Andrew P. Wright

Visceral Adipose Tissue Inflammation Accelerates Atherosclerosis in Apolipoprotein E–Deficient Mice

Background— Fat inflammation may play an important role in comorbidities associated with obesity such as atherosclerosis. Methods and Results— To first establish feasibility of fat transplantation, epididymal fat pads were harvested from wild-type C57BL/6J mice and transplanted into leptin-deficient (Lepob/ob) mice. Fat transplantation produced physiological leptin levels and prevented obesity and infertility in Lepob/ob mice. However, the transplanted fat depots were associated with chronically increased macrophage infiltration with characteristics identical to those observed in fat harvested from obese animals. The inflammation in transplanted adipose depots was regulated by the same factors that have been implicated in endogenous fat inflammation such as monocyte chemoattractant protein-1. To determine whether this inflamed adipose depot could affect vascular disease in mice, epididymal fat depots were transplanted into atherosclerosis-prone apolipoprotein E-deficient ApoE−/− mice. Plasma from ApoE−/− mice receiving fat transplants contained increased leptin, resistin, and monocyte chemoattractant protein-1 compared with plasma from sham-operated ApoE−/− mice. Furthermore, mice transplanted with visceral fat developed significantly more atherosclerosis compared with sham-operated animals, whereas transplants with subcutaneous fat did not affect atherosclerosis despite a similar degree of fat inflammation. Treatment of transplanted ApoE−/− mice with pioglitazone decreased macrophage content of the transplanted visceral fat pad and reduced plasma monocyte chemoattractant protein-1. Importantly, pioglitazone also reduced atherosclerosis triggered by inflammatory visceral fat but had no protective effect on atherosclerosis in the absence of the visceral fat transplantation. Conclusions— Our results indicate that visceral adipose-related inflammation accelerates atherosclerosis in mice. Drugs such as thiazolidinediones might be a useful strategy to specifically attenuate the vascular disease induced by visceral inflammatory fat.

Visceral Adipose Tissue and Atherosclerosis

Obesity is a risk factor for complications of atherosclerotic vascular disease such as myocardial infarction and stroke. Recent studies have demonstrated that the vascular risk associated with obesity is correlated particularly with visceral adiposity. These clinical observations indicate that various adipose tissue depots may have differential effects on vascular risk. Cellular constituents of adipose tissue secrete cytokines and chemokines that may affect vascular disease. Visceral fat has been demonstrated to express more inflammatory cytokines than subcutaneous fat in obese states. The adipose tissue secretory profile may reflect the influx of macrophages that has been shown to occur with expansion of fat stores. This macrophage infiltration may lead to a chronic low grade, systemic, inflammatory state. Since circulating markers of inflammation are associated with cardiovascular events, the inflammation triggered by adipose tissue may contribute to increased vascular disease. While the vasculopathic effects of visceral obesity may be best treated by weight loss, long term weight loss is difficult to achieve, even with currently available pharmacotherapies. Therapies that target macrophage accumulation in fat or the adipocyte expression profile may be potentially beneficial in reducing the vascular risk associated with obesity. Further characterization of the factors responsible for promoting atherosclerosis in the setting of visceral obesity may lead to new targets for the prevention of atherosclerosis.

P-Selectin Glycoprotein Ligand-1 Regulates Adhesive Properties of the Endothelium and Leukocyte Trafficking Into Adipose Tissue

Rationale Adhesive interactions between endothelial cells and leukocytes affect leukocyte trafficking in adipose tissue. The role of P-selectin glycoprotein ligand-1 (Psgl-1) in this process is unclear. Objective The goal of this study was to determine the effect of Psgl-1 deficiency on adhesive properties of the endothelium and on leukocyte recruitment into obese adipose depots. Methods and Results A genetic model of obesity was generated to study the effects of Psgl-1 deficiency on leukocyte trafficking. Leukocyte-endothelial interactions were increased in obese leptin receptor mutant mice (Leprdb/db,Psgl-1+/+) but not obese Psgl-1–deficient mice (Leprdb/db,Psgl-1−/−), when compared with lean mice (Lepr+/+,Psgl-1+/+). This effect of Psgl-1 deficiency was due to indirect effects of Psgl-1, because Psgl-1+/+ adoptively transferred leukocytes did not exhibit enhanced rolling in Leprdb/db,Psgl-1−/− mice. Additionally, circulating levels of P-selectin, E-selectin, monocyte chemoattractant protein-1, and macrophage content of visceral adipose tissue were reduced in Leprdb/db,Psgl-1−/− compared with Leprdb/db,Psgl-1+/+ mice. Reduced leukocyte-endothelial interactions and macrophage content of visceral adipose tissue due to Psgl-1 deficiency was also observed in a diet-induced obese mouse model. Psgl-1−/− mice were resistant to the endothelial effects of exogenous IL-1&bgr;, suggesting that defective cytokine signaling contributes to the effect of Psgl-1 deficiency on leukocyte-endothelial interactions. Mice deficient in the IL-1 receptor also had reduced levels of circulating P-selectin, similar to those observed in Psgl-1−/− mice. Conclusions Deficiency of Psgl-1 is associated with reduced IL-1 receptor-mediated adhesive properties of the endothelium and is protective against visceral fat inflammation in obese mice.

