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)

Oxidized LDL (OxLDL) induces proliferation in human umbilical vein endothelial cells (HUVEC). The influence of OxLDL on the cyclin-dependent kinase inhibitor p27(Kip1), on the activity of the small GTPase RhoA as a known regulator of p27(Kip1), and on resulting cell proliferation and hypertrophy was studied. HUVEC were stimulated with OxLDL (1 to 50 mug/ml). Proliferation was quantified by (3)H-thymidine incorporation, colorimetric 3-(4,5-dimethyl-2-thiazyl)-2,5-diphenyl-2h-tetrazolium bromide assay, and cell count and was compared with proliferation of HUVEC that were transfected with dominant negative RhoA or treated with the Rho-kinase inhibitor Y27632. Hypertrophy was quantified by (3)H-leucine incorporation and by planimetry. p27(Kip1) expression was determined by Western blot analysis. p27(Kip1) was downregulated by transient transfection with antisense oligonucleotides. Low concentrations of OxLDL induced proliferation of HUVEC, paralleled by a persistent decrease of p27(Kip1) expression. With the use of antisense oligonucleotides, further downregulation of p27(Kip1) expression enhanced the OxLDL-induced proliferative response. High concentrations of OxLDL resulted in cellular hypertrophy and caused a delayed increase in p27(Kip1) expression after initial downregulation. Concomitant, OxLDL caused a significant activation of the small GTPase RhoA. In cells that were transfected with dominant negative RhoA, the effect of OxLDL on p27(Kip1) expression and on cellular proliferation was abolished. HUVEC that were preincubated with the Rho-kinase inhibitor Y27632 also showed a significantly decreased proliferative response to OxLDL stimulation. In summary, OxLDL has a dual effect on cell-cycle progression via regulation of p27(Kip1) expression, resulting in cellular proliferation and hypertrophy, involving activation of RhoA. OxLDL may importantly contribute to vascular hyperplasia in atherosclerosis and other diseases associated with increased levels of OxLDL.
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PMID:Oxidized LDL induces proliferation and hypertrophy in human umbilical vein endothelial cells via regulation of p27Kip1 expression: role of RhoA. 1557 5

Resistance arteries are able to adapt to physiological and pathophysiological stimuli to maintain adequate perfusion according to the metabolic demand of the tissue. Although vasomotor control allows rapid adaptation of lumen diameter, vascular remodeling constitutes an active process that occurs in response to long-term alterations of hemodynamic parameters. Unfortunately, this initially adaptive process contributes to the pathology of vascular diseases. Recent studies have demonstrated the participation of Rho protein signaling pathways in several cardiovascular pathologies including hypertension, coronary artery spasm, effort angina, atherosclerosis, and restenosis. Functional analyses have further revealed that RhoA-dependent pathways are involved in excessive contraction, migration, and proliferation associated with arterial diseases. The present review focuses on the role of Rho proteins, in particular RhoA, in vascular smooth muscle cells and the involvement of Rho-dependent signaling pathways in resistance artery remodeling, more particularly in relation to hypertension.
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PMID:RhoA and resistance artery remodeling. 1570 42

RhoA and Rho-kinase (ROCK) participate in a wide variety of cell signal functions such as cell growth, smooth and cardiac muscle contraction, cytoskeleton rearrangement, cell migration and proliferation. In vascular smooth muscle cells, RhoA and ROCK play an important role in Ca2+ sensitization and regulate vascular smooth muscle tone. In the heart, RhoA and ROCK mediate hypertrophic response leading to cardiac hypertrophy. Recent cellular and molecular biology studies using ROCK inhibitors such as Y-27632 and fasudil have indicated a pivotal role of the RhoA-ROCK cascade in many aspects of cardiovascular function such as cardiac hypertrophy and ventricular remodeling following myocardial infarction. Inhibition of the RhoA-ROCK signaling pathway may be a suitable target for a number of cardiovascular diseases including hypertension, atherosclerosis, diabetes and hypertrophic heart failure. This review focuses on the current understanding of the RhoA-ROCK signal pathway in heart diseases and discusses the use of ROCK inhibitors as therapeutic agents for heart diseases ranging from hypertensive cardiomyopathy to heart failure.
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PMID:Small guanine nucleotide-binding protein Rho and myocardial function. 1571 22

