Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gene targeting studies have indicated that the two receptors for PDGF, alpha and beta, direct unique functions during development. Distinct ligand affinities, patterns of gene expression, and/or mechanisms of signal relay may account for functional specificity of the two PDGF receptor isoforms. To distinguish between these factors, we have created two complementary lines of knockin mice in which the intracellular signaling domains of one PDGFR have been removed and replaced by those of the other PDGFR. While both lines demonstrated substantial rescue of normal development, substitution of the PDGFbetaR signaling domains with those of the PDGFalphaR resulted in varying degrees of vascular disease. This observation provides a framework for discussing the evolution of receptor tyrosine kinase functional specificity.
Mol Cell 2001 Feb
PMID:The two PDGF receptors maintain conserved signaling in vivo despite divergent embryological functions. 1123 63

Coronary heart disease (CHD) has been and remains a major contributor to morbidity and mortality in developed countries. The most common form of CHD in the western world is atherosclerosis (AS), especially of the major coronary arteries. Failure to maintain an intact endothelium, as a result of episodic and/or persistent injury and perturbation of the vascular endothelium, promotes formation of fatty streaks which are considered initiation events of AS. Cellular constituents contributing to endothelial injury include endothelial cells, monocytes, platelets, and smooth muscle cells. Individuals diagnosed with AS face complex, enduring clinical complications and enormous medical costs. Simple and easily compliant prevention and treatment measures are therefore strategic considerations in the management of this vascular disease. Based on known risk factors for CHD, priorities in AS prevention should include smoking cessation, blood pressure control, and diet modification. In recent years, the possible benefits of low to moderate consumption of alcoholic beverages, particularly of red wine, in the prevention of heart disease has received increasing attention and debate in the popular media as well as in the scientific community. Such attention has been prompted by research findings supporting a relationship between red wine consumption and the French paradox. This phenomenon refers to people residing in certain parts of France where red wine is customarily consumed during meals having a low CHD mortality, despite living a lifestyle considered to have comparably high CHD risks, as those in the US and many other developed countries. Studies have reported that the cardioprotective effects of red wine are greater than those attributed solely to ethanol and other types of alcoholic beverages. The mechanism(s) underlying the greater CHD protective benefits of red wine have not been elucidated. Recently the polyphenol resveratrol (3,5,4'-trihydroxy-trans-stilbene), known to be abundantly present in red wine, compared to white wine, beer, or spirits, has been demonstrated to elicit a broad spectrum of biological responses in in vitro and in animal studies, including effects that are compatible with the cardioprotective roles proposed for red wine. These recently described effects of resveratrol will be reviewed in this article. We will first summarize published data showing an inverse association between consumption of alcoholic beverages/red wine and risk of CHD. A review of biosynthesis of resveratrol and its presence in food groups and wines will follow. Recent studies relating exposure to wine/resveratrol with reduction in myocardial damage during ischemia-reperfusion, modulation of vascular cell functions, inhibition of LDL oxidation, and suppression of platelet aggregation will be presented. The last section of this review will focus on a discussion of mechanism(s) by which resveratrol acts as a potential cardioprotective agent.
Int J Mol Med 2001 Jul
PMID:Mechanism of cardioprotection by resveratrol, a phenolic antioxidant present in red wine (Review). 1140 43

Human herpesviruses have been recognized as a pathogen involved in interstitial pneumonia (IP), especially in immunocompromised patients. So far, little is known about involvement of human herpesvirus 6 (HHV-6) in systemic respiratory tract disease. Currently, routine diagnostic tests for HHV-6 are inefficient for HHV-6 reactivation, therefore, we established a rapid quantification system of HHV-6 using real-time PCR in order to determine the possible role of human HHV-6 reactivation in immunocompromised patients showing IP. Bronchoalveolar lavage fluid (BALF) specimens were obtained from 84 consecutively treated patients with interstitial lung diseases (ILD) including various types of IP. First, we determined the viral burden in BALF and peripheral blood obtained from healthy volunteers. In healthy volunteers, the prevalence of HHV-6 in BALF was higher (4/12, 33.3%) than in peripheral blood (8/53, 15.1%), ranging from 0 to 101.65 HHV-6 genome copies per 1 microg of DNA. Among 84 patients with ILD analyzed, the prevalence of HHV-6 in BALF was 27.4% (23/84), ranging from 0 to 103.87 copies per 1 microg of DNA. Three specimens obtained from patients with collagen vascular disease, 2 from Hodgkin's disease, and 1 with sarcoidosis had high level of HHV-6 viral DNA, while none of the patients with idiopathic IP showed elevation of HHV-6 (more than 102) in BALF. Our results suggest that measurement of HHV-6 genomes in BALF using real-time PCR may be useful in management of the care of respiratory complications in immunocompromised patients.
Int J Mol Med 2001 Oct
PMID:Detection and quantification of human herpesvirus 6 genomes using bronchoalveolar lavage fluid in immunocompromised patients with interstitial pneumonia. 1156 75

Amyloid beta-protein (Abeta) assembly into toxic oligomeric and fibrillar structures is a seminal event in Alzheimer's disease, therefore blocking this process could have significant therapeutic benefit. A rigorous mechanistic understanding of Abeta assembly would facilitate the targeting and design of fibrillogenesis inhibitors. Prior studies have shown that Abeta fibrillogenesis involves conformational changes leading to the formation of extended beta-sheets and that an alpha-helix-containing intermediate may be involved. However, the significance of this intermediate has been a matter of debate. We report here that the formation of an oligomeric, alpha-helix-containing assembly is a key step in Abeta fibrillogenesis. The generality of this phenomenon was supported by conformational studies of 18 different Abeta peptides, including wild-type Abeta(1-40) and Abeta(1-42), biologically relevant truncated and chemically modified Abeta peptides, and Abeta peptides causing familial forms of cerebral amyloid angiopathy. