Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0007222 (cardiovascular disease)
 65,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The insulin resistance syndrome is characterized by several risk factors for cardiovascular disease. Chronic chemical activation of AMP-activated protein kinase by the adenosine analog 5-aminoimidazole-4-carboxamide-1-beta -D-ribofuranoside (AICAR) has been shown to augment insulin action, upregulate mitochondrial enzymes in skeletal muscles, and decrease the content of intra-abdominal fat. Furthermore, acute AICAR exposure has been found to reduce sterol and fatty acid synthesis in rat hepatocytes incubated in vitro as well as suppress endogenous glucose production in rats under euglycemic clamp conditions. To investigate whether chronic AICAR administration, in addition to the beneficial effects on insulin sensitivity, is capable of improving other phenotypes associated with the insulin resistance syndrome, obese Zucker (fa/fa) rats (n = 6) exhibiting insulin resistance, hyperlipidemia, and hypertension were subcutaneously injected with AICAR (0.5 mg/g body wt) daily for 7 weeks. Obese control rats were either pair-fed (PF) (n = 6) or ad libitum-fed (AL) (n = 6). Lean Zucker rats (fa/-) (n = 8) served as a reference group. AICAR administration significantly reduced plasma triglyceride levels (P < 0.01 for AICAR vs. AL, and P = 0.05 for AICAR vs. PF) and free fatty acids (P < 0.01 for AICAR vs. AL, and P < 0.05 for AICAR vs. PF) and increased HDL cholesterol levels (P < 0.01 for AICAR vs. AL and PF). AICAR treatment also lowered systolic blood pressure by 14.6 +/- 4.3 mmHg (P < 0.05), and AICAR-treated animals exhibited a tendency toward decreased intra-abdominal fat content. Furthermore, AICAR administration normalized the oral glucose tolerance test and decreased fasting concentrations of glucose and insulin close to the level of the lean animals. Finally, in line with previous findings, AICAR treatment was also found to enhance GLUT4 protein expression and to increase maximally insulin-stimulated glucose transport in primarily white fast-twitch muscles. Our data provide strong evidence that long-term administration of AICAR improves glucose tolerance, improves the lipid profile, and reduces systolic blood pressure in an insulin-resistant animal model. The present study gives additional support to the hypothesis that AMPK activation might be a potential future pharmacological strategy for treating the insulin resistance syndrome.
 ...
PMID:Long-term AICAR administration reduces metabolic disturbances and lowers blood pressure in rats displaying features of the insulin resistance syndrome. 1208 50

Based on available evidence, we would propose the following. (i) Excesses of glucose and free fatty acids cause insulin resistance in skeletal muscle and damage to the endothelial cell by a similar mechanism. (ii) Key pathogenetic events in this mechanism very likely include increased fatty acid esterification, protein kinase C activation, an increase in oxidative stress (demonstrated to date in endothelium) and alterations in the inhibitor kappa B kinase/nuclear factor kappa B system. (iii) Activation of AMP-activated protein kinase (AMPK) inhibits all of these events and enhances insulin signalling in the endothelial cell. It also enhances insulin action in muscle; however, the mechanism by which it does so has not been well studied. (iv) The reported beneficial effects of exercise and metformin on cardiovascular disease and insulin resistance in humans could be related to the fact that they activate AMPK. (v) The comparative roles of AMPK in regulating metabolism, signalling and gene expression in muscle and endothelial cells warrant further study.
 ...
PMID:Malonyl-CoA and AMP-activated protein kinase (AMPK): possible links between insulin resistance in muscle and early endothelial cell damage in diabetes. 1254 85

Obesity is an epidemic in Western society, and causes rapidly accelerating rates of type 2 diabetes and cardiovascular disease. The evolutionarily conserved serine/threonine kinase, AMP-activated protein kinase (AMPK), functions as a 'fuel gauge' to monitor cellular energy status. We investigated the potential role of AMPK in the hypothalamus in the regulation of food intake. Here we report that AMPK activity is inhibited in arcuate and paraventricular hypothalamus (PVH) by the anorexigenic hormone leptin, and in multiple hypothalamic regions by insulin, high glucose and refeeding. A melanocortin receptor agonist, a potent anorexigen, decreases AMPK activity in PVH, whereas agouti-related protein, an orexigen, increases AMPK activity. Melanocortin receptor signalling is required for leptin and refeeding effects on AMPK in PVH. Dominant negative AMPK expression in the hypothalamus is sufficient to reduce food intake and body weight, whereas constitutively active AMPK increases both. Alterations of hypothalamic AMPK activity augment changes in arcuate neuropeptide expression induced by fasting and feeding. Furthermore, inhibition of hypothalamic AMPK is necessary for leptin's effects on food intake and body weight, as constitutively active AMPK blocks these effects. Thus, hypothalamic AMPK plays a critical role in hormonal and nutrient-derived anorexigenic and orexigenic signals and in energy balance.
 ...
PMID:AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus. 1505 5

