Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0042373 (vascular disease)
 17,070 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Two linked silent dimorphisms, 807 C --> T (Phe224) and 873 G --> A (Thr246) within the glycoprotein Ia (GPIa) gene have been correlated with low and high platelet receptor density, respectively, and associated with vascular disease. A multiplexed allele-specific PCR assay was used to determine the GPIa 807T/873A allele frequency among 331 Caucasian venous thrombosis patients and 3571 unrelated individuals belonging to six different racial groups. The 807T/873A allele frequencies were 54%, 51%, 39%, 39%, 38%, 34% and 30% among Native Americans, Hispanics, Caucasians, Caucasian venous thrombosis patients, Asian Indians, African-Americans, and Koreans, respectively. Significant differences in the GPIa allele frequency among racial groups were revealed which emphasized the need for appropriate controls in studies evaluating the association of GPIa genotype to vascular disease.
 ...
PMID:Allelic distribution of the glycoprotein Ia (alpha2-integrin) C807T/G873A dimorphisms among caucasian venous thrombosis patients and six racial groups. 1058 59

Increased expression of the glycoprotein tenascin-C (TN) is associated with progression of clinical and experimental pulmonary hypertension. In cultured smooth muscle cells (SMCs) TN is induced by matrix metalloproteinases (MMPs) and amplifies the proliferative response to growth factors. Conversely, suppression of TN leads to SMC apoptosis. We now report that hypertrophied rat pulmonary arteries in organ culture, which progressively thicken in association with cell proliferation and matrix accumulation, can be made to regress by inhibiting either serine elastases or MMPs. This effect is associated with reduced TN, suppression of SMC proliferation, and induction of apoptosis. Selective repression of TN by transfecting pulmonary arteries with antisense/ribozyme constructs also induces SMC apoptosis and arrests progressive vascular thickening but fails to induce regression. This failure is related to concomitant expansion of a SMC population, which produces an alternative cell survival alpha(v)beta(3) ligand, osteopontin (OPN), in response to pro-proliferative cues provided by a proteolytic environment. OPN rescues MMP inhibitor-induced SMC apoptosis, and alpha(v)beta(3) blockade induces apoptosis in hypertrophied arteries. Our data suggest that proteinase inhibition is a novel strategy to induce regression of vascular disease because this overcomes the pluripotentiality of SMC-matrix survival interactions and induces coordinated apoptosis and resorption of matrix.
 ...
PMID:Elastase and matrix metalloproteinase inhibitors induce regression, and tenascin-C antisense prevents progression, of vascular disease. 1061 58

Cartilage oligomeric matrix protein (COMP/thrombospondin [TSP]-5) belongs to the thrombospondin gene family and is an extracellular glycoprotein found predominantly in cartilage and tendon. To date, there is limited evidence of COMP/TSP-5 expression outside of the skeletal system. The aim of the present study was to investigate the expression of COMP/TSP-5 in cultured human vascular smooth muscle cells and human arteries. COMP/TSP-5 mRNA and protein expression was detected in cultured human vascular smooth muscle cells with both Northern blotting and immunoprecipitation. Serum, as well as transforming growth factor (TGF)beta1 and TGF-beta3, stimulated COMP/TSP-5 mRNA expression. COMP/TSP-5 was detected in normal as well as atherosclerotic and restenotic human arteries with immunohistochemistry. The majority of COMP/TSP-5 was expressed in close proximity to vascular smooth muscle cells. In vitro attachment assays demonstrated strong adhesion of smooth muscle cells to COMP/TSP-5-coated surfaces, with the majority of cells spreading and forming stress fibers. In addition, COMP/TSP-5 supported the migration of smooth muscle cells in vitro. The present study shows that COMP/TSP-5 is present in human arteries and may play a role in the adhesion and migration of vascular smooth muscle cells during vasculogenesis and in vascular disease settings such as atherosclerosis.
 ...
PMID:Cartilage oligomeric matrix protein (thrombospondin-5) is expressed by human vascular smooth muscle cells. 1114 32

Three platelet glycoprotein (GP) IIb/IIIa receptor antagonists have been approved as adjunctive therapy to decrease the ischemic complications of percutaneous coronary interventions (PCI) and/or unstable angina. They include the chimeric murine/human monoclonal antibody 7E3 Fab fragment (abciximab), a cyclic heptapeptide based on the KGD amino acid sequence (eptifibatide), and a nonpeptide mimetic of the RGD sequence (tirofiban). The agents are very effective in providing both short-term and long-term benefit after PCI, and one agent has also demonstrated a progressive long-term mortality benefit. The long-term mortality benefit is highly cost-effective when compared to other medical interventions. The benefits in treating unstable angina without PCI are less dramatic and robust, with some agents providing no benefit. Severe thrombocytopenia is an infrequent, but potentially serious, complication of therapy with all of the agents. The risk of major bleeding is increased only minimally or not at all by the drugs. Currently, a number of new indications for GPIIb/IIIa antagonists are under study, including acute myocardial infarction (+/- thrombolytic therapy, +/- PCI) and stroke. In addition to their impact on improving outcome, the results of clinical trials with these agents provide crucial insights into the contribution of GPIIb/IIIa-mediated platelet function in the pathophysiology of thrombotic vascular disease.
 ...
PMID:Anti-GPIIb/IIIa drugs: current strategies and future directions. 1148 34

