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 (Lepr(db/db),Psgl-1(+/+)) but not obese Psgl-1-deficient mice (Lepr(db/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 Lepr (db/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 Lepr(db/db),Psgl-1(-/-) compared with Lepr(db/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-1beta, 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. CONCLUSIONS: Recipient Mcp-1 deficiency protects against atherosclerosis induced by transplanted visceral adipose tissue.

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.

Leptin regulates neointima formation after arterial injury through mechanisms independent of blood pressure and the leptin receptor/STAT3 signaling pathways involved in energy balance.

BACKGROUND: Leptin is an adipocyte-derived hormone critical for energy homeostasis and implicated in vascular disease processes. The relevant cellular leptin receptor pools and signaling pathways involved in leptin-related vascular phenotypes in vivo are unclear. METHODS AND RESULTS: Arterial injury was induced in wild-type (wt), leptin-deficient (lep(ob/ob)), and leptin receptor-deficient (lepr(db/db)) mice. Compared with wt mice, lep(ob/ob) and lepr(db/db) mice were protected from the development of neointima. Bone marrow transplantation experiments between wt and lepr(db/db) mice indicated that the vascular protection in lepr(db/db) mice was not attributable to lack of leptin receptor expression on bone marrow-derived elements. To investigate the role of the lepr-mediated signal transducer and activator of transcription 3 (STAT3) signaling pathway in the response to vascular injury, lepr(s/s) mice homozygous for a leptin receptor defective in STAT3 signaling underwent femoral arterial injury. Despite similar obesity and blood pressure levels, the neointimal area in lepr(s/s) mice was significantly increased compared with lepr(db/db) mice. CONCLUSIONS: The molecular mechanism by which the leptin receptor mediates neointima formation and vascular smooth muscle cell proliferation is largely independent of the STAT3-dependent signaling pathways involved in energy balance.

Recent advances in understanding endogenous fibrinolysis: implications for molecular-based treatment of vascular disorders.

The fate of a forming thrombus is determined through the delicate balance between the coagulation cascade, favouring clot formation, and the fibrinolytic system, favouring clot lysis. These processes occur simultaneously, and enhancement of fibrinolysis has been shown to reduce occlusive thrombus formation in animal models. This review examines the roles of the major fibrinolytic factors involved in clot lysis. The regulation of plasmin activity by plasminogen activators, alpha-2-antiplasmin, plasminogen activator inhibitor 1, and thrombin-activatable fibrinolysis inhibitor, and their effects on thrombus formation in vivo are discussed. Since alterations in fibrinolytic capacity appear to affect thrombus formation in animal models, there is considerable interest in the pharmacological manipulation of fibrinolysis.

Leptin receptor-induced STAT3-independent signaling pathways are protective against atherosclerosis in a murine model of obesity and hyperlipidemia.

AIMS: Leptin is an adipocyte-derived hormone that has been shown to exert both beneficial metabolic effects and potentially adverse vascular effects in preclinical studies. The primary aim of this study was to determine the effects of leptin receptor signaling pathways on atherosclerosis in the setting of obesity and hyperlipidemia. METHODS AND RESULTS: Mice were generated with deficiency of apolipoprotein E (ApoE(-/-)) and either wild-type leptin receptor expression (Lepr(+/+), ApoE(-/-)), mutant leptin receptor expression defective in all leptin receptor signaling pathways (Lepr(db/db), ApoE(-/-)), or mutant leptin receptor expression with selective deficiency of leptin receptor-STAT3 signaling (Lepr(s/s), ApoE(-/-)). At 27 weeks of age (including 7 weeks on a Western diet), Lepr(db/db), ApoE(-/-) developed severe obesity, hypercholesterolemia, and increased atherosclerosis compared to Lepr(+/+), ApoE(-/-) mice. Despite similar obesity and hyperlipidemia to Lepr(db/db), ApoE(-/-) mice, Lepr(s/s), ApoE(-/-) developed less atherosclerosis than Lepr(db/db), ApoE(-/-) mice. Adipose tissue macrophage content, monocyte chemoattractant protein-1 and fatty-acid-binding protein 4 levels were also reduced in Lepr(s/s), ApoE(-/-) mice compared to Lepr(db/db), ApoE(-/-) mice. CONCLUSIONS: In a mouse model of obesity and hyperlipidemia, leptin receptor-mediated STAT3-independent signaling pathways confer protection against atherosclerosis. These differences occur independently of leptin effects on energy balance.

Effect of leptin on arterial thrombosis following vascular injury in mice.

CONTEXT: Complications of atherosclerosis are the leading cause of morbidity and mortality in industrialized societies. Obesity has emerged as an independent risk factor for complications of atherosclerotic vascular disease. Leptin, a hormone produced by the adipocyte, increases with obesity and appears to modulate energy balance and food intake. In addition, other actions of leptin have been proposed, including an in vitro effect on platelet aggregation. Thus, the elevated plasma leptin levels in obese individuals may promote vascular thrombosis. OBJECTIVE: To test the hypothesis that leptin contributes to in vivo thrombosis via the leptin receptor. DESIGN AND MATERIALS: Between September 2000 and September 2001, a vascular thrombosis model was used to test male 10- to 12-week-old mice completely deficient in leptin or the leptin receptor and mice with platelet leptin-receptor deficiency. MAIN OUTCOME MEASURE: Time to formation of an occlusive thrombus in the common carotid artery following experimentally induced endothelial injury. RESULTS: Following onset of vascular injury, wild-type mice (n = 8) formed occlusive thrombosis in a mean (SD) of 42.2 (4.6) minutes, whereas leptin-deficient (n = 5) and leptin receptor-deficient mice (n = 7) formed occlusive thrombosis in 75.2 (10.1) and 68.6 (10.3) minutes, respectively (leptin deficient vs wild-type mice, P =.008; leptin-receptor-deficient vs wild-type, P =.03). When recombinant murine leptin was administered to leptin-deficient mice (n = 4), the time to occlusion was reduced to 41.8 (6.6) minutes (P =.035 vs vehicle control). Following bone marrow transplantation from leptin receptor-deficient (donor) mice to wild-type (recipient) mice, the time to occlusion was prolonged from 22.3 (2.8) minutes in wild-type mice receiving wild-type marrow (n = 3) to 56.8 (5.0) minutes in wild-type mice receiving leptin receptor-deficient bone marrow (n = 5) (P =.003). CONCLUSIONS: Leptin contributes to arterial thrombosis following vascular injury in vivo and these prothrombotic effects appear to be mediated through the platelet leptin receptor.