As the cellular and molecular mechanisms of major arterial diseases such as atherosclerosis and hypertension are being more clearly defined, it is becoming apparent that these pathological processes share a number of functional and biochemical features in the vessel wall. Typically, arterial diseases are associated with functional and structural wall alterations including modified contractile properties, smooth muscle cell hypertrophy and proliferation, endothelial dysfunction, excessive extracellular matrix accumulation and inflammation. Small G proteins of the Rho family are defined as major regulators of cell functions including migration, proliferation, differentiation and gene transcription. Recent studies have demonstrated that activation of Rho proteins appears to be a common component for the pathogenesis of hypertension and vascular proliferative disorders. Functional analyses have further revealed that RhoA-dependent pathways are involved in excessive contraction, migration and proliferation associated with arterial diseases. This review focuses on the role of Rho proteins, in particular RhoA, in vascular smooth muscle cells and the involvement of Rho-dependent signaling pathways in vascular diseases.
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PMID:Rho proteins and vascular diseases. 1581 29

Recent clinical studies have revealed that increased serum triglyceride (TG) levels are closely related to atherosclerosis, independently of serum levels of high-density lipoproteins (HDL) and low-density lipoproteins (LDL). Among triglyceride-rich lipoproteins (TRLs), remnant lipoproteins (RLPs) are considered to be atherogenic and an independent coronary risk factor. We previously reported that monocytes cultured in the presence of RLPs increased their adhesion to vascular endothelial cells. The underlying mechanism involved activation of RhoA, a member of small GTP binding proteins, resulting in activation of focal adhesion kinase (FAK) and s1-integrin. It is also known that RLPs enter vessel walls. In another study, we reported that RLPs induced smooth muscle cell (SMC) proliferation, independently of oxidative stress. Recently, we identified the molecular mechanisms, in which RLPs from hypertriglyceridemic patients stimulated SMC proliferation via epidermal growth factor (EGF) receptor transactivation and heparin-binding EGF-like growth factor (HB-EGF) shedding. More recently, we reported that apoB48 receptor was involved in RLP-induced foam cell formation in macrophages. The current review focused on the molecular mechanisms for the atherogenicity of RLPs.
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PMID:Remnant lipoproteins and atherogenesis. 1594 16

Differentiated vascular smooth muscle cells (SMCs) exhibit a work phenotype characterized by expression of several well documented contractile apparatus-associated proteins. However, SMCs retain the ability to de-differentiate into a proliferative phenotype, which is involved in the progression of vascular diseases such as atherosclerosis and restenosis. Understanding the mechanisms involved in maintaining SMC differentiation is critical for preventing proliferation associated with vascular disease. In this study, the molecular mechanisms through which transforming growth factor-beta1 (TGF-beta1) induces differentiation of SMCs were examined. TGF-beta1 stimulated actin re-organization, inhibited cell proliferation, and up-regulated SMC marker gene expression in PAC-1 SMCs. These effects were blocked by pretreatment of cells with either HA1077 or Y-27632, which inhibit the kinases downstream of RhoA. Moreover, TGF-beta1 activated RhoA and its downstream target PKN. Overexpression of active PKN alone was sufficient to increase the transcriptional activity of the promoters that control expression of smooth muscle (SM) alpha-actin, SM-myosin heavy chain, and SM22alpha. In addition, PKN increased the activities of serum-response factor (SRF), GATA, and MEF2-dependent enhancer-reporters. RNA interference-mediated inhibition of PKN abolished TGF-beta1-induced activation of SMC marker gene promoters. Finally, examination of MAPK signaling demonstrated that TGF-beta1 increased the activity of p38 MAPK, which was required for activation of the SMC marker gene promoters. Co-expression of dominant negative p38 MAPK was sufficient to block PKN-mediated activation of the SMC marker gene promoters as well as the serum-response factor, GATA, and MEF2 enhancers. Taken together, these results identify components of an important intracellular signaling pathway through which TGF-beta1 activates PKN to promote differentiation of SMCs.
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PMID:Transforming growth factor-beta1-induced expression of smooth muscle marker genes involves activation of PKN and p38 MAPK. 1598 Apr 30

In the process of atherosclerosis, platelet activating factor (PAF) promotes the infiltration of inflammatory cells into atherosclerotic plaque by modulating their cytoskeleton. Here, we examined whether Rho family proteins are involved in PAF-induced cytoskeletal reorganization in THP-1 macrophages. PAF stimulation rapidly induced cell elongation, accompanied by filopodia formation. The inhibition of Rho family proteins by the overexpression of Rho-GDI attenuated the PAF-mediated morphological changes. Both RhoA and Cdc42 were activated in response to PAF. Inhibition of RhoA or Cdc42 by dominant negative mutants abrogated morphological changes induced by PAF. Collectively, PAF regulates cytoarchitecture through Rho family proteins in macrophages.
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PMID:Platelet activating factor induces cytoskeletal reorganization through Rho family pathway in THP-1 macrophages. 1600 86

