Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0406810 (NAME)
 13,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Adiponectin is an adipocyte-derived anti-atherogenic protein. Adiponectin levels are decreased in patients and animal models with obesity, diabetes, and coronary artery disease. However, the mechanism by which adiponectin levels are reduced remains unknown. Since hypoadiponectinemia is closely linked to endothelial dysfunction, we examined the regulation of adiponectin in a rat model of chronic blockade of nitric oxide (NO) synthesis by N omega-nitro-L-arginine methyl ester (L-NAME). Decreased production of NO and increased production of O2- were observed in aorta from L-NAME-treated rats. Plasma adiponectin levels and adiponectin mRNA levels of adipose tissue were markedly decreased in L-NAME-treated rats. Cotreatment of pioglitazone (PIO) or allopurinol (ALL) with L-NAME restored plasma adiponectin concentration and fat adiponectin mRNA levels to control levels. Thus, adiponectin levels were decreased in L-NAME-treated rats, however, they returned to normal following administration of PIO due to transcriptional activation of the adiponectin gene, as well as administration of ALL, likely due to elimination of oxidative stress. Oxidative stress appears to be an important cause of hypoadiponectinemia.
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PMID:Hypoadiponectinemia is caused by chronic blockade of nitric oxide synthesis in rats. 2196 Nov 61

A close relationship between oxidative stress, endothelial dysfunction, and hypoadiponectinemia has been observed. The present study was performed to investigate how glutathione depletion via buthionine sulfoximine (BSO) administration affects endothelial function and adiponectin levels in rats. Acetylcholine (Ach)-induced vasodilation was significantly enhanced in BSO-treated rats, compared with control rats. This was completely abolished by L-NAME, and Ach-induced vasodilation was not observed in the aorta without endothelium. These results suggest that Ach-induced hyper-relaxation of the aorta in BSO-treated rats is completely dependent on the presence of endothelium and mediated by changes in eNOS activity. Catalase significantly inhibited this relaxation to Ach and no effect of catalase on sodium nitroprusside-induced relaxation of the aorta without endothelium was observed in BSO-treated rats. Thus, hyper-relaxation of the aorta in BSO-treated rats is likely caused by H2O2 in addition to NO produced by the endothelium via an eNOS-dependent mechanism. Hypoadiponectinemia and decreased levels of adiponectin mRNA in adipose tissue were observed in BSO-treated rats. Protein expression of eNOS and SODs (SOD-1 and SOD-2) in the aorta was increased and plasma NOx levels were decreased in BSO-treated rats. Our results suggest that oxidative stress induced by BSO causes eNOS uncoupling and hyper-relaxation by producing H2O2, and that BSO-induced oxidative stress causes hypoadiponectinemia, probably by increasing H2O2 production in adipose tissue.
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PMID:Buthionine sulfoximine causes endothelium dependent hyper-relaxation and hypoadiponectinemia. 1713 3

Epigallocatechin gallate (EGCG), a bioactive polyphenol in green tea, may augment metabolic and vascular actions of insulin. Therefore, we investigated effects of EGCG treatment to simultaneously improve cardiovascular and metabolic function in spontaneously hypertensive rats (SHR; model of metabolic syndrome with hypertension, insulin resistance, and overweight). In acute studies, EGCG (1-100 microM) elicited dose-dependent vasodilation in mesenteric vascular beds (MVB) isolated from SHR ex vivo that was inhibitable by N(omega)-nitro-L-arginine methyl ester (L-NAME; nitric oxide synthase antagonist) or wortmannin [phosphatidylinositol (PI) 3-kinase inhibitor]. In chronic studies, 9-wk-old SHR were treated by gavage for 3 wk with EGCG (200 mg.kg(-1).day(-1)), enalapril (30 mg.kg(-1).day(-1)), or vehicle. A separate group of SHR receiving L-NAME (80 mg/l in drinking water) was treated for 3 wk with either EGCG or vehicle. Vasodilator actions of insulin were significantly improved in MVB from EGCG- or enalapril-treated SHR (when compared with vehicle-treated SHR). Both EGCG and enalapril therapy significantly lowered systolic blood pressure (SBP) in SHR. EGCG therapy of SHR significantly reduced infarct size and improved cardiac function in Langendorff-perfused hearts exposed to ischemia-reperfusion (I/R) injury. In SHR given L-NAME, beneficial effects of EGCG on SBP and I/R were not observed. Both enalapril and EGCG treatment of SHR improved insulin sensitivity and raised plasma adiponectin levels. We conclude that acute actions of EGCG to stimulate production of nitric oxide from endothelium using PI 3-kinase-dependent pathways may explain, in part, beneficial effects of EGCG therapy to simultaneously improve metabolic and cardiovascular pathophysiology in SHR. These findings may be relevant to understanding potential benefits of green tea consumption in patients with the metabolic syndrome.
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PMID:EGCG, a green tea polyphenol, improves endothelial function and insulin sensitivity, reduces blood pressure, and protects against myocardial I/R injury in SHR. 1722 56

This study reports on what we believe are novel mechanism(s) of the vascular protective action of adiponectin. We used intravital microscopy to measure leukocyte-endothelium interactions in adiponectin-deficient (Ad(-/-)) mice and found that adiponectin deficiency was associated with a 2-fold increase in leukocyte rolling and a 5-fold increase in leukocyte adhesion in the microcirculation. Measurement of endothelial NO (eNO) revealed that adiponectin deficiency drastically reduced levels of eNO in the vascular wall. Immunohistochemistry demonstrated increased expression of E-selectin and VCAM-1 in the vascular endothelium of Ad(-/-) mice. Systemic administration of the recombinant globular adiponectin domain (gAd) to Ad(-/-) mice significantly attenuated leukocyte-endothelium interactions and adhesion molecule expression in addition to restoring physiologic levels of eNO. Importantly, prior administration of gAd also protected WT mice against TNF-alpha-induced leukocyte-endothelium interactions, indicating a pharmacologic action of gAd. Mechanistically, blockade of eNOS with N(omega)-nitro-L-arginine methyl ester ( L-NAME) abolished the inhibitory effect of gAd on leukocyte adhesion, demonstrating the obligatory role of eNOS signaling in the antiinflammatory action of gAd. We believe this is the first demonstration that gAd protects the vasculature in vivo via increased NO bioavailability with suppression of leukocyte-endothelium interactions. Overall, we provide evidence that loss of adiponectin induces a primary state of endothelial dysfunction with increased leukocyte-endothelium adhesiveness.
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PMID:Adiponectin deficiency increases leukocyte-endothelium interactions via upregulation of endothelial cell adhesion molecules in vivo. 1754 59

Genetic deletion of inducible nitric oxide synthase (NOS) in mice has been shown to improve high-fat diet (HFD)-induced insulin resistance. However, a pathophysiological role of endogenous nitric oxide (NO) in obesity-related insulin resistance remains controversial. To address this issue, we examined the metabolic phenotypes in HFD-induced obese mice with chronic blockade of NO synthesis by a NOS inhibitor, N(G)-nitro-l-arginine methyl ester (L-NAME). Six-week-old male C57BL/6j mice were provided free access to either a standard diet (SD) or a HFD and tap water with or without L-NAME (100 mg/kg.d) for 12 wk. L-NAME treatment significantly attenuated body weight gain of mice fed either SD or HFD without affecting calorie intake. L-NAME treatment in HFD-fed mice improved glucose tolerance and insulin sensitivity. HFD feeding induced inducible NOS mRNA expression, but not the other two NOS isoforms, in white adipose tissue (WAT) and skeletal muscle. L-NAME treatment up-regulated uncoupling protein-1 in brown adipose tissue of HFD-fed mice but down-regulated monocyte chemoattractant protein-1 and CD68 mRNAs levels in WAT. HFD feeding up-regulated leptin mRNA levels but conversely down-regulated adiponectin mRNA levels in WAT, but these effects were unaffected by L-NAME treatment. Moreover, L-NAME treatment also increased peroxisome proliferator-uncoupling protein-3 mRNA levels in skeletal muscles of HFD-fed mice. Increased urinary excretion of norepinephrine after HFD feeding was augmented in L-NAME-treated mice. Insulin-stimulated tyrosine phosphorylation of insulin receptor substrate-1 and serine phosphorylation of Akt/Akt2 in soleus muscle was markedly impaired in HFD-fed mice but reversed by L-NAME treatment. In conclusion, chronic NOS blockade by L-NAME in mice ameliorates HFD-induced adiposity and glucose intolerance, accompanied by reduced adipose inflammation and improved insulin signaling in skeletal muscle, suggesting that endogenous NO plays a modulatory role in the development of obesity-related insulin resistance.
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PMID:Chronic blockade of nitric oxide synthesis reduces adiposity and improves insulin resistance in high fat-induced obese mice. 1787 34

