Phosphodiesterase type 4 blockade prevents platelet-mediated neutrophil recruitment at the site of vascular injury.

Objective: Platelet-neutrophil interactions play a key role in cardiovascular disease and inflammatory processes. Src family kinases mediate P-selectin glycoprotein ligand-1-Mac-1 cross talk necessary for firm platelet-neutrophil adhesion. Because Src family kinase activity can be regulated by cAMP-dependent pathways, in this work, we evaluated the role of phosphodiesterases in the signaling events that are required to sustain platelet-neutrophil interactions and neutrophil recruitment at the site of vascular injury.

Postprandial metabolite profiles reveal differential nutrient handling after bariatric surgery compared with matched caloric restriction.

Background: Roux-en-Y gastric bypass (RYGB) surgery results in exaggerated postprandial insulin and incretin responses and increased susceptibility to hypoglycemia.

Objective: We examined whether these features are due to caloric restriction (CR) or altered nutrient handling.

Methods: We performed comprehensive analysis of postprandial metabolite responses during a 2-hour mixed-meal tolerance (MMT) test in 20 morbidly obese subjects with type 2 diabetes who underwent RYGB surgery or matched CR.

Effects of Roux-en-Y gastric bypass or diabetes support and education on insulin sensitivity and insulin secretion in morbidly obese patients with type 2 diabetes.

Objective: The long-term changes in insulin sensitivity and β-cell function in morbidly obese patients with type 2 diabetes mellitus who undergo Roux-en-Y gastric bypass (RYGB) surgery or standard medical care remain unclear. We prospectively studied longitudinal changes of glucostatic parameters in morbidly obese patients with type 2 diabetes mellitus undergoing RYGB surgery or diabetes support and education (DSE).

Research Methods And Design: Sixty-one morbidly obese subjects (41.

Serum leptin levels are inversely correlated with omental gene expression of adiponectin and markedly decreased after gastric bypass surgery.

Background: Adipose tissue is the most abundant endocrine tissue in the body, producing leptin, a hormone important in regulating hunger, and adiponectin, a hormone involved in insulin sensitivity and inflammation. This study aimed to assess the impact of gastric bypass surgery (GBS) on leptin levels and its relation to the adipose tissue expression of adiponectin.

Methods: Omental and subcutaneous adipose tissue and serum were obtained from 40 obese patients undergoing GBS, from 13 patients 1 year or more after GBS, and from 16 non-obese individuals with a body mass index of 20 to 29 kg/m(2).

Necdin-E2F4 interaction provides insulin-sensitizing effect after weight loss induced by gastric bypass surgery.

Background: The insulin-like growth factor-1 (IGF-1) signaling pathway promotes adipocyte differentiation and, therefore, insulin sensitivity by suppression of necdin expression, which represses peroxisome proliferator-activated receptor-gamma promoter activity by interaction with E2F4 in mouse adipocytes. The aim of the present study was to test the hypothesis that this pathway represents one of the mechanisms by which Roux-en-Y gastric bypass surgery (RYGB) induces resolution of insulin resistance.

Methods: Clinical samples were collected and the key biomarkers measured to test the hypothesis that the IGF-1 pathway represents 1 of the mechanisms by which RYGB induces resolution of insulin resistance in obese individuals.

Gastric bypass surgery restores meal stimulation of the anorexigenic gut hormones glucagon-like peptide-1 and peptide YY independently of caloric restriction.

Background: The effects of gastric bypass surgery on the secretion of the anorexigenic gut-derived hormones glucagon-like peptide-1 (GLP-1) and peptide YY (PYY), independent of caloric restriction and due to different dietary macronutrients, is not well characterized. This study examines the effects of a mixed-nutrient or high-fat liquid meal on the postprandial stimulation of GLP-1 and PYY following gastric bypass or equivalent hypocaloric diet.

Methods: Total PYY and active GLP-1 were measured fasting and at multiple points after standardized mixed-nutrient and high-fat liquid meals in two matched groups of obese subjects.

Autotaxin/lysopholipase D and lysophosphatidic acid regulate murine hemostasis and thrombosis.

The lipid mediator lysophosphatidic acid (LPA) is a potent regulator of vascular cell function in vitro, but its physiologic role in the cardiovasculature is largely unexplored. To address the role of LPA in regulating platelet function and thrombosis, we investigated the effects of LPA on isolated murine platelets. Although LPA activates platelets from the majority of human donors, we found that treatment of isolated murine platelets with physiologic concentrations of LPA attenuated agonist-induced aggregation.

Therapeutic potential of autotaxin/lysophospholipase d inhibitors.

Lysophosphatidic acids (LPAs) are structurally simple lipid phosphate esters with a widely appreciated role as extracellular signaling molecules. LPA binds to selective cell surface receptors to promote cell growth, survival, motility and differentiation. Studies using LPA receptor knockout mice and experimental therapeutics targeting these receptors identify roles for LPA signaling in processes that include cardiovascular disease and function, angiogenesis, reproduction, cancer progression and neuropathic pain.

Individual heterogeneity in platelet response to lysophosphatidic acid: evidence for a novel inhibitory pathway.

Objective: The bioactive lipid lysophosphatidic acid (LPA) stimulates platelet actin reorganization, adhesion, shape change, and aggregation. LPA is present in blood and exposure or release of LPA after atherosclerotic plaque rupture has been proposed to trigger platelet thrombus formation.

Methods And Results: In this report, we characterize heterogeneity in LPA responses among individuals.

Effects of unfractionated heparin and glycoprotein IIb/IIIa antagonists versus bivalirdin on myeloperoxidase release from neutrophils.

Unlabelled: OBJECTIVES The objective of this study was to determine whether adjunctive therapy during percutaneous coronary intervention (PCI) affects markers of systemic inflammation or platelet activation. Despite different mechanisms of action, direct-thrombin inhibition with bivalirudin during PCI provided similar protection from periprocedural and chronic ischemic complications as compared with unfractionated heparin (UFH) plus planned use of GPIIb/IIIa antagonists in the REPLACE-2 and ACUITY trials.

Methods And Results: Patients undergoing nonurgent PCI of a native coronary artery were randomized to receive adjunctive therapy with bivalirudin or UFH+eptifibatide.

Src family kinases mediate neutrophil adhesion to adherent platelets.

Polymorphonuclear leukocyte (PMN)-platelet interactions at sites of vascular damage contribute to local and systemic inflammation. We sought to determine the role of "outside-in" signaling by Src-family tyrosine kinases (SFKs) in the regulation of alphaMbeta2-integrin-dependent PMN recruitment by activated platelets under (patho)physiologic conditions. Activation-dependent epitopes in beta2 integrin were exposed at the contact sites between PMNs and platelets and were abolished by SFK inhibitors.

Lipid phosphate phosphatases regulate lysophosphatidic acid production and signaling in platelets: studies using chemical inhibitors of lipid phosphate phosphatase activity.

Blood platelets play an essential role in ischemic heart disease and stroke contributing to acute thrombotic events by release of potent inflammatory agents within the vasculature. Lysophosphatidic acid (LPA) is a bioactive lipid mediator produced by platelets and found in the blood and atherosclerotic plaques. LPA receptors on platelets, leukocytes, endothelial cells, and smooth muscle cells regulate growth, differentiation, survival, motility, and contractile activity.