Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Octacosa-10,19-dien-1-ol is a newly synthesized long-chain alcohol, an unsaturated analogue of 1-octacosanol, the major component of policosanol, the purified natural mixture of different higher aliphatic alcohols obtained from sugarcane wax. Our efficient synthetic protocol (five steps with 50% overall yield) is well suited for gram scale preparations and a rapid generation of analogues with different degrees of unsaturation. Beneficial effects of policosanol in the prevention of atherosclerosis and thromboembolic disorders have been reported and related to the inhibition of sterol biosynthesis possibly by the regulation of the activity of HMGCoA reductase mediated by AMP-dependent kinase AMPK. We have compared the effect of octacosadienol and policosanol on the regulation of HMGCoA reductase in HUVEC and HepG2 human hepatoma cells. Octacosadienol was as effective as policosanol in inhibiting the upregulation of HMGCoA reductase, in inducing the phosphorylation of AMPK and in downregulating the HMGCoA reductase mRNA.
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PMID:Regulation of HMGCoA reductase activity by policosanol and octacosadienol, a new synthetic analogue of octacosanol. 1976 55

Macrophage-derived foam cells play important roles in the progression of atherosclerosis. We reported previously that ERK1/2-dependent granulocyte/macrophage colony-stimulating factor (GM-CSF) expression, leading to p38 MAPK/ Akt signaling, is important for oxidized low density lipoprotein (Ox-LDL)-induced macrophage proliferation. Here, we investigated whether activation of AMP-activated protein kinase (AMPK) could suppress macrophage proliferation. Ox-LDL-induced proliferation of mouse peritoneal macrophages was assessed by [(3)H]thymidine incorporation and cell counting assays. The proliferation was significantly inhibited by the AMPK activator 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) and restored by dominant-negative AMPKalpha1, suggesting that AMPK activation suppressed macrophage proliferation. AICAR partially suppressed Ox-LDL-induced ERK1/2 phosphorylation and GM-CSF expression, suggesting that another mechanism is also involved in the AICAR-mediated suppression of macrophage proliferation. AICAR suppressed GM-CSF-induced macrophage proliferation without suppressing p38 MAPK/Akt signaling. GM-CSF suppressed p53 phosphorylation and expression and induced Rb phosphorylation. Overexpression of p53 or p27(kip) suppressed GM-CSF-induced macrophage proliferation. AICAR induced cell cycle arrest, increased p53 phosphorylation and expression, and suppressed GM-CSF-induced Rb phosphorylation via AMPK activation. Moreover, AICAR induced p21(cip) and p27(kip) expression via AMPK activation, and small interfering RNA (siRNA) of p21(cip) and p27(kip) restored AICAR-mediated suppression of macrophage proliferation. In conclusion, AMPK activation suppressed Ox-LDL-induced macrophage proliferation by suppressing GM-CSF expression and inducing cell cycle arrest. These effects of AMPK activation may represent therapeutic targets for atherosclerosis.
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PMID:Activation of AMP-activated protein kinase suppresses oxidized low-density lipoprotein-induced macrophage proliferation. 1984 15

