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)

Recently, a growing number of epidemiological, histopathological and microbiological studies have shown that chronic Chlamydia pneumoniae (C. pneumoniae) infection accelerates the progression of atherosclerosis of carotid and cerebral arteries and thus could constitute a risk factor for stroke. We present a number of mechanisms postulated in recent papers that link C. pneumoniae infection with the development of atherosclerosis. The one most important seems to be the effect of activation of nuclear factor--kappa B and the phenomenon of antigenic mimicry between human and C. pneumoniae heat shock proteins. We also discuss the problem of immunological reaction against myosin filaments of carotid artery wall smooth muscle cells and the problem of antigenic mimicry between heavy chains of myosin filaments and antigens presented on C. pneumoniae outer membrane.
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PMID:[Effect of Chlamydia pneumoniae infection on carotid atherosclerosis development]. 1205 4

Regulation of vascular smooth muscle cell contractile state is critical for the maintenance of blood vessel tone. Abnormal vascular smooth muscle cell contractility plays an important role in the pathogenesis of hypertension, blood vessel spasm, and atherosclerosis. Myosin phosphatase, the key enzyme controlling myosin light chain dephosphorylation, regulates smooth muscle cell contraction. Vasoconstrictor and vasodilator pathways inhibit and activate myosin phosphatase, respectively. G-protein-coupled receptor agonists can inhibit myosin phosphatase and cause smooth muscle cell contraction by activating RhoA/Rho kinase, whereas NO/cGMP can activate myosin phosphatase and cause smooth muscle cell relaxation by activation of cGMP-dependent protein kinase. We have used yeast two-hybrid screening to identify a 116-kDa human protein that interacts with both myosin phosphatase and RhoA. This myosin phosphatase-RhoA interacting protein, or M-RIP, is highly homologous to murine p116RIP3, is expressed in vascular smooth muscle, and is localized to actin myofilaments. M-RIP binds directly to the myosin binding subunit of myosin phosphatase in vivo in vascular smooth muscle cells by an interaction between coiled-coil and leucine zipper domains in the two proteins. An adjacent domain of M-RIP directly binds RhoA in a nucleotide-independent manner. M-RIP copurifies with RhoA and Rho kinase, colocalizes on actin stress fibers with RhoA and MBS, and is associated with Rho kinase activity in vascular smooth muscle cells. M-RIP can assemble a complex containing both RhoA and MBS, suggesting that M-RIP may play a role in myosin phosphatase regulation by RhoA.
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PMID:Myosin phosphatase-Rho interacting protein. A new member of the myosin phosphatase complex that directly binds RhoA. 1450 64

Caveolae are flask-shaped invaginations in the membrane that depend on the contents of cholesterol and on the structural protein caveolin. The organisation of caveolae in parallel strands between dense bands in smooth muscle is arguably unique. It is increasingly recognised, bolstered in large part by recent studies in caveolae deficient animals, that caveolae sequester and regulate a variety of signalling intermediaries. The role of caveolae in smooth muscle signal transduction, as inferred from studies on transgenic animals and in vitro approaches, is the topic of the current review. Both G-protein coupled receptors and tyrosine kinase receptors are believed to cluster in caveolae, and the exciting possibility that caveolae provide a platform for interactions between the sarcoplasmic reticulum and plasmalemmal ion channels is emerging. Moreover, messengers involved in Ca2+ sensitization of myosin phosphorylation and contraction may depend on caveolae or caveolin. Caveolae thus appear to constitute an important signalling domain that plays a role not only in regulation of smooth muscle tone, but also in proliferation, such as seen in neointima formation and atherosclerosis.
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PMID:Caveolae-associated signalling in smooth muscle. 1521 28

Diabetes mellitus is associated with an increased risk of heart failure, resulting from a specific cardiomyopathy independent of coronary atherosclerosis. It is not yet established whether altered myocardial function is related to changes in molecular mechanics of myosin. Accordingly, we investigated the total number, single force and kinetics of myosin crossbridges (CB) in a rat model of streptozotocin-induced diabetic cardiomyopathy. Experiments were conducted on left ventricular papillary muscles from male diabetic (D) Wistar (n = 16) and age-matched control (C) rats (n = 15). Mechanical indices including the maximum unloaded shortening velocity V(max) and the maximum total isometric tension normalized per cross-sectional area TF(max) were determined. Using A. F. Huxley's equations, we calculated the total cycling CB number per mm(2) Psi, the elementary force per single CB Pi, the maximum values of the rate constant for CB attachment f(1) and detachment g(1) and g(2), and the turnover rate of myosin ATPase per site k(cat). The D rats exhibited a 25% decrease in TF(max) and a 34% decrease in V(max) as compared to C. This contractile dysfunction was associated with a significant reduction in Psi (9.0 +/- 1.6 in D versus 11.4 +/- 1.9 10(9)mm(-2) in C, P < 0.001) without significant change in Pi (6.1 +/- 0.8 in D versus 6.3 +/- 0.9 pN in C, NS). In the 2 groups, TF(max) correlated positively with Psi (r = 0.76, P < 0.001 and r = 0.64, P < 0.01, in D and C respectively) but no relationship was found between TF(max) and Pi. As compared to C, D showed lower values of f(1), g(1) and g(2), and a slower turnover rate of myosin ATPase. Thus, present data suggested that the cardiac contractile impairment observed in streptozotocin-induced diabetic rat cardiomyopathy was mainly related to a decrease in active CB total number and CB kinetics alterations without significant change in CB single force.
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PMID:Changes in crossbridge mechanical properties in diabetic rat cardiomyopathy. 1564 63

