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

Bone morphogenetic proteins (BMPs) and their serine/threonine kinase receptors have been identified in atherosclerotic arteries and vascular smooth muscle cells, respectively. Thus, BMPs (the largest subfamily of the TGF-beta superfamily) have been implicated in the pathogenesis of atherosclerosis. However, the origins of BMP biosynthesis and the functional roles of BMP in blood vessels are unclear. The present study explored BMP-2 gene expression in various human blood vessels and vascular cell types. Functional in vitro studies were also performed to determine the effects of recombinant human BMP-2 on migration (transwell assay) and proliferation ([3H]-thymidine incorporation) of human aortic vascular smooth muscle cells (HASMC). RT-PCR experiments revealed BMP-2 gene expression in normal and atherosclerotic human arteries as well as cultured human aortic and coronary vascular smooth muscle cells, human umbilical vein endothelial cells (HUVECs) and human macrophages. In cellular migration studies, incubation with BMP-2 produced efficacious (</=610-fold), concentration- and time-dependent chemotaxis of HASMCs (EC50 = 0.8 microM) with little or no effect on HUVEC chemotaxis. The increased HASMC motility induced by BMP-2 was inhibited by coincubation with an anti-BMP-2 mAb. In addition, subthreshold concentrations of BMP-2 produced a dramatic synergistic effect upon platelet-derived growth factor (PDGF)-induced chemotaxis. In contrast to PDGF, BMP-2 had no significant effet on [3H]-thymidine incorporation in HASMC at chemotaxic concentrations (</=6.0 microM) nor did it synergize with the mitogenic effects of PDGF. In conclusion, the expression of BMP-2 by numerous cell types in the blood vessel wall may play a chemotactic or cochemotactic role in the smooth muscle cell response to vascular injury.
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PMID:BMP-2 gene expression and effects on human vascular smooth muscle cells. 1021 7

Angiotensin (A) II is a potent constrictor as well as growth stimulant of vascular smooth muscle cell caused by activation of AT1 receptor signal transduction systems. There are two major signal systems of AT1 receptor: one leads to an increase in cytosolic free calcium levels causing smooth muscle contraction which may result in high blood pressure, and the other leads to smooth muscle proliferation and inflammation which may result in atherosclerosis. AT1 receptor activation induces phosphinositide hydrolysis by phospholipase C and creates an inositol phosphate, which release calcium from cytosolic calcium pools. Cytosolic calcium can also be elevated by activation of calcium channel via a link between AT1 receptor and a G protein. Protein phosphorylation triggered by AT1 receptor is important for cell growth, in which tyrosine kinase, serine/threonine kinase and protein kinase C are involved. Free radicals are generated by NADH/NADPH oxidase in response to AT1 receptor activation, causing expression of genes leading to atherosclerosis. On the other hand, activation of AT2 receptor is shown to play a role of lowering blood pressure. Some phosphatases and NO/cyclic GMP would be involved in the mechanism. In renal vasculature, endothelium dependent epoxygenase products are synthesized by AT2 receptor stimulation causing vasorelaxation. In summary, AT1 receptor signals are vasopressive and evoke atherosclerosis, whereas AT2 receptor signals may possibly be vasodilatory.
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PMID:[Signal transduction systems of angiotensin II receptors]. 1036 37

The growth arrest-specific gene 6 encodes a secreted protein, Gas6, which was originally identified as the ligand of a receptor, Axl, with tyrosine kinase activity. The class A scavenger receptor (SRA) mediates lipid uptake into cells, leading to the formation of foam cells, an important step in atherogenesis. Although Gas6 induces SRA expression, the underlying mechanism is not clear. In this report, we show that the Gas6-induced expression of SRA was mediated by the phosphatidylinositol 3-OH kinase (PI3-kinase)-serine/threonine kinase (Akt/protein kinase B [PKB]) pathway involving Akt phosphorylation. This pathway was activated by exposure to Gas6. Furthermore, the effect of Gas6 was abrogated by wortmannin, a specific inhibitor of PI3-kinase. We also demonstrated that the constitutively active form of Akt enhanced activity of the SRA promoter but that the dominant-negative mutant of Akt completely abolished the expression of SRA after treatment with Gas6. These results show that the PI3-kinase-Akt/PKB pathway participates in Gas6-induced SRA expression and suggests that the activation of Akt/PKB plays an important role in Gas6-induced atherosclerosis and foam cell formation in human vascular smooth muscle cells.
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PMID:Phosphatidylinositol 3-OH kinase-Akt/protein kinase B pathway mediates Gas6 induction of scavenger receptor a in immortalized human vascular smooth muscle cell line. 1159 31