Adiponectin, produced predominantly by differentiating adipocytes, is a protein hormone with antidiabetic and immunosuppressive properties. Here, we report evidence that treatment with globular adiponectin (gAd) induces apoptosis in murine macrophage-like RAW264 cells through the generation of reactive oxygen and/or nitrogen species (ROS/RNS). Treatment with gAd induced apoptosis and enhanced the activities of caspase-3 and -9, but not caspase-8. The gAd stimulation increased ROS generation and significantly reduced the ratio of NADPH to total NADP. Pretreatment with diphenyleneiodonium or apocynin reduced ROS and apoptosis in gAd-treated cells. In addition, transfection with p47(phox)- or gp91(phox)-specific small interfering RNA (siRNA) partially reduced ROS and apoptosis in response to gAd treatment. These results suggest that the administration of gAd induces apoptosis after ROS generation involving activation of NADPH oxidases. The gAd stimulation increased the release of NO into the culture medium, the activity of nitric oxide synthase (NOS), and the expression of inducible NOS (iNOS) mRNA in RAW264 cells. l-NAME reduced gAd-induced apoptotic cell death. In addition, transfection with an iNOS-specific siRNA markedly reduced the generation of NO and the population of apoptotic cells. Taken together, these results demonstrate that the gAd-induced apoptotic process in RAW264 cells involves ROS and RNS, which are generated by NADPH oxidases and iNOS, respectively.
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PMID:Regulation of globular adiponectin-induced apoptosis by reactive oxygen/nitrogen species in RAW264 macrophages. 1877 88

Propionyl-L-carnitine (PLC) is an SCFA esterified to carnitine that plays an important role in fatty acid oxidation and energy expenditure, in addition to having a protective effect on the endothelium. In order to evaluate the effect of PLC on an animal model of obesity, insulin resistance and, consequently, endothelial dysfunction, lean and obese Zucker rats (OZR) received either vehicle- or PLC-supplemented drinking water (200 mg/kg per d) for 20 weeks. Body weight, food intake, systolic blood pressure and heart rate were controlled weekly and an oral glucose tolerance test was performed. Fasting glucose, TAG, cholesterol, HDL, NEFA, adiponectin and insulin were analysed in serum. Visceral adipose tissue and liver were weighed and liver TAG liver composition was evaluated. Endothelial and vascular functions were assessed in the aorta and small mesenteric arteries by response to acetylcholine, sodium nitroprusside and phenylephrine (Phe); NO participation was evaluated after incubation with the NO synthase (NOS) inhibitor NG-nitro-L-arginine methyl ester (L-NAME) and endothelial NOS protein expression by Western blotting. PLC decreased body-weight gain, food intake, adiposity, insulin serum concentration and TAG liver content and improved insulin resistance. Aortae from OZR receiving either vehicle or PLC exhibited a lower contractile response to Phe. PLC-treated OZR showed an enhanced release of endothelial NO upon the adrenergic stimulation. The protection of vascular function found after treatment with PLC in an animal model of insulin resistance supports the necessity of clinical trials showing the effect of L-carnitine supplements on metabolic disorders.
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PMID:Oral supplementation of propionyl-l-carnitine reduces body weight and hyperinsulinaemia in obese Zucker rats. 1954 58

Rimonabant (RM) is a cannabinoid CB1 receptor antagonist useful in the treatment of obesity associated cardiovascular risk factors. Since cannabinoids are vasoactive compounds, the aim of this study is to evaluate the effect of chronic treatment with RM on systolic blood pressure (SBP), and endothelial and vascular reactivity. Obese Zucker rats (OZRs) and their lean counterparts were orally treated during 20 weeks with either RM (10 mg/kg/day). Endothelial and vascular function was assessed in aorta and small mesenteric arteries (SMAs) by concentration response curves to acetylcholine (ACh) and phenylephrine (Phe), respectively. Participation of nitric oxide (NO) was evaluated by incubation with the NO synthase (NOS) inhibitor N(G)-nitro-l-arginine methyl ester (L-NAME) and cyclooxygenase (COX)-derived products involvement was analyzed by incubation with indomethacin (INDO). Plasma lipid profile, insulin and adiponectin were also analyzed. Sympathetic activity was evaluated by urinary excretion of noradrenaline. As expected, RM decreased body weight gain and enhanced adiponectin concentration. Insulin resistance and sympathetic activity were also decreased. The increase in SBP observed in OZRs was reduced by treatment with RM. Aortae and SMAs from OZRs exhibited lower contractile response to Phe, being this effect prevented by RM administration. Although ACh-induced response and NO participation remained unaltered with obesity, enhanced COX-derived constrictor products were found in OZRs. RM treatment neither altered endothelium-dependent relaxation nor L-NAME-sensitive component of the response. Nevertheless, it was able to regulate COX-derived vasoactive products participation. Those effects may contribute to explain some of the cardiovascular protective actions elicited by this drug.
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PMID:Effects of chronic treatment with the CB1 antagonist, rimonabant on the blood pressure, and vascular reactivity of obese Zucker rats. 1955 24