Cell migration is important in the development of atherosclerotic lesions. Macrophages and smooth muscle cells migrate into the subendothelial space of arteries, leading to plaque formation. Long-term inhibition of the activity of Rho-kinase induces a regression of atherosclerotic coronary lesions, probably by preventing migration of macrophages and smooth muscle cells. Previous reports concerning the effect of Rho-kinase inhibitors on cell migration are contradictory, however. We examined here the cell type specificity of Rho-kinase inhibitors and found that migration of endothelial cells, macrophages, and smooth muscle cells was inhibited by treatment with Rho-kinase inhibitors in a dose-dependent fashion in a three-dimensional migration assay, whereas that of fibroblasts and epithelial cells was not inhibited. Myosin II inhibitor prevented cell migration in a manner similar to Rho-kinase inhibitors. In contrast, in a two-dimensional migration assay, cell migration was not inhibited by Rho-kinase or myosin II inhibitors for any of the cell types examined. Taken together, these results indicate that Rho-kinase inhibitors suppress migration of specific cell types under specific conditions through the regulation of myosin II activity. Our findings suggest that Rho-kinase is the therapeutic target of atherosclerosis accompanied with invasion by leukocytes and smooth muscle cells.
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PMID:Rho-kinase and myosin II activities are required for cell type and environment specific migration. 1567 22

Phenotypic modulation of vascular smooth muscle cells (SMCs) in atherosclerosis and restenosis involves responses to the surrounding microenvironment. SMCs obtained by enzymatic digestion from tunica media of newborn, young adult (YA) and old rats and from the thickened intima (TI) and underlying media of young adult rat aortas 15 days after ballooning were entrapped in floating populated collagen lattice (PCL). TI-SMCs elongated but were poor at PCL contraction and remodeling and expressed less alpha2 integrin compared to other SMCs that appeared more dendritic. During early phases of PCL contraction, SMCs showed a marked decrease in the expression of alpha-smooth muscle actin and myosin. SMCs other than TI-SMCs required 7 days to re-express alpha-smooth muscle actin and myosin. Only TI-SMCs in PCL were able to divide in 48 h, with a greater proportion in S and G2-M cell cycle phases compared to other SMCs. Anti-alpha2 integrin antibody markedly inhibited contraction but not proliferation in YA-SMC-PLCs; anti-alpha1 and anti-alpha2 integrin antibodies induced a similar slight inhibition in TI-SMC-PCLs. Finally, TI-SMCs rapidly migrated from PCL on plastic reacquiring their epithelioid phenotype. Heterogeneity in proliferation and cytoskeleton as well the capacity to remodel the extracellular matrix are maintained, when SMCs are suspended in PCLs.
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PMID:Phenotypic heterogeneity influences the behavior of rat aortic smooth muscle cells in collagen lattice. 1626 12

Osteopontin (OPN) and CD44 have been implicated in the development of autoimmune diseases, including arthritis and multiple sclerosis, as well as chronic inflammatory diseases, such as atherosclerosis and colitis. To investigate their roles in autoimmune myocarditis induced by immunization with heart alpha-myosin (MyHC-alpha), a mouse model of human cardiomyopathy, we analyzed mice lacking OPN or CD44v6/v7, a CD44 isoform that binds OPN. Both, OPN(-/-) and CD44v6/v7(-/-) mice developed myocarditis with the same prevalence and severity as BALB/c wild-type controls. Furthermore, treatment of BALB/c mice with a pan-neutralizing anti-CD44 antibody did not affect the disease outcome. Consistently, expansion of MyHC-alpha-specific autoimmune CD4(+) T cells and MyHC-alpha autoantibody responses from either CD44v6/v7(-/-) mice or OPN(-/-) mice was indistinguishable from their wild-type controls. Thus, OPN and CD44v6/v7 are merely spectators rather than protagonists in autoimmune myocarditis.
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PMID:The osteopontin - CD44 pathway is superfluous for the development of autoimmune myocarditis. 1640 10

