Receptor for advanced glycation end products (RAGE) has been shown to be involved in adiposity as well as atherosclerosis even in nondiabetic conditions. In this study, we examined mechanisms underlying how RAGE regulates adiposity and insulin sensitivity. RAGE overexpression in 3T3-L1 preadipocytes using adenoviral gene transfer accelerated adipocyte hypertrophy, whereas inhibitions of RAGE by small interfering RNA significantly decrease adipocyte hypertrophy. Furthermore, double knockdown of high mobility group box-1 and S100b, both of which are RAGE ligands endogenously expressed in 3T3-L1 cells, also canceled RAGE-medicated adipocyte hypertrophy, implicating a fundamental role of ligands–RAGE ligation. Adipocyte hypertrophy induced by RAGE overexpression is associated with suppression of glucose transporter type 4 and adiponectin mRNA expression, attenuated insulin-stimulated glucose uptake, and insulin-stimulated signaling. Toll-like receptor (Tlr)2 mRNA, but not Tlr4 mRNA, is rapidly upregulated by RAGE overexpression, and inhibition of Tlr2 almost completely abrogates RAGE-mediated adipocyte hypertrophy. Finally, RAGE−/− mice exhibited significantly less body weight, epididymal fat weight, epididymal adipocyte size, higher serum adiponectin levels, and higher insulin sensitivity than wild-type mice. RAGE deficiency is associated with early suppression of Tlr2 mRNA expression in adipose tissues. Thus, RAGE appears to be involved in mouse adipocyte hypertrophy and insulin sensitivity, whereas Tlr2 regulation may partly play a role.
BackgroundClinical trials demonstrate the effectiveness of cell-based therapeutic angiogenesis in patients with severe ischemic diseases; however, their success remains limited. Maintaining transplanted cells in place are expected to augment the cell-based therapeutic angiogenesis. We have reported that nano-hydroxyapatite (HAp) coating on medical devices shows marked cell adhesiveness. Using this nanotechnology, HAp-coated poly(l-lactic acid) (PLLA) microspheres, named nano-scaffold (NS), were generated as a non-biological, biodegradable and injectable cell scaffold. We investigate the effectiveness of NS on cell-based therapeutic angiogenesis.Methods and ResultsBone marrow mononuclear cells (BMNC) and NS or control PLLA microspheres (LA) were intramuscularly co-implanted into mice ischemic hindlimbs. When BMNC derived from enhanced green fluorescent protein (EGFP)-transgenic mice were injected into ischemic muscle, the muscle GFP level in NS+BMNC group was approximate fivefold higher than that in BMNC or LA+BMNC groups seven days after operation. Kaplan-Meier analysis demonstrated that NS+BMNC markedly prevented hindlimb necrosis (P<0.05 vs. BMNC or LA+BMNC). NS+BMNC revealed much higher induction of angiogenesis in ischemic tissues and collateral blood flow confirmed by three-dimensional computed tomography angiography than those of BMNC or LA+BMNC groups. NS-enhanced therapeutic angiogenesis and arteriogenesis showed good correlations with increased intramuscular levels of vascular endothelial growth factor and fibroblast growth factor-2. NS co-implantation also prevented apoptotic cell death of transplanted cells, resulting in prolonged cell retention.ConclusionA novel and feasible injectable cell scaffold potentiates cell-based therapeutic angiogenesis, which could be extremely useful for the treatment of severe ischemic disorders.
Aim:A recent clinical trial showed the preventive effect of cilostazol on cerebrovascular diseases. We compared the effects of cilostazol with aspirin on circulating endothelial progenitor cells (EPCs), a surrogate marker for cardiovascular disease, and lipid metabolism in a randomized controlled trial (UMIN000000537). Methods: Forty-nine diabetic outpatients with leukoaraiosis or asymptomatic old cerebral infarction were enrolled in the study with written informed consent. They were randomly assigned to a cilostazol (200 mg daily, n 24) or aspirin group (100 mg daily, n 25), and followed for 16 weeks. Changes in circulating CD34 CD45 low CD133 VEGFR2 EPCs ( EPC) were a primary endpoint. Changes in CD34 CD45 low CD133 progenitor cells ( PC), p-selectin-positive platelet, plateletmonocyte binding measured by flow cytometry, LDL-, HDL-, small dense LDL (sdLDL)-cholesterol and triacylglycerol were the secondary endpoints. Results: Twenty patients in each group completed the study. EPC were significantly higher in the cilostazol group than aspirin group at 16 weeks, while PC were already significantly higher at 4 weeks in the cilostazol group. Changes in p-selectin-positive platelets and platelet-monocyte binding were similar in both groups. The cilostazol group showed significantly less sdLDL-and higher HDLcholesterol than the aspirin group at both 4 and 16 weeks. EPC were significantly and inversely correlated with changes of sdLDL, while positively with those of HDL. Analysis of covariance showed that a significant relation of EPCs with cilostazol treatment was confounded by changes in HDL-and sdLDL-cholesterol. Conclusion: Cilostazol increases circulating EPCs and decreases small-dense LDL in diabetic patients with cerebral ischemia. J Atheroscler Thromb, 2011; 18:883-890.
A 75-year-old man with paroxysmal atrial fibrillation developed a traumatic intracranial hemorrhage during warfarin treatment. The administration of warfarin was stopped and rivaroxaban therapy, a novel oral anticoagulant (NOAC), was started. Immediately, his platelet count decreased to 3.7×10 4 /μL. The platelet count recovered rapidly after cessation of rivaroxaban administration. Development of thrombocytopenia and its rapid recovery was observed again after another administration, and subsequent cessation, of the drug. A diagnosis of rivaroxaban-induced thrombocytopenia was made. The incidence of thrombocytopenia due to NOACs is rare. Careful attention to thrombocytopenia, which is associated with a higher risk for life-threatening bleeding, is therefore necessary during treatment with NOACs.
Aims: Despite the clinical usefulness of transcutaneous oxygen tension (TcPO2) to assess the severity of limb ischemia, the factors determining TcPO2 in patients with peripheral arterial disease (PAD) have not been fully clarified. We therefore examined the regions of arterial stenosis and clinical factors affecting lower-extremity TcPO2. Methods: Resting TcPO2 (REST-TcPO2) and postexercise TcPO2 (Ex-TcPO2) in the calf region and the dorsalis pedis were measured simultaneously in 66 patients (132 limbs) with clinically suspected PAD, in whom angiography was also performed. Results: The peripheral arteries of the lower extremities were divided into five segments, and the impact of significant stenosis in each segment on ipsilateral TcPO2 was evaluated by multiple regression analysis. In the calf region, significant stenosis of the proximal arteries (common-external iliac artery) revealed stronger involvement determining Ex-TcPO2 than the peripheral segment (posterior tibial artery). In the dorsalis pedis, the peripheral segment (anterior tibial artery) more strongly determined Ex-TcPO2 and REST-TcPO2 than proximal segments. Age, creatinine, and diabetes were associated with REST-TcPO2 of the calf region independent of arterial stenoses, while those of the dorsalis pedis were independently associated with age, and creatinine. In contrast, Ex-TcPO2 in both regions was not independently associated with clinical factors, except for stenosis of the perfusing arteries. Conclusion: The vascular lesions affecting TcPO2 differ between the calf region (proximal peripheral) and the dorsalis pedis (proximal peripheral). In addition postexercise TcPO2 is solely determined by stenosis of the perfusing arteries, while TcPO2 at rest is affected by multiple clinical factors.J Atheroscler Thromb, 2010; 17:858-869.
Objective Intravascular catheter procedures are often performed in patients undergoing antithrombotic therapy. However, methods for the management of antithrombotic agents in the perioperative period are currently unclear. Therefore, the safety and management of antithrombotic agents in these patients were investigated. Methods A prospective, multicenter, observational study [Management of Antithrombotic Agents During Surgery or Medical Procedures with Bleeding (MARK study)] at 58 National Hospital Organization institutions in Japan was performed. 1,040 patients were enrolled in the MARK study and underwent an intravascular catheter procedure. For all participants, the details of the procedure, method of perioperative management of antithrombotic agents, and occurrence of thrombosis, embolism, and bleeding complications during the study period were investigated. Results The use of antithrombotic agents was continued in 1,017 patients (98%, continuation group) and discontinued in the other 23 (2%, discontinuation group). Continuation of the antithrombotic agents did not have a significant effect on the overall occurrence of thromboembolism [hazard ratio (HR), 0.15; p=0.08] or bleeding events (HR, 0.19; p=0.12). However, the overall adverse event risk was significantly lower in the continuation group than in the discontinuation group (HR, 0.18; p=0.03). Conclusion It is both safe and appropriate to perform intravascular catheter procedures in patients continuing with antithrombotic therapy.
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