The recently discovered peptide apelin is known to be involved in the maintenance of insulin sensitivity. However, questions persist regarding its precise role in the chronic setting. Fasting glucose, insulin, and adiponectin levels were determined on mice with generalized deficiency of apelin (APKO). Additionally, insulin (ITT) and glucose tolerance tests (GTT) were performed. To assess the impact of exogenously delivered apelin on insulin sensitivity, osmotic pumps containing pyroglutamated apelin-13 or saline were implanted in APKO mice for 4 wk. Following the infusion, ITT/GTTs were repeated and the animals euthanized. Soleus muscles were harvested and homogenized in lysis buffer, and insulin-induced Akt phosphorylation was determined by Western blotting. Apelin-13 infusion and ITTs/GTTs were also performed in obese diabetic db/db mice. To probe the underlying mechanism for apelin's effects, apelin-13 was also delivered to cultured C2C12 myotubes. 2-[3H]deoxyglucose uptake and Akt phosphorylation were assessed in the presence of various inhibitors. APKO mice had diminished insulin sensitivity, were hyperinsulinemic, and had decreased adiponectin levels. Soleus lysates had decreased insulin-induced Akt phosphorylation. Administration of apelin to APKO and db/db mice resulted in improved insulin sensitivity. In C2C12 myotubes, apelin increased glucose uptake and Akt phosphorylation. These events were fully abrogated by pertussis toxin, compound C, and siRNA knockdown of AMPKalpha1 but only partially diminished by LY-294002 and not at all by L-NAME. We conclude that apelin is necessary for the maintenance of insulin sensitivity in vivo. Apelin's effects on glucose uptake and Akt phosphorylation are in part mediated by a G(i) and AMPK-dependent pathway.
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PMID:Apelin is necessary for the maintenance of insulin sensitivity. 1986 85

Previous studies related impaired myocardial microcirculation in diabetes to oxidative stress and endothelial dysfunction. Thus, this study was aimed to determine the effect of up-regulating pAMPK-pAKT signaling on coronary microvascular reactivity in the isolated heart of diabetic mice. We measured coronary resistance in wild-type and streptozotocin (STZ)-treated mice, during perfusion pressure changes. Glucose, insulin, and adiponectin levels in plasma and superoxide formation, NOx levels and heme oxygenase (HO) activity in myocardial tissue were determined. In addition, the expression of HO-1, 3-nitrotyrosine, pLKB1, pAMPK, pAKT, and peNOS proteins in control and diabetic hearts were measured. Coronary response to changes in perfusion pressure diverged from control in a time-dependent manner following STZ administration. The responses observed at 28 weeks of diabetes (the maximum time examined) were mimicked by L-NAME administration to control animals and were associated with a decrease in serum adiponectin and myocardial pLKB1, pAMPK, pAKT, and pGSK-3 expression. Cobalt protoporphyrin treatment to induce HO-1 expression reversed the microvascular reactivity seen in diabetes towards that of controls. Up-regulation of HO-1 was associated with an increase in adiponectin, pLKB1, pAKT, pAMPK, pGSK-3, and peNOS levels and a decrease in myocardial superoxide and 3-nitrotyrosine levels. In the present study we describe the time course of microvascular functional changes during the development of diabetes and the existence of a unique relationship between the levels of serum adiponectin, pLKB1, pAKT, and pAMPK activation in diabetic hearts. The restoration of microvascular function suggests a new therapeutic approach to even advanced cardiac microvascular derangement in diabetes.
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PMID:Improved myocardial perfusion in chronic diabetic mice by the up-regulation of pLKB1 and AMPK signaling. 2010 50


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