Monocyte Chemoattractant Protein-1 Deficiency Protects Against Visceral Fat–Induced Atherosclerosis

Objective—To determine the role of monocyte chemoattractant protein-1 (Mcp-1) on the progression of visceral fat–induced atherosclerosis. Methods and Results—Visceral fat inflammation was induced by transplantation of perigonadal fat. To determine whether recipient Mcp-1 status affected atherosclerosis induced by inflammatory fat, apolipoprotein E–deficient (ApoE−/−) and ApoE−/− and Mcp-1–deficient (Mcp-1−/−) mice underwent visceral fat transplantation. Intravital microscopy was used to study leukocyte-endothelial interactions. To study the primary tissue source of circulating Mcp-1, both fat and bone marrow transplantation experiments were used. Transplantation of visceral fat increased atherosclerosis in ApoE−/− mice but had no effect on atherosclerosis in ApoE−/−, Mcp-1−/− mice. Intravital microscopy revealed increased leukocyte attachment to the endothelium in ApoE−/− mice compared with ApoE−/−, Mcp-1−/− mice after receiving visceral fat transplants. Transplantation of visceral fat increased plasma Mcp-1, although donor adipocytes were not the source of circulating Mcp-1 because no Mcp-1 was detected in plasma from ApoE−/−, Mcp-1−/− mice transplanted with Wt fat, indicating that recipient Mcp-1-producing cells were affecting the atherogenic response to the fat transplantation. Consistently, transplantation of Mcp-1−/− fat to ApoE−/− mice did not lead to atheroprotection in recipient mice. Bone marrow transplantation between Wt and Mcp-1−/− mice indicated that the primary tissue source of circulating Mcp-1 was the endothelium. Conclusion—Recipient Mcp-1 deficiency protects against atherosclerosis induced by transplanted visceral adipose tissue.

Atherosclerosis and leukocyte–endothelial adhesive interactions are increased following acute myocardial infarction in apolipoprotein E deficient mice

OBJECTIVE To determine the effect of myocardial infarction (MI) on progression of atherosclerosis in apolipoprotein E deficient (ApoE-/-) mice. METHODS AND RESULTS MI was induced following left anterior descending coronary artery (LAD) ligation in wild-type (WT) (n=9) and ApoE-/- (n=25) mice. Compared to sham-operated animals, MI mice demonstrated increased intravascular leukocyte rolling and firm adhesion by intravital microscopy, reflecting enhanced systemic leukocyte-endothelial interactions. To determine if MI was associated with accelerated atherogenesis, LAD ligation was performed in ApoE-/- mice. Six weeks following surgery, atherosclerosis was quantitated throughout the arterial tree by microdissection and Oil-Red-O staining. There was 1.6-fold greater atherosclerotic burden present in ApoE-/- MI mice compared to sham-operated mice. CONCLUSIONS Acute MI accelerates atherogenesis in mice. These results may be related to the increased risk of recurrent ischemic coronary events following MI in humans.

Stepwise endoscopic eradication of refractory nodular gastric antral vascular ectasia by use of detachable snare and band ligation

re 1. A, Endoscopic image from the index endoscopy, demonstrating multiple erythematous friable antral polypoid and nodular lesions ranging in rom 3 to 25 mm in a radial pattern extending from the pylorus, representing nodular gastric antral vascular ectasia (GAVE). B, Endoscopic image from econd endoscopy, demonstrating detachable snare ligature deployment over a large area of nodular GAVE with tissue ischemia. C, Endoscopic image the second endoscopy, after detachable snare ligature and endoscopic band deployment over a large area of nodular GAVE. D, Endoscopic e from the second endoscopy, after detachable snare ligature and endoscopic band deployment over areas of nodular GAVE with tissue ischemia. doscopic image from the fourth endoscopy, demonstrating significant improvement in the extent of nodular GAVE. F, Endoscopic images from the through the fourth endoscopies, demonstrating stepwise improvement in nodular GAVE. G, Graphic depiction of patient’s hemoglobin level, blood fusion requirement, and endoscopic therapies over 8-month period before and after initiation of endoscopic ligation therapy of GAVE. GAVE, gastric l vascular ectasia; RBC, red blood cells.