Constitutive activation of serine/threonine kinase Akt causes uncontrolled cell-cycle progression in different cell types and in malignancy. To investigate how Akt activation modulates cell-cycle progression in vascular smooth muscle cells (SMCs) in vitro and in the intact animal, we inhibited Akt-dependent signaling by adenovirus-mediated transfection of a dominant-negative Akt mutant (AA-Akt). We observed reduced proliferation rate (P<0.01), DNA synthesis (P<0.01), and a significant arrest in G1/S exit (P<0.01) both in vitro in response to serum stimulation and in vivo after vascular injury. In vivo transfection of the balloon-injured vessel with AA-Akt reduced SMC proliferation, resulting in decreased neointima compared with control virus (P<0.01). These effects were at least in part modulated, both in vitro and in vivo, by increased p21Cip1 expression, as demonstrated by lack of effect of AA-Akt on cell proliferation in p21-/- mouse SMCs. In conclusion, this study demonstrates that Akt-dependent signaling enhances cell-cycle progression of nontransformed SMCs in vitro and in response to vascular injury in the intact animal. These results suggest a role for Akt signaling in modulating the response of normal tissues to stress and the response of the arterial wall to acute and possibly repetitive injuries that ultimately contribute to restenosis and atherosclerosis.
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PMID:Akt controls vascular smooth muscle cell proliferation in vitro and in vivo by delaying G1/S exit. 1460 18

Platelet-derived growth factor (PDGF) and transforming growth factor-beta (TGF-beta) are examples of signaling molecules which control the growth, survival motility and differentiation of cells. PDGF stimulates the growth mainly of connective tissue cells, whereas TGF-beta inhibits the growth of most cell types. PDGF and TGF-beta exert their cellular effects by binding to receptors equipped with tyrosine and serine/threonine kinase activities, respectively. Both factors have important roles e.g. during the embryonal development and in wound healing. Overactivity of PDGF or PDGF receptors contributes to the development of certain diseases characterized by excessive cell growth including fibrotic disorders, atherosclerosis and malignancies. Overactivity of TGF-beta also contributes to fibrotic conditions, since TGF-beta promotes accumulation of extracellular matrix molecules. In cancer, TGF-beta is initially a tumor suppressor due to its ability to inhibit cell growth, however, at later stages of tumor progression TGF-beta has tumor promoting activity by enhancing the invasive properties of tumor cells and by suppressing the immune system and promoting angiogenesis. The involvement of PDGF in TGF-beta in serious diseases makes clinically useful antagonists highly desirable. A low molecular weight receptor kinase inhibitor of the PDGF receptor kinase is now tested clinically, and TGF-beta antagonists are under development. The present review discusses the development and possible clinical use of antagonsts for PDGF and TGF-beta.
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PMID:Development and possible clinical use of antagonists for PDGF and TGF-beta. 1550 23

Intraplaque neovascularization contributes to the progression of atherosclerosis. Our aim is to understand the mobilization of cells and factors involved in this process. We investigated the localization of hepatocyte growth factor (HGF) and its receptor, c-Met, in human atherosclerotic plaques, together with the effects of HGF on pericyte migration in vitro. Atherosclerotic femoral arterial segments were collected and analysed from 13 subjects who were undergoing lower limb amputation. Pericytes were identified in human lesions using a 3G5 antibody. Immunohistochemical analysis localized HGF mainly around microvessels, in association with some, but not all, CD31-positive endothelial cells. c-Met expression was mainly associated with smooth muscle cells and pericytes, around some, but not all, microvessels within the atherosclerotic lesions; no detection was apparent in normal internal mammary arteries. Using RT-PCR, we demonstrated expression of HGF and c-Met in a rat pericyte cell-line, TR-PCT1, and in primary pericytes. HGF treatment of TR-PCT1 cells induced their migration, but not their proliferation, in a dose-dependent manner (10-100 ng/ml, p<0.01), an effect mediated by activation of the serine/threonine kinase Akt, shown by western blot analysis. Treating the cells with the PI3K inhibitors Wortmannin (0.1 microM) or LY294002 (10 microM) abolished these effects. This work demonstrates the expression of c-Met and HGF in human atherosclerotic arteries, in association with SM-actin-positive cells and CD-31-positive cells, respectively. HGF induces pericyte migration via PI3-kinase and Akt activation in vitro. HGF and c-Met may be involved in neovascularization during plaque development, and may recruit pericytes to neovessels. Since pericytes are thought to mechanically stabilize new blood vessels, these factors may function to protect against haemorrhage.
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PMID:Hepatocyte growth factor and c-Met expression in pericytes: implications for atherosclerotic plaque development. 1740 87

Inflammation plays a critical role in promoting smooth muscle migration and proliferation during vascular diseases such as postangioplasty restenosis and atherosclerosis. Another common feature of many vascular diseases is the contribution of reactive oxygen (ROS) and reactive nitrogen (RNS) species to vascular injury. Primary sources of ROS and RNS in smooth muscle are several isoforms of NADPH oxidase (Nox) and the cytokine-regulated inducible nitric oxide (NO) synthase (iNOS). One important example of the interaction between NO and ROS is the reaction of NO with superoxide to yield peroxynitrite, which may contribute to the pathogenesis of hypertension. In this review, we discuss the literature that supports an alternate possibility: Nox-derived ROS modulate NO bioavailability by altering the expression of iNOS. We highlight data showing coexpression of iNOS and Nox in vascular smooth muscle demonstrating the functional consequences of iNOS and Nox during vascular injury. We describe the relevant literature demonstrating that the mitogen-activated protein kinases are important modulators of proinflammatory cytokine-dependent expression of iNOS. A central hypothesis discussed is that ROS-dependent regulation of the serine/threonine kinase protein kinase Cdelta is essential to understanding how Nox may regulate signaling pathways leading to iNOS expression. Overall, the integration of nonphagocytic NADPH oxidase with cytokine signaling in general and in vascular smooth muscle in particular is poorly understood and merits further investigation.
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PMID:Regulation of smooth muscle by inducible nitric oxide synthase and NADPH oxidase in vascular proliferative diseases. 1821 30