Adiponectin (also called AdipoQ, gelatin-binding protein 28, Acrp30) is a novel adipocytokine with important metabolic effects. It is physiologically released from adipose tissue and circulates in serum as a hexamer and larger multimeric structure of high molecular weight. Serum level of the protein correlates with systemic insulin sensitivity. Recently adiponectin receptors AdipoR1 and AdipoR2 have been discovered by expression cloning. AdipoR1 is abundantly expressed in skeletal muscles, whereas AdipoR2 is predominantly expressed in the liver. Marked expression of mRNA for AdipoR1 and AdipoR2 has been lately reported in pancreatic beta cells. Both of the receptors activate AMPK and PPAR alpha metabolic pathways leading to an increase in fatty acid oxidation, glucose uptake and a decreased rate of gluconeogenesis, thus enhancing insulin sensitivity. Moreover effects of adiponectin mimic many metabolic actions of insulin such as augmenting blood flow and glucose disposal in NO-dependent manner. The precise mechanism of regulation of plasma adiponectin level is unknown. Recently the mechanism of transcriptional activation of adiponectin gene via PPAR gamma was described. Its level seems to be decreased by TNFalfa and beta-adrenergic agonists. Furthermore there is increasing evidence that some genetic variants in the adiponectin gene may be associated with its ethnical differences in level as well as its likely clinical consequences. Hipoadiponectynemia is associated with obesity, metabolic syndrome, diabetes type 2, cardiovascular disease, lipodystrophy in AIDS. In patients with chronic renal failure, anorexia nervosa plasma adlponectin level is increased. Weight loss and therapy with thlazolidinediones are proved to enhance endogenous adlponectin production in humans. In summary, the ability of adiponectin to increase insulin sensitivity in conjunction with its anti-inflammatory and antiatherogenic properties have made this novel adipocytokine a promising therapeutic tool for the future, especially in individuals with low plasma levels of adiponectin.
 ...
PMID:[Adiponectin--adipocytokine with a broad clinical spectrum]. 1523 Jan 53

Adiponectin, a novel hormone made by fat tissue, regulates energy metabolism and endothelial activation. Serum levels of adiponectin are reduced in conditions that are associated with an increased risk of cardiovascular disease, such as diabetes and the metabolic syndrome. Adiponectin trimers assemble into higher-order oligomers, which have different signaling properties. Adiponectin trimers and a C-terminal globular domain activate AMP-activated protein kinase, whereas hexamer and high-molecular weight isoforms activate nuclear factor-kappa B signaling pathways. Exogenous adiponectin corrects metabolic defects that are associated with insulin resistance, and might protect the endothelium from the progression of cardiovascular disease. Receptors for adiponectin have been described and might provide future therapeutic targets for the treatment of cardiovascular disease.
 ...
PMID:The role of the adipocyte hormone adiponectin in cardiovascular disease. 1578 Aug 20

Glucocorticoid therapy is often associated with impaired insulin sensitivity and cardiovascular disease. The present study was designed to evaluate cardiac fatty acid (FA) composition and metabolism following acute dexamethasone (Dex) treatment. Using the euglycemic hyperinsulinemic clamp, rats injected with Dex demonstrated a reduced glucose infusion rate. This whole body insulin resistance was also associated with a heart-specific increase in pyruvate dehydrogenase kinase 4 gene expression and a reduction in the rate of glucose oxidation. Dex treatment increased basal and postheparin plasma lipolytic activity. In the heart, palmitic and oleic acid levels were higher after 4 h of Dex and decreased to control (CON) levels within 8 h. Measurement of polyunsaturated FAs demonstrated a drop in linoleic and gamma-linolenic acid, with an increase in arachidonic acid (AA) after acute Dex injection. Tissue FA can be either oxidized or stored as triglyceride (TG). At 4 h, Dex augmented cardiac TG accumulation. However, this increase in tissue TG could not be maintained, such that at 8 h following Dex, TG declined to CON levels. AMP-activated protein kinase (AMPK) activation is known to promote FA oxidation through its control of acetyl-CoA carboxylase (ACC). Acute Dex promoted ACC phosphorylation, and increased cardiac palmitate oxidation, likely through its effects in increasing AMPK phosphorylation and total AMPK protein and gene expression. Whether these acute effects of Dex on FA oxidation, TG storage, and arachidonic acid accumulation can be translated into increased cardiovascular risk following chronic therapy has yet to be determined.
 ...
PMID:Altered cardiac fatty acid composition and utilization following dexamethasone-induced insulin resistance. 1660 85

