protein (CHOP) pathway in macrophages is involved in the rupture of atherosclerotic plaques. Methods and Results-Increases in macrophage-derived foam cell death in coronary atherosclerotic plaques cause the plaque to become vulnerable, thus resulting in acute coronary syndrome. The ER stress-CHOP/growth arrest and DNA damage-inducible gene-153 (GADD153) pathway is induced in the macrophage-derived cells in atherosclerotic lesions and is involved in plaque formation. However, the role of CHOP in the final stage of atherosclerosis has not been fully elucidated. Many CHOP-expressing macrophages showed apoptosis in advanced ruptured atherosclerotic lesions in wild-type mice, whereas few apoptotic cells were observed in Chop Ϫ/Ϫ mice. The rupture of atherosclerotic plaques was significantly reduced in high cholesterol-fed Chop Ϫ/Ϫ /Apoe Ϫ/Ϫ mice compared with Chop ϩ/ϩ /Apoe Ϫ/Ϫ mice. Furthermore, using mice that underwent bone marrow transplantation, we showed that expression of CHOP in macrophages significantly contributes to the formation of ruptures. By using primary cultured macrophages, we further showed that unesterified free cholesterol derived from incorporated denatured low-density lipoprotein was accumulated in the ER and induced ER stress-mediated apoptosis in a CHOP-Bcl2-associated X protein (Bax) pathway-dependent manner. Key Words: acute coronary syndrome Ⅲ CHOP Ⅲ ER stress Ⅲ Bax Ⅲ apoptosis A cute coronary syndrome, including myocardial infarction and unstable angina, is most frequently caused by an occlusive coronary thrombosis at the site of a preexisting atherosclerotic plaque. [1][2][3][4][5] The formation of coronary thrombosis is generally the result of the rupture of an atherosclerotic plaque, followed by the aggregation of platelets and the formation of fibrin. Therefore, clarification of the mechanisms by which an atherosclerotic plaque becomes vulnerable to rupture would be useful for preventing the onset of acute coronary syndrome. Atherosclerosis is a chronic inflammatory disease of the arterial wall. [1][2][3]6 Macrophages ingest an excess amount of oxidized low-density lipoprotein (LDL) and are converted into foam cells, which then secrete various inflammatory cytokines. Metalloproteinases secreted by macrophages and apoptosis of macrophage-derived foam cells affect the stability of plaques. Thus, monocytes/macrophages play a key role in the instability of atherosclerotic plaques. Conclusion-TheRecently, Myoishi et al 5 reported that the induction of apoptosis and the activation of the endoplasmic reticulum (ER) stress pathway, including the induction of C/EBP homologous protein (CHOP)/growth arrest and DNA damage-inducible gene0153 (GADD153), a member of the CCAAT/enhancer-binding protein (C/EBP) family of transcription factors, were detected in macrophages and smooth muscle cells within ruptured plaques, but not within stable fibrous plaques, in humans. They also reported that the levels of ...

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. Key Words: abdominal aortic aneurysm n angiopoietin-like protein 2 n chronic inflammation n macrophage n matrix metalloproteinase Conclusions-Macrophage-derived

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Objective: To evaluate limb-salvage surgery including vascular resection for lower-extremity soft-tissue sarcomas and carcinomas for adult patients.Materials and Methods: Eight consecutive patients (median age, 59 years) who underwent vascular replacement during surgery for malignant tumors in the lower limbs between November 2006 and March 2018 were evaluated. Patient data were retrospectively obtained in a computerized database. Arterial and venous reconstructions were performed for seven patients, with one additional patient receiving venous reconstruction only. Autologous-vein (n=6) and synthetic bypasses were used for arterial repairs, whereas only autologous veins were implanted for venous repairs.Results: Morbidity was 62.5%, and in-hospital mortality was 12.5%. At a median follow-up of 24 months, the primary patency rates of arterial and venous reconstructions were 85.7% and 62.5%, respectively. Limb salvage was achieved in all cases.Conclusion: Early and mid-term bypass patency rates, the high percentage of limb salvage, and the oncologic outcome underline the efficacy of en bloc resection of soft-tissue tumors involving major vessels of the lower limbs. The anticipated need for vascular resection and reconstruction should not be a contraindication to sarcoma and carcinoma resections. However, efforts to achieve better control over systemic spread are required for long-term survival.

Nifedipine, an L-type calcium (Ca) channel blocker, is one of the most widely used Ca channel-blocking medications for hypertension. Previous studies have reported an association of nifedipine hypertensive treatment with decreased body weight in obese hypertensive humans and rat models. However, the precise mechanism underlying how nifedipine functions metabolically has not been elucidated. Here, we investigated the long-term effect of a non-hypotensive nifedipine dose using a mildly obese, endothelial NO synthase-deficient mouse model. Treating these mice with nifedipine decreased their body weight gain ratio, and white adipose tissue weight compared with the untreated controls. Metabolic analyses indicated that nifedipine treatment upregulated whole-body energy expenditure through increasing oxygen consumption and reducing the respiratory exchange ratio, suggesting that nifedipine promotes lipid oxidation rather than carbohydrate utilization. Furthermore, nifedipine treatment upregulated the expression of the peroxisome proliferator-activated receptor-c coactivator -1a (PGC-1a) in skeletal muscle. Overall, these results suggest that a non-hypotensive dose of nifedipine has pleiotropic effects on energy expenditure that could ameliorate obesity.

BackgroundAtherosclerotic stenosis of the brachiocephalic artery sometimes occurs in patients with coronary artery disease, and can cause stroke during the perioperative period of coronary artery bypass grafting.Case presentationWe describe the case of a 77-year old male with severe stenosis of the brachiocephalic artery and severe coronary artery disease. He successfully underwent aorto-right subclavian artery bypass that was performed concomitantly with off-pump coronary artery bypass.ConclusionConcomitant aorto-subclavian artery bypass with off-pump coronary artery bypass grafting is a therapeutic option that minimizes the risk of perioperative stroke in patients with brachiocephalic artery stenosis and coronary artery disease.