Vascular smooth muscle cell (SMC) migration and proliferation contribute to arterial wound repair and thickening of the intimal layer in atherosclerosis, restenosis and transplant vascular disease. These processes are influenced by cell adhesion to molecules present in the extracellular matrix, and regulated by the integrin family of cell-surface matrix receptors. An important signaling molecule acting downstream of integrin receptors is integrin-linked kinase (ILK), a serine/threonine kinase and scaffolding protein. ILK has been implicated in cancer cell growth and survival through modulation of downstream targets, notably Akt and glycogen synthase kinase-3beta (GSK3beta). Evidence also exists to establish ILK as a molecular adaptor protein linking integrins to the actin cytoskeleton and regulating actin polymerization, and this function may not necessarily depend upon the kinase activity of ILK. ILK has been implicated in anchorage-independent growth, cell cycle progression, epithelial-mesenchymal transition (EMT), invasion and migration. In addition, ILK has been shown to be involved in vascular development, tumor angiogenesis and cardiac hypertrophy. Despite the documented involvement of integrin signaling in vascular pathologies, the function of ILK has not been well characterized in the SMC response to vascular injury. This brief review summarizes and puts into context the current literature on ILK expression and function in the vascular smooth muscle cell.
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PMID:Integrin linked kinase (ILK) expression and function in vascular smooth muscle cells. 1926 69

Mammalian target of rapamycin (mTOR), a serine/threonine kinase and component of the mTORC1 signaling complex, acts as an energy, nutrient, growth factor, stress, and redox sensor to increase protein synthesis and decrease macroautophagy. mTORC1 plays a central role in the maintenance of homeostasis and its deterioration, seen in aging. The Food and Drug Administration (FDA)-approved immunosuppressive macrolide rapamycin binds immunophilin FKBP12 (FK506-binding protein) to inhibit mTORC1. Unlike most other interventions tested to date, inhibition of mTORC1 by rapamycin extends life span in old mice, likely by a combination of increased autophagy and decreased mRNA translation. Hutchinson-Gilford progeria syndrome (HGPS) is a lethal genetic disorder affecting children that is characterized by symptoms of premature aging, such as atherosclerosis. Increased autophagy induced by rapamycin reduces accumulation of progerin, an alternate spliced form of lamin A/C, that forms insoluble toxic aggregates, resulting in reduced HGPS-associated nuclear blebbing, growth inhibition, epigenetic dysregulation, and genomic instability. Rapamycin-induced autophagy also suppresses symptoms in mouse models of Alzheimer, Parkinson, and Huntington diseases, where toxic insoluble protein aggregates accumulate. On the basis of these results, modulation of mTORC1 function is a promising target for the development of therapeutics for neurodegenerative diseases and HGPS. Rapamycin is the obvious candidate for near-term evaluation in the treatment of these diseases. However, the substantial set of rapamycin-associated adverse effects, as well as the lack of aging-specific human data, should caution the routine use of rapamycin as an antiaging agent. The use of safer, but perhaps weaker, indirect mTORC1 inhibitors, such as metformin and resveratrol, may prove useful. Further study will ascertain whether such compounds extend human health or life span.
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PMID:Rapamycin as an antiaging therapeutic?: targeting mammalian target of rapamycin to treat Hutchinson-Gilford progeria and neurodegenerative diseases. 2185 Nov 76

Obesity leads to insulin resistance and atherosclerosis, which precede Type 2 diabetes and cardiovascular disease. Immunometabolism addresses how metabolic and inflammatory pathways converge to maintain health and a contemporary problem is determining how obesity-induced inflammation precipitates chronic diseases such as insulin resistance and atherosclerosis. AMP-activated protein kinase (AMPK) is an important serine/threonine kinase well known for regulating metabolic processes and maintaining energy homeostasis. However, both metabolic and immunological AMPK-mediated effects play a role in disease. Pro-inflammatory mediators suppress AMPK activity and hinder lipid oxidation. In addition, AMPK activation curbs inflammation by directly inhibiting pro-inflammatory signaling pathways and limiting the build-up of specific lipid intermediates that elicit immune responses. In the context of obesity and chronic disease, these reciprocal responses involve both immune and metabolic cells. Therefore, the immunometabolism of AMPK-mediated processes and therapeutics should be considered in atherosclerosis and insulin resistance.
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PMID:Immunometabolism of AMPK in insulin resistance and atherosclerosis. 2236 21


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