Oxidized LDL (OxLDL) is a proatherogenic lipoprotein, accumulating in the vascular wall and contributing to the pathogenesis of vascular dysfunction early in the development of atherosclerosis. Enhanced serum levels of OxLDL, as well as antibodies against its epitopes, are predictive for endothelial dysfunction and coronary heart disease. While enhanced oxidative stress is one factor triggering formation of OxLDL, OxLDL itself has been identified as a potent stimulus for vascular oxygen radical formation, causing a vicious circle. OxLDL-induced O(2)(-) formation, largely through activation of NADPH oxidase, but also through uncoupling of endothelial NO-synthase and through direct O(2)(-) release, leads to endothelial dysfunction. Furthermore, OxLDL-induced O(2)(-) formation has a strong impact on tissue remodeling, resulting in either cell growth - proliferation or hyperplasia - or apoptotic cell death. The effect of OxLDL on cell cycle regulation is mediated by activation of the small GTPase RhoA and consequent regulation of p27(KIP1), a key enzyme of the cell cycle. In addition, OxLDL-induced activation of RhoA sensitizes the contractile apparatus of the vessel wall, enhancing the contractile tonus and favoring vasospasm. Thus, through a variety of mechanisms, OxLDL importantly contributes to vascular dysfunction and remodeling.
Atherosclerosis 2006 Apr
PMID:Impact of oxidized low density lipoprotein on vascular cells. 1628 60

Fluid shear stress caused by blood flow is a major determinant of vascular remodeling and arterial tone and can lead to development of atherosclerosis. The endothelial monolayer in vivo acts as a signal transduction interface for hemodynamic forces; these forces determine the shape, cytoskeletal organization, and function of endothelial cells, allowing the vessels to cope with physiological or pathological conditions. The Ras superfamily of GTPases have been revealed to be master regulators of many cellular activities. In particular, the GTPases RhoA, Rac1, and Cdc42 are known to regulate cell shape changes through effects on the cytoskeleton, but their ability to influence polarity, microtubule dynamics, and transcription factor activity is just as significant. Shear stress modulates the activity of small GTPases, which are critical for both cytoskeletal reorganization and changes in gene expression in response to shear stress. The goal of this article is to review what is known about Ras and more so about Rho GTPases in mechanotransduction and the responses of cells to fluid flow. Several distinct signaling pathways can be coordinately activated by flow, and small GTPases are strongly implicated in some of them; thus possible connections will be explored and a unifying hypothesis offered.
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PMID:Role of small GTPases in endothelial cytoskeletal dynamics and the shear stress response. 1645 10

Rho-associated kinases (ROCKs), the immediate downstream targets of RhoA, are ubiquitously expressed serine-threonine protein kinases that are involved in diverse cellular functions, including smooth muscle contraction, actin cytoskeleton organization, cell adhesion and motility, and gene expression. Recent studies have shown that ROCKs may play a pivotal role in cardiovascular diseases such as vasospastic angina, ischemic stroke, and heart failure. Indeed, inhibition of ROCKs by statins or other selective inhibitors leads to the upregulation and activation of endothelial nitric oxide synthase (eNOS) and reduction of vascular inflammation and atherosclerosis. Thus inhibition of ROCKs may contribute to some of the cholesterol-independent beneficial effects of statin therapy. Currently, two ROCK isoforms have been identified, ROCK1 and ROCK2. Because ROCK inhibitors are nonselective with respect to ROCK1 and ROCK2 and also, in some cases, may be nonspecific with respect to other ROCK-related kinases such as myristolated alanine-rich C kinase substrate (MARCKS), protein kinase A, and protein kinase C, the precise role of ROCKs in cardiovascular disease remains unknown. However, with the recent development of ROCK1- and ROCK2-knockout mice, further dissection of ROCK signaling pathways is now possible. Herein we review what is known about the physiological role of ROCKs in the cardiovascular system and speculate about how inhibition of ROCKs could provide cardiovascular benefits.
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PMID:Physiological role of ROCKs in the cardiovascular system. 1646 61


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