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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To explore altered platelet function in recurrent coronary event risk among diabetic postinfarction patients, we investigated a function-altering genetic polymorphism (T145M) in the von Willebrand factor binding region of the platelet glycoprotein Ibalpha (GPIbalpha) subunit. The study comprised diabetic and nondiabetic patients of the Thrombogenic Factors and Recurrent Coronary Events postinfarction study. Cox proportional hazards multivariable modeling, adjusted for significant clinical covariates, was performed using the polymorphism and metabolic, inflammatory, and thrombogenic blood markers. Nondiabetic patients demonstrated risk for elevated lipoprotein-associated phospholipase A(2) (Lp-PLA(2)). In contrast, diabetic patients demonstrated significant and independent risk for the M allele of the T145M polymorphism (MT plus MM versus TT, hazard ratio [HR] 3.73, 95% CI 1.90-7.33, P < 0.001), hypertriglyceridemia (2.91, 1.52-5.56, P = 0.001), and elevated Lp-PLA(2) (2.78, 1.45-5.35, P = 0.002). Joint risk (one, two, or three risk factors) expressed as relative outcome rates (compared with no risk factors) were 2.4, 4.0, and 8.2, respectively. We conclude that the M allele of the T145M polymorphism of the GPIbalpha subunit predicts risk for recurrent coronary events in diabetic postinfarction patients, but not in nondiabetic postinfarction patients, supportive of an important role for platelet hyperactivation in diabetic coronary heart disease.
Diabetes 2007 May
PMID:Glycoprotein Ibalpha polymorphism T145M, elevated lipoprotein-associated phospholipase A2, and hypertriglyceridemia predict risk for recurrent coronary events in diabetic postinfarction patients. 1730 2

Class A scavenger receptors (SR-A) participate in multiple macrophage functions including adhesion to modified extracellular matrix proteins present in various inflammatory disorders such as atherosclerosis and diabetes. By mediating macrophage adhesion to modified proteins and increasing macrophage retention, SR-A may contribute to the inflammatory process. Eicosanoids produced after phospholipase A(2) (PLA(2))-catalyzed release of arachidonic acid (AA) are important regulators of macrophage function and inflammatory responses. The potential roles of AA release and metabolism in SR-A-mediated macrophage adhesion were determined using macrophages adherent to modified protein. SR-A-dependent macrophage adhesion was abolished by selectively inhibiting calcium-independent PLA(2) (iPLA(2)) activity and absent in macrophages isolated from iPLA(2) beta(-/-) mice. Our results further demonstrate that 12/15-lipoxygenase (12/15-LOX)-derived, but not cyclooxygenase- or cytochrome P450-dependent epoxygenase-derived AA metabolites, are specifically required for SR-A-dependent adhesion. Because of their role in regulating actin polymerization and cell adhesion, Rac and Cdc42 activation were also examined and shown to be increased via an iPLA(2)- and LOX-dependent pathway. Together, our results identify a novel role for iPLA(2)-catalyzed AA release and its metabolism by 12/15-LOX in coupling SR-A-mediated macrophage adhesion to Rac and Cdc42 activation.
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PMID:Class A scavenger receptor-mediated macrophage adhesion requires coupling of calcium-independent phospholipase A(2) and 12/15-lipoxygenase to Rac and Cdc42 activation. 1787 77

Multiple strategies are available for clinicians to identify patients at high risk for cardiovascular events. Two commonly discussed strategies are the identification of vulnerable plaques and the identification of vulnerable patients. The strategy of identifying vulnerable patients is less invasive, easy to implement and not restricted primarily to one vascular bed (e.g. coronary or cerebral). This review discusses the utility as well as the limitations of global risk assessment tools to identify such patients. The utility of biomarkers [C-reactive protein, lipoprotein-associated phospholipase A(2) and lipoprotein(a)] and non-invasive measures of atherosclerosis burden (coronary artery calcium scores, carotid intima-media thickness and ankle-brachial index) in identifying patients at high risk for cardiovascular events are also discussed.
Diabetes Obes Metab 2008 Sep
PMID:How to identify patients with vulnerable plaques. 1797 Jul 57

Peroxisome proliferator-activated receptor is a nuclear receptor that has been implicated in blastocyst implantation, cell cycle, and pathogenesis of diabetes. However, the signal cascades underlying this effect are largely unknown in embryo stem cells. This study examined whether or not there is an association between the reactive oxygen species-mediated prostaglandin E(2) (PGE(2))/peroxisome proliferator-activated receptor (PPAR) delta and the growth response to high glucose levels in mouse ESCs. A high concentration of glucose (25 mM) significantly increased the level of [3H]thymidine incorporation, the level of 5-bromo-2'-deoxyuridine incorporation, and the number of cells. Moreover, 25 mM glucose increased the intracellular reactive oxygen species, phosphorylation of the cytosolic phospholipase A(2) (cPLA(2)), and the release of [3H]arachidonic acid ([3H]AA). In addition, 25 mM glucose also increased the level of cyclooxygenase-2 (COX-2) protein expression, which stimulated the synthesis of PGE(2). Subsequently, high glucose-induced PGE(2) stimulated PPARdelta expression directly or through Akt phosphorylation indirectly through the E type prostaglandin receptor receptors. The PPARdelta antagonist inhibited the 25 mM glucose-induced DNA synthesis. Moreover, transfection with a pool of PPARdelta-specific small interfering RNA inhibited the 25 mM glucose-induced DNA synthesis and G1/S phase progression. Twenty-five millimolar glucose also increased the level of the cell cycle regulatory proteins (cyclin E/cyclin-dependent kinase [CDK] 2 and cyclin D1/CDK 4) and decreased p21(WAF1/Cip1) and p27(Kip1), which were blocked by the inhibition of the cPLA(2), COX-2, or PPARdelta pathways. In conclusion, high glucose promotes mouse ESC growth in part through the cPLA(2)-mediated PGE(2) synthesis and in part through PPARdelta pathways.
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PMID:High-glucose-induced prostaglandin E(2) and peroxisome proliferator-activated receptor delta promote mouse embryonic stem cell proliferation. 1809 20