Lipoid proteinosis (LP), also known as hyalinosis cutis et mucosae or Urbach-Wiethe disease (OMIM 247100) is a rare, autosomal recessive disorder typified by generalized thickening of skin, mucosae and certain viscera. Classical features include beaded eyelid papules and laryngeal infiltration leading to hoarseness. Histologically, there is widespread deposition of hyaline (glycoprotein) material and disruption/reduplication of basement membrane. The aetiology of LP is currently unknown. Using DNA from three affected siblings in a consanguineous Saudi Arabian family we performed genome-wide linkage and mapped the disorder to 1q21 (marker D1S498) with a two-point LOD score of 3.45 at theta = 0. A further 28 affected individuals from five other unrelated consanguineous family groups from different geographical regions also showed complete linkage and resulted in a maximum two-point LOD score of 21.85 at theta = 0. Using available markers in the interval between D1S442 and D1S305, the observed recombinants placed the gene in a 2.3 cM critical interval between D1S2344 and D1S2343 (Marshfield genetic map) corresponding to an approximately 6.5 Mb region on the UCSC physical map. Using a candidate gene approach (comparison of control versus LP gene expression in cultured fibroblasts) and subsequent direct sequencing of genomic DNA, we identified six different homozygous loss-of-function mutations in the extracellular matrix protein 1 gene (ECM1). Although the precise function of ECM1 is not known, our findings provide the first clinical indication of its relevance to skin adhesion, epidermal differentiation, wound healing, scarring, angiogenesis/angiopathy and basement membrane physiology, as well as defining the molecular basis of this inherited disorder.
 ...
PMID:Lipoid proteinosis maps to 1q21 and is caused by mutations in the extracellular matrix protein 1 gene (ECM1). 1192 56

Thrombospondin-1 (TSP-1), an acute phase reactant implicated in vascular disease, is a matricellular glycoprotein with six domains that confer different functions. The authors have shown TSP-1 induces vascular smooth muscle cell (VSMC) chemotaxis via extracellular signal-regulated kinases-1 and -2 (ERK) and p38 kinase (p38) and that a fusion protein of the carboxyl terminal (COOH) and type 3 repeat (T3) domains independently induce VSMC chemotaxis. The purpose of this study was to determine whether COOH-, T3-induced VSMC chemotaxis, or both, is dependent upon ERK or p38 activation. To determine if the T3, COOH, or type 2 repeat domain (T2, control domain not associated with chemotaxis) activate ERK, p38, or both, VSMCs were exposed to each fusion protein (20 microg/ml for 15, 30, 60, or 120 min), serum-free media (SFM, negative control), or TSP-1 (20 microg/ml for 30 min, positive control). Western immunoblotting was performed for activation studies. Using a microchemotaxis chamber, VSMCs pre-incubated in SFM, DMSO (vehicle control), PD98059 (10 microM), or SB202190 (10 microM) were exposed to each domain, TSP-1, or SFM. After 4 h (37 degrees C), migrated VSMCs were recorded as cells/five fields (400 x) and analyzed by paired t-test. ERK was activated by T2, T3, and COOH. However, p38 was activated by T3 and COOH, but not T2. T3 and COOH-induced VSMC chemotaxis were inhibited by PD98059 or SB202190, but more completely by SB202190. The T2 domain had no effect on VSMC chemotaxis. These results suggest activation of the p38 pathway may be more specific than ERK for COOH- and T3-induced VSMC chemotaxis.
 ...
PMID:Thrombospondin-1-induced vascular smooth muscle cell chemotaxis: the role of the type 3 repeat and carboxyl terminal domains. 1276 83