Adiponectin is an important antiatherogenic adipocytokine that inhibits inflammation, insulin resistance, and oxide stress. Inflammation in the vascular adventitia is a crucial factor in the pathogenesis of atherosclerosis. Adventitial fibroblasts (AFs) can proliferate, divide into myofibroblasts, and migrate to the intima to become a new component of atherosclerotic plaque under inflammation and atherosclerosis. We investigated whether adiponectin might prevent AFs from proliferating, migrating, and transforming into myofibroblasts. Cultured AFs were stimulated with lipopolysaccharide (LPS) in the presence or absence of adiponectin. Methyl thiazolyl tetrazolium assay and migration and scratch-wound assays demonstrated that adiponectin reduced the AF proliferation and migration induced by LPS, respectively, whereas treatment with AdipoR1 small interfering (si) RNA (siAdipoR1), AMP-activated protein kinase (AMPK) siRNA (siAMPK), and an AMPK inhibitor reversed the effect. Immunocytochemistry and Western blot revealed that adiponectin reduced the transition of AFs to myofibroblasts, and treatment with siAdipoR1, siAMPK, and the AMPK inhibitor increased the transition. RT-PCR, Western blotting, and nitric oxide (NO) assay showed that adiponectin reduces induced NO synthase (iNOS) and nitrotyrosine expression and NO and ONOO(-) production induced by LPS. Treatment with siAdipoR1, siAMPK, and the AMPK inhibitor significantly attenuated adiponectin-induced phosphorylation of AMPK and its downstream target acetyl-coenzyme A carboxylase and up-regulated iNOS mRNA and protein expression, which resulted in a marked increase of NO and ONOO(-) production. In apolipoprotein E-deficient mice, immunohistochemistry of treated vascular adventitia showed that both iNOS expression and ONOO(-) production could be reversed with an adenovirus-adiponectin vector. Taken together, these results suggest that adiponectin reduces LPS-induced NO production and nitrosative stress and prevents AFs from proliferating, transforming to myoflbroblasts, and migrating to the intima, thus worsening atherosclerosis, by inhibiting the AdipoR1-AMPK-iNOS pathway in AFs.
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PMID:Adiponectin inhibits lipopolysaccharide-induced adventitial fibroblast migration and transition to myofibroblasts via AdipoR1-AMPK-iNOS pathway. 1988 16

Ataxia-telangiectasia mutated (ATM) is a cellular damage sensor that coordinates the cell cycle with damage-response checkpoints and DNA repair to preserve genomic integrity. However, ATM also has been implicated in metabolic regulation, and ATM deficiency is associated with elevated reactive oxygen species (ROS). ROS has a central role in many physiological and pathophysiological processes including inflammation and chronic diseases such as atherosclerosis and cancer, underscoring the importance of cellular pathways involved in redox homeostasis. We have identified a cytoplasmic function for ATM that participates in the cellular damage response to ROS. We show that in response to elevated ROS, ATM activates the TSC2 tumor suppressor via the LKB1/AMPK metabolic pathway in the cytoplasm to repress mTORC1 and induce autophagy. Importantly, elevated ROS and dysregulation of mTORC1 in ATM-deficient cells is inhibited by rapamycin, which also rescues lymphomagenesis in Atm-deficient mice. Our results identify a cytoplasmic pathway for ROS-induced ATM activation of TSC2 to regulate mTORC1 signaling and autophagy, identifying an integration node for the cellular damage response with key pathways involved in metabolism, protein synthesis, and cell survival.
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PMID:ATM signals to TSC2 in the cytoplasm to regulate mTORC1 in response to ROS. 2016 76

Advanced glycosylation end products (AGE) and its receptor (RAGE) axis is involved in the regulation of lipid homeostasis and is critical in the pathogenesis of diabetic atherosclerosis. We investigated the protective role of resveratrol against the AGE-induced impairment on macrophage lipid homeostasis. In THP-1-derived macrophages, RAGE was dose-dependently induced by AGE and played a key role in the AGE-induced cholesterol accumulation. Resveratrol markedly reduced RAGE expression via peroxisome proliferator-activated receptor (PPAR) gamma but not PPARalpha or AMP-activated protein kinase. Importantly, pretreatment with resveratrol significantly ameliorated AGE-induced up-regulation of scavenger receptor-A (SR-A) and down-regulation of ATP-binding cassette (ABC) A1 and ABCG1 and thus effectively prevented the cholesterol accumulation in macrophages as shown by cellular cholesterol analysis and oil red O staining. Moreover, blockade of PPARgamma abolished all these effects of resveratrol. Collectively, our results indicate that resveratrol prevents the impairment of AGE on macrophage lipid homeostasis partially by suppressing RAGE via PPARgamma activation, which might provide new insight into the protective role of resveratrol against diabetic atherosclerosis.
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PMID:Resveratrol prevents the impairment of advanced glycosylation end products (AGE) on macrophage lipid homeostasis by suppressing the receptor for AGE via peroxisome proliferator-activated receptor gamma activation. 2037 16