Lysophosphatidic acid (LPA, 1- or 2-acyl-sn-glycerol 3-phosphate) is a simple phospholipid but displays an intriguing cell biology that is mediated via interactions with G protein-coupled seven transmembrane receptors (GPCRs). So far, five GPCRs, designated LPA1-5, and, more recently, two additional GPCRs, GPR87 and P2Y5, have been identified as receptors for LPA. These LPA receptors can be classified into two families, the EDG and P2Y families, depending on their primary structures. Recent studies on gene targeting mice and family diseases of these receptors revealed that LPA is involved in both pathological and physiological states including brain development (LPA1), neuropathy pain (LPA1), lung fibrosis (LPA1), renal fibrosis (LPA1) protection against radiation-induced intestinal injury (LPA2), implantation (LPA3) and hair growth (P2Y5). LPA is produced both in cells and biological fluids, where multiple synthetic reactions occur. There are at least two pathways for LPA production. In serum or plasma, LPA is predominantly produced by a plasma enzyme called autotaxin (ATX). ATX is a multifunctional ectoenzyme and is involved in many patho-physiological conditions such as cancer, neuropathy pain, lymphocyte tracking in lymph nodes, obesity, diabetes and embryonic blood vessel formation. LPA is also produced from phosphatidic acid (PA) by its deacylation catalyzed by phospholipase A (PLA)-type enzymes. However, the physiological roles of this pathway as well as the enzymes involved remained to be solved. A number of phospholipase A1 and A2 isozymes could be involved in this pathway. One PA-selective PLA1 called mPA-PLA1alpha/LIPH is specifically expressed in hair follicles, where it has a critical role in hair growth by producing LPA through a novel LPA receptor called P2Y5.
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PMID:Two pathways for lysophosphatidic acid production. 1862 Nov 44

Group VI phospholipase A2 (PLA2) is a family of acyl hydrolases that targets the sn-2 fatty acid on the glycerophospholipid (GPL) backbone. These enzymes are grouped together based on structural homologies and catalytic activities that are independent of calcium and hence are also called the iPLA(2)s. Although the best characterized of these enzymes, iPLA2beta and iPLA2gamma, have long been proposed as homeostatic enzymes involved in basal GPL metabolism, recent studies indicate roles for these enzymes in biomedically relevant processes as well. For example, iPLA2 modulates calcium homeostasis by promoting replenishment of intracellular calcium stores. This function is likely of importance in the pathogenesis of Duchenne muscular dystrophy and potentially allergy as well. iPLA2 has a variety of roles in bacterial pathogenesis and the host response against bacterial and fungal infections. These characteristics suggest that the enzyme as a potential target to control infectious diseases. iPLA2 is linked to both proliferation and chemotherapy-induced apoptosis of tumor cells. As such, the enzyme is a potential target for cancer chemotherapy. Recent studies indicate essential roles for iPLA2 in glucose homeostasis, maintenance of energy balance, adipocyte development, and hepatic lipogenesis. Thus, the enzyme is an attractive target for drugs to control type II diabetes, fatty liver disease, and other manifestations of the metabolic syndrome. Several recent studies have associated iPLA2 inactivation with neurodegenerative diseases, suggesting the possibility that products of the iPLA2 reaction as potential treatments for these disorders. Together, these observations suggest iPLA2 as a novel and important target for drug development. However given the ubiquitous expression of the enzyme and its roles in basal GPL metabolism, drug strategies targeting iPLA2 must exhibit exquisite selectivity to avoid undesired side effects. Furthermore, the cell-specific nature of many iPLA2 functions may present another challenge in the design and implementation of drugs targeted to the enzyme.
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PMID:Group VI phospholipases A2: homeostatic phospholipases with significant potential as targets for novel therapeutics. 1869 Oct 15