cGMP-dependent protein kinase (PKG) is the major intracellular receptor for cyclic guanosine monophosphate (cGMP). Two forms of PKG, PKG-I and PKG-II, occur in mammalian tissues. PKG may mediate nitric oxide-cGMP-induced vasodilation through decreasing intracellular calcium concentration by the activation of calcium-activated potassium channel on the cell membrane and phosphorylation of phospholamban (PLB) and IP3 receptor-associated PKG-I substrate (IRAG) on the sarcoplasmic reticulum. PKG may also decrease the sensitivity of myosin to calcium by stimulating the activity of myosin light chain phosphatase and by inhibiting Rho kinase activity. PKG plays an important role in regulating the gene expression, phenotype, and proliferation of vascular smooth muscle cells. PKG activation inhibits platelet aggregation and myocardial hypertrophy. Recent studies indicate that the alternations of PKG expression and activity are closely related with the pathogenesis of atherosclerosis, restenosis, hypertension, hyperlipemia as well as nitrate tolerance.
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PMID:[Role of cGMP-dependent protein kinase in the cardiovascular system]. 1640 66

Reactive oxygen species (ROS) contribute to the pathogenesis of atherosclerosis in part by promoting vascular smooth muscle cell (VSMC) growth. Previously we demonstrated that cyclophilin A (CyPA) is a secreted oxidative stress-induced factor (SOXF) that promotes inflammation, VSMC growth, and endothelial cell apoptosis. However, the mechanisms that regulate CyPA secretion are unknown. In this study, we hypothesized that ROS-induced CyPA secretion from VSMC requires a highly regulated process of vesicle transport, docking, and fusion at the plasma membrane. Conditioned medium and plasma membrane sheets were prepared by exposing VSMC to 1 micromol/L LY83583, which generates intracellular superoxide. A vesicular transport mechanism was confirmed by colocalization at the plasma membrane with vesicle-associated membrane protein (VAMP). CyPA transport to the plasma membrane and secretion were significantly increased by LY83583. Reduction of VAMP-2 expression by small interfering RNA inhibited LY83583-induced CyPA secretion. Pretreatment with 3 micromol/L cytochalasin D, an actin depolymerizing agent, abrogated CyPA secretion. Infection with dominant-negative RhoA and Cdc42 adenovirus inhibited CyPA secretion by 72% and 63%, respectively, whereas dominant-negative Rac1 had a small effect (11%). Pretreatment with the Rho kinase inhibitor Y27632 (3 to 30 micromol/L) and myosin II inhibitor blebbistatin (1 to 10 micromol/L) inhibited CyPA secretion in a dose-dependent manner. Simvastatin (3 to 30 micromol/L) also dose-dependently inhibited LY83583-induced CyPA secretion likely via decreased isoprenylation of small GTPases. Our findings define a novel VSMC vesicular secretory pathway for CyPA that involves actin remodeling and myosin II activation via RhoA-, Cdc42-, and Rho kinase-dependent signaling events.
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PMID:Cyclophilin A is secreted by a vesicular pathway in vascular smooth muscle cells. 1652 92

Rho-associated kinases (ROCKs) have been shown to be involved in the pathogenesis of atherosclerosis. Although smoking is associated with endothelial dysfunction and ROCK inhibitors improve endothelial function in smokers, it is not known whether ROCK activity is increased in smokers and whether this correlates with endothelial dysfunction. The purpose of this study was to evaluate the relationship between ROCK activity and endothelial function in smokers. We evaluated flow-mediated vasodilatation (FMD) using ultrasonography and ROCK activity in peripheral leukocytes using western blot analysis in 14 male smokers (28.1+/-3.9 years) and 15 healthy male non-smokers (28.3+/-3.6 years). ROCK activity was defined as the ratio of phospho-myosin-binding subunit (MBS) on myosin light-chain phosphatase to total MBS. FMD was significantly less in smokers than in non-smokers (4.7+/-3.1 vs. 9.0+/-3.8%, P=0.005). Nitroglycerine-induced vasodilation was similar in the two groups. ROCK activity was greater in smokers than in non-smokers (0.78+/-0.27 vs. 0.54+/-018, P=0.012). The expression of total MBS, ROCK1 and ROCK2 were similar in the two groups. ROCK activity correlated with systolic blood pressure (r=0.42, P=0.039). Multiple regression analysis revealed that smoking is an independent predictor of ROCK activity. There was a significant correlation between FMD and ROCK activity (r=-0.42, P=0.035). No other variable was correlated with FMD. These findings suggest that ROCK activity is enhanced by smoking and is a predictor of endothelial function.
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PMID:Increased leukocyte rho kinase (ROCK) activity and endothelial dysfunction in cigarette smokers. 2013 19


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