Rosiglitazone (RSG) has a variety of actions on both insulin sensitization and anti-atherogenic effects. The molecular effect of RSG on monocyte/macrophage function in terms of de novo synthesis of adiponectin is not fully understood. Here, we examined the regulation of adiponectin expression in human monocytes/macrophages by RSG and its function on monocyte adhesion during initiation of atherosclerosis. Adiponectin expression in monocytes and macrophages was studied by RT-PCR, quantitative real-time PCR, Western blot, and immunocytochemistry. Signal transduction and adhesion molecules were studied in order to describe the function of de novo synthesized adiponectin in monocyte adhesion. Adiponectin was expressed and upregulated during monocyte differentiation. The expression of adiponectin was enhanced, albeit at a much lesser degree, by a peroxisome proliferator-activated receptor gamma (PPAR gamma) agonist RSG, which was similar to what was found in adipocytes. Monocyte adhesion was remarkably reduced when the cells were treated with RSG for 12 h. This inhibitory effect of RSG was abolished by specific anti-adiponectin antibodies but not by non-immune immunoglobulin G in a serum-free condition. Adiponectin-induced suppression on monocyte adhesion was inhibited by a selective AMP-activated protein kinase (AMPK) inhibitor compound C. The reduced expression and/or function of adhesion molecule integrins may underlie the mechanism contributing to reduced monocyte adhesion upon AMPK activation. Our data suggest that the inhibitory effect of RSG on monocyte adhesion might be at least in part through de novo adiponectin expression and activation of an AMPK-dependent pathway, which might play an important role in atherogenesis.
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PMID:Rosiglitazone inhibits monocyte/macrophage adhesion through de novo adiponectin production in human monocytes. 2050 17

Altered macrophage kinetics is a pivotal mechanism of visceral obesity-induced inflammation and cardiometabolic risk. Because monocytes can differentiate into either proatherogenic M1 macrophages or anti-inflammatory M2 macrophages, approaches that limit M1 while promoting M2 differentiation represent a unique therapeutic strategy. We hypothesized that adiponectin may prime human monocytes toward the M2 phenotype. Adiponectin promoted the alternative activation of human monocytes into anti-inflammatory M2 macrophages as opposed to the classically activated M1 phenotype. Adiponectin-treated cells displayed increased M2 markers, including the mannose receptor (MR) and alternative macrophage activation-associated CC chemokine-1. Incubation of M1 macrophages with adiponectin-treated M2-derived culture supernatant resulted in a pronounced inhibition of tumor necrosis factor-alpha and monocyte chemotactic protein-1 secretion. Activation of human monocytes into M2 macrophages by adiponectin was mediated, in addition to AMP-activated protein kinase and peroxisome proliferator-activated receptor (PPAR)-gamma, via PPAR-alpha. Furthermore, macrophages isolated from adiponectin knockout mice demonstrated diminished levels of M2 markers such as MR, which were restored with adiponectin treatment. We report a novel immunoregulatory mechanism through which adiponectin primes human monocyte differentiation into anti-inflammatory M2 macrophages. Conditions associated with low adiponectin levels, such as visceral obesity and insulin resistance, may promote atherosclerosis, in part through aberrant macrophage kinetics.
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PMID:Adiponectin primes human monocytes into alternative anti-inflammatory M2 macrophages. 2062 8