Periodontal disease has been associated with cardiovascular disease (CVD), and inflammation may represent a common pathophysiology. Oral health screening in the context of CVD risk assessment represents a potential opportunity to identify individuals at risk for CVD. The purposes of this study were to determine if self-reported oral health status is independently associated with inflammatory markers and if oral health assessment as part of CVD risk screening can identify at-risk individuals without traditional CVD risk factors. A baseline analysis was conducted among participants in the National Heart, Lung, and Blood Institute's Family Intervention Trial for Heart Health (FIT Heart; n = 421, mean age 48 +/- 13.5 years, 36% nonwhite) without CVD or diabetes who underwent standardized assessment of oral health, lifestyle, CVD risk factors, and the inflammatory markers high-sensitivity C-reactive protein and lipoprotein-associated phospholipase A(2). Statistical associations between oral health, risk factors, and inflammatory markers were assessed, and logistic regression was used to adjust for effects of lifestyle and potential confounders. Periodontal disease was independently associated with being in the top quartile of lipoprotein-associated phospholipase A(2) compared with the lower 3 quartiles (odds ratio 1.9, 95% confidence interval 1.1 to 3.2) after adjustment for lifestyle and risk factors. Histories of periodontal disease were reported by 24% of non-overweight, non-hypertensive, non-hypercholesterolemic participants, and of these participants, 37% had elevated high-sensitivity C-reactive protein (> or =3 mg/L) or lipoprotein-associated phospholipase A(2) (> or =215 ng/ml) levels. In conclusion, self-reported periodontal disease is independently associated with inflammation and common in individuals without traditional CVD risk factors.
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PMID:Usefulness of self-reported periodontal disease to identify individuals with elevated inflammatory markers at risk of cardiovascular disease. 1902 5

Pancreatic phospholipase A2 (phospholipase A2 group 1B, G1B) belongs to the superfamily of secreted phospholipase A2 (PLA2) enzymes. G1B has been proposed to be a potential target for diseases such as hypertension, obesity, and diabetes. Human pancreatic prophospholipase A2 (pro-hG1B) is activated by cleavage of the first seven-residue propeptide (phospholipase A2 propeptide, PROP). However, questions still remain on the mode of action for pro-hG1B. In this work, we expressed pro-hG1B in Pichia pastoris and determined the crystal structure at 1.55-A resolution. The x-ray structure demonstrates that pro-hG1B forms a trimer. In addition, PROP occupies the catalytic cavity and can be self-cleaved at 37 degrees C. A new membrane-bound surface and activation mechanism are proposed based on the trimeric model of pro-hG1B. We also propose a new autoproteolytic mechanism for pro-hG1B by the reaction triad Asp49-Arg0-Ser(-2) that is similar to the serine protease catalytic triad.
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PMID:Structural insight into the activation mechanism of human pancreatic prophospholipase A2. 1929 24

This study investigated the correlation of sPLA2 (secretory phospholipase A2) activity with the atheromatosis extent in subjects with coronary artery disease (CAD) undergoing coronary angiography. We analyzed 123 patients, including 35 subjects with angiographically normal coronary arteries (controls), 31 with mild/moderate atheromatosis (stenosis of 30-70% of the luminal diameter in one or more coronary arteries) and 57 with severe atheromatosis (>70% stenosis). Plasma sPLA2 activity was significantly higher in subjects with severe [127.7 U/ml (102.3-162.7); p < 0.0001] and mild/moderate [112.0 U/ml (100.6-146.9); p < 0.0001] atheromatosis than in controls [19.8 U/ml (15.1-32.1)]. In a multiple logistic regression model, adjusted for age, gender, body mass index, tabagism, hypertension, sedentarism, family history for coronary artery disease, diabetes mellitus, total cholesterol, HDLc, LDLc, triglycerides, high sensitivity C-reactive protein and phospholipase A2, only sPLA2 was observed to be independently associated with severe CAD (>70% of stenosis) (p < 0.0001).
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PMID:Secretory phospholipase A2 in patients with coronary artery disease. 1944 49

Coupling factor 6 (CF6) is composed of 76 amino acids and is present in the peripheral stalk of mitochondrial ATP synthase. The generation of CF6 is positively regulated by tumor necrosis factor alpha and shear stress via nuclear factor kappaB, and by high glucose via protein kinase C and p38 mitogen-activated protein kinase. CF6 is released outside of the cells from vascular endothelial cells, and binds to the beta-subunit of the plasma membrane-bound ATP synthase in vascular endothelial cells and leads to intracellular acidosis. CF6 produces vasoconstriction, and the biological active site resides at the C-terminal portion. CF6 suppresses prostacyclin generation via inhibition of cytosolic phospholipase A(2). CF6 also suppresses nitric oxide synthase activity via an increase in asymmetric dimethylarginine and a decrease in platelet/endothelial cell adhesion molecule-1. CF6 induces the gene and protein expression of proatherogenic molecules such as endothelin 2, urokinase type plasminogen activator receptor, estrogen receptor beta, a soluble short form of vascular endothelial growth factor receptor-1, and lectin-like oxidized low-density lipoprotein receptor-1. The plasma level of CF6 is elevated in patients with essential hypertension, diabetes mellitus, end-stage renal disease, acute myocardial infarction, and coronary heart disease. It is likely that CF6 contributes to the pathogenesis of cardiovascular diseases, but further intensive investigation is needed.
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PMID:Coupling factor 6 as a novel vasoactive and proatherogenic peptide in vascular endothelial cells. 1948 38


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