Chronic immune thrombocytopenic purpura (ITP) is an autoimmune disorder characterized by thrombocytopenia due to autoantibody-induced platelet destruction. The majority of these autoantibodies are directed to epitopes on either glycoprotein (GP) IIb-IIIa or GPIb-IX. The newer antigen-specific autoantibody assays are capable of detecting both platelet-associated and plasma autoantibodies and have a definite role in the diagnosis of immune thrombocytopenia. A positive assay provides strong evidence for the presence of immune thrombocytopenia both in chronic ITP and in other diseases where immune thrombocytopenia may occur, such as collagen vascular disease and lymphoproliferative disorders. However, a negative assay does not rule out the presence of ITP. Somewhat concerning is the large number of patients who have negative assays. Several possible explanations for these observations are discussed. Recent studies have localized some ITP autoepitopes to specific regions of GPIIb-IIIa and GPIb-IX. Most autoepitopes on GPIIb-IIIa are conformational, in view of their dependence on divalent cations, and are localized to the N-terminal portion of GPIIb, while the GPIb-IX autoepitopes that have been identified are localized to GPIb amino acids 333-341.
 ...
PMID:Antiplatelet antibodies in chronic adult immune thrombocytopenic purpura: assays and epitopes. 1466 42

Several molecules are known to be closely associated with amyloid deposits in human brain. Among these, apolipoproteins such as apolipoproteins E (apo E) and J (apo J) have been found in two neuropathological hallmarks of Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA): senile plaques (SPs) and cerebrovascular amyloid. These apolipoproteins may be implicated in amyloid fibrillogenesis. Apo D is a multiligand-multifunctional glycoprotein present in SPs, as we previously reported. The aim of this work is to study the link between immunolocalization of apo E and apo D in AD and CAA brains. Both apolipoproteins were found in all types of SPs, but apo E was observed more often than apo D in mature plaques. Whereas apo E is always located overlapping the amyloid core, apo D seems to situate preferably around and near the amyloid. Immunohistochemistry revealed that these apolipoproteins behave differently in cerebral vessels. Apo E labeling in vessels appears mainly linked to amyloid deposits, whereas apo D shows a distribution almost opposite to that of apo E. This could be an indication of the different roles that each apolipoprotein plays in the pathogenesis of amyloid deposition.
 ...
PMID:Immunohistochemical study of distribution of apolipoproteins E and D in human cerebral beta amyloid deposits. 1476 61

The last several years have seen an abundance of studies of genetic risk factors for vascular disease, and platelet glycoprotein (GP) polymorphisms have been a primary focus of this area of research. This article reviews GP receptor polymorphisms, particularly those on GPIa-IIa (integrin alpha2beta1), GPIb-IX-V, GPIIb-IIIa (integrin alpha(IIb)beta3), and GPVI, and summarizes clinical and functional studies that have attempted to clarify their roles in human disease. Our focus is on recent work relevant to thrombotic and hemostatic processes and advances in pharmacogenetics. We consider issues affecting our ability to derive firm conclusions from these studies, and discuss future directions in this rapidly evolving area.
 ...
PMID:Clinical and functional consequences of platelet membrane glycoprotein polymorphisms. 1549 1

Membrane glycoprotein (GP) IIb/IIIa plays a major role in platelet function; indeed it enables stimulated platelets to bind fibrinogen and related adhesive proteins, a process that is considered key in the development of thrombosis. The gene encoding GPIIIa (ITGB3, also known as GP3A) shows a common platelet antigen polymorphism [PL(A1)/PL(A2); expressed by alleles ITGB3*001 and ITGB3*002] that was variably associated with vascular disease. In 1996, the presence of the PL(A2) allele (ITGB3*001) was first reported to increase the risk of coronary heart disease. Shortly after, the interest in this study was increased by the publication of a case report on the death from myocardial infarction of an Olympic athlete who was found to be homozygous for the PL(A2) allele. Overviews of the published studies on the PL(A1)/PL(A2) polymorphism and coronary risk suggest an influence of the PL(A2) allele on the clinical phenotype and the interaction with other environmental factors. In particular, the strongest effect of the ITGB3 PL(A2) allele was expressed on the risk of occlusion after revascularization procedures, mainly after stent implantation, a condition in which platelet activation is more important as compared with other stenotic mechanisms. In the future, the identification of patients who are particularly responsive to GPIIb/IIIa antagonist therapy (e.g. those with the PL(A2) allele) might help to improve the treatment efficacy in this relatively small population. In a mechanism possibly unrelated to its effect on platelet reactivity to aggregating stimuli, the presence of the PL(A2) allele might influence the antiaggregatory effect of platelet inhibitory drugs such as aspirin (acetylsalicylic acid), clopidogrel, and GPIIb/IIIa antagonists. Although interesting, current data does not yet have direct clinical implications for patient risk identification and drug therapy tailoring. Larger studies are necessary to define the role of the PL(A2) allele in more homogeneous groups where platelet GPIIb/IIIa activation might be particularly relevant.
 ...
PMID:Platelet glycoprotein IIb/IIIa polymorphism and coronary artery disease: implications for clinical practice. 1581 72


<< Previous 1 2 3 4 5 6 7 Next >>