Obesity is strongly associated with the pathogenesis of type 2 diabetes, hypertension, and cardiovascular disease. Levels of the hormone adiponectin are downregulated in obese individuals, and several experimental studies show that adiponectin protects against the development of various obesity-related metabolic and cardiovascular diseases. Adiponectin exhibits favorable effects on atherogenesis, endothelial function, and vascular remodeling by modulation of signaling cascades in cells of the vasculature. More recent findings have shown that adiponectin directly affects signaling in cardiac cells and is beneficial in the setting of pathological cardiac remodeling and acute cardiac injury. Several of these effects of adiponectin have been attributed to the activation of the 5' AMP-activated protein kinase signaling cascade and other signaling proteins. This review will discuss the epidemiological and experimental studies that have elucidated the role of adiponectin in a variety of cardiovascular diseases.
 ...
PMID:Adiponectin actions in the cardiovascular system. 1714 May 53

Regular endurance exercise has profound benefits on overall health, including the prevention of obesity, cardiovascular disease, and diabetes. The objective of this study was to determine whether AMP-activated protein kinase (AMPK) mediates commonly observed adaptive responses to exercise training in skeletal muscle. Six weeks of voluntary wheel running induced a significant (P < 0.05) fiber type IIb to IIa/x shift in triceps muscle of wild-type mice. Despite similar wheel running capacities, this training-induced shift was reduced by approximately 40% in transgenic mice expressing a muscle-specific AMPKalpha2 inactive subunit. Sedentary mice carrying an AMPK-activating mutation (gamma1TG) showed a 2.6-fold increase in type IIa/x fibers but no further increase with training. To determine whether AMPK is involved in concomitant metabolic adaptations to training, we measured markers of mitochondria (citrate synthase and succinate dehydrogenase) and glucose uptake capacity (GLUT4 and hexokinase II). Mitochondrial markers increased similarly in wild-type and AMPKalpha2-inactive mice. Sedentary gamma1TG mice showed a approximately 25% increase in citrate synthase activity but no further increase with training. GLUT4 protein expression was not different in either line of transgenic mice compared with wild-type mice and tended to increase with training, although this increase was not statistically significant. Training induced a approximately 65% increase in hexokinase II protein in wild-type mice but not in AMPKalpha2-inactive mice. Hexokinase II was significantly elevated in sedentary gamma1TG mice, without an additional increase with training. AMPK is not necessary for exercise training-induced increases in mitochondrial markers, but it is essential for fiber type IIb to IIa/x transformation and increases in hexokinase II protein.
 ...
PMID:Skeletal muscle adaptation to exercise training: AMP-activated protein kinase mediates muscle fiber type shift. 1751 99

AMP-activated protein kinase (AMPK) is a major regulator of energy metabolism at both the cell and at the whole body level. Numerous genetic and obesity models as well as human studies have suggested a role for AMPK in the physiological regulation of fatty acid and glucose metabolism, and in the regulation of appetite. Changes in AMPK activity have been reported in obesity, type 2 diabetes, the metabolic syndrome and cardiovascular disease, which jointly represent a major health and economical problem worldwide. Whether AMPK changes are one of the causes or the consequence of these pathological conditions remains a matter of debate, but AMPK clearly represents a major potential pharmacological target in the treatment of these conditions.
 ...
PMID:The role of AMP-activated protein kinase in obesity. 1823 Sep 4

Obesity is characterized by an expanded adipose tissue mass, and reversing obesity reduces the risk of insulin resistance and cardiovascular disease. Ciliary neurotrophic factor (CNTF) reverses obesity by promoting the preferential loss of white adipose tissue. We evaluated the cellular and molecular mechanisms by which CNTF regulates adiposity. Obese mice fed a high-fat diet were treated with saline or recombinant CNTF for 10 d, and adipose tissue was removed for analysis. Another group fed a high-fat diet was pair fed to CNTF mice. In separate experiments, 3T3-L1 adipocytes were treated with CNTF to examine metabolic responses and signaling. CNTF reduced adipose mass that resulted from reductions in adipocyte area and triglyceride content. CNTF treatment did not affect lipolysis but resulted in decreases in fat esterification and lipogenesis and enhanced fatty acid oxidation. The enhanced fat oxidation was associated with the expression of peroxisome proliferator-activated receptor coactivator-1alpha (PGC1alpha) and nuclear respiratory factor 1 and increases in oxidative phosphorylation subunits and mitochondrial biogenesis as determined by electron microscopy. Studies in cultured adipocytes revealed that CNTF activates p38 MAPK and AMP-activated protein kinase. Inhibiting p38 activation prevented the CNTF-induced increase in PGC1alpha but not AMP-activated protein kinase activation. Diminished food intake with pair feeding induced similar decreases in fat mass, but this was related to increased expression of uncoupling protein 1. We conclude that CNTF reprograms adipose tissue to promote mitochondrial biogenesis, enhancing oxidative capacity and reducing lipogenic capacity, thereby resulting in triglyceride loss.
 ...
PMID:Metabolic remodeling in adipocytes promotes ciliary neurotrophic factor-mediated fat loss in obesity. 1827 54


1 2 3 4 5 6 7 8 9 10 Next >>