Cardiovascular diseases remain the leading cause of mortality worldwide. Recent studies of AMP-activated protein kinase (AMPK), a highly conserved sensor of cellular energy status, suggest that there might be therapeutic value in targeting the AMPK signaling pathway. AMPK is found in most mammalian tissues, including those of the cardiovascular system. As cardiovascular diseases are typically associated with blood flow occlusion and blood occlusion may induce rapid energy deficit, AMPK activation may occur during the early phase upon nutrient deprivation in cardiovascular organs. Therefore, investigation of AMPK in cardiovascular organs may help us to understand the pathophysiology of defence mechanisms in these organs. Recent studies have provided proof of concept for the idea that AMPK is protective in heart as well as in vascular endothelial and smooth muscle cells. Moreover, dysfunction of the AMPK signalling pathway is involved in the genesis and development of various cardiovascular diseases, including atherosclerosis, hypertension and stroke. The roles of AMPK in the cardiovascular system, as they are currently understood, will be presented in this review. The interaction between AMPK and other cardiovascular signalling pathways such as nitric oxide signalling is also discussed.
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PMID:Protective effects of AMP-activated protein kinase in the cardiovascular system. 2087 22

In type 1 diabetes, insulin treatment reduces complications related to microvascular disease and atherosclerosis. The same holds true in patients with short duration of type 2 diabetes, treated either with oral antidiabetic drugs or with insulin. Conversely, in patients with long-standing type 2 diabetes, advanced age or history of cardiovascular disease, treatment with oral diabetic drugs or insulin must be given with caution because of the unfavorable risk-benefit profile when these drugs are used with too aggressive aims. In the last year, several studies have clearly demonstrated that an excessive reduction of glycated hemoglobin exposes the patient at risk of hypoglycemia and fattening, with neutral results about clinical events or even with a paradoxical increase of cardiovascular events (hospitalization and mortality). The glycemic goal in heart disease and diabetic patients should be settled on higher values (probably 7-8%). There are no significant differences among drugs that reduce insulin resistance and drugs that stimulate its secretion. The only drug that proved to be effective in reducing cardiovascular events is metformin, which increases AMP-activated protein kinase activity and has a potent cardioprotective effect against ischemia-reperfusion injury. These findings should be confirmed in larger longitudinal studies in heart disease patients. Patients in intensive care units should be treated with intravenous insulin with a glycemic target <180 mg/dl (mean 142 mg/dl) because more aggressive goals may lead to increased mortality. These results demand important considerations about the management of heart disease patients with type 2 diabetes, also because self-monitoring of blood glucose concentration seems to induce an increase in depression. Conversely, an aggressive multifactorial intervention (improvement of lifestyle, blood pressure and dyslipidemia control, platelet aggregation inhibitors in secondary prevention) reduces effectively cardiovascular events and mortality.
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PMID:[Hypoglycemic therapy in heart disease patients with type 2 diabetes mellitus]. 2092 71

Adiponectin (Ad) is an abundant protein hormone regulatory of numerous metabolic processes. The 30 kDa protein originates from adipose tissue, with full-length and globular domain circulatory forms. A collagenous domain within Ad leads to spontaneous self-assemblage into various oligomeric isoforms, including trimers, hexamers, and high-molecular-weight multimers. Two membrane-spanning receptors for Ad have been identified, with differing concentration distribution in various body tissues. The major intracellular pathway activated by Ad includes phosphorylation of AMP-activated protein kinase, which is responsible for many of Ad's metabolic regulatory, anti-inflammatory, vascular protective, and anti-ischemic properties. Additionally, several AMP-activated protein kinase-independent mechanisms responsible for Ad's anti-inflammatory and anti-ischemic (resulting in cardioprotective) effects have also been discovered. Since its 1995 discovery, Ad has garnered considerable attention for its role in diabetic and cardiovascular pathology. Clinical observations have demonstrated the association of hypoadiponectinemia in patients with obesity, cardiovascular disease, and insulin resistance. In this review, we elaborate currently known information about Ad malfunction and deficiency pertaining to cardiovascular disease risk (including atherosclerosis, endothelial dysfunction, and cardiac injury), as well as review evidence supporting Ad resistance as a novel risk factor for cardiovascular injury, providing insight about the future of Ad research and the protein's potential therapeutic benefits.
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PMID:Systemic adiponectin malfunction as a risk factor for cardiovascular disease. 2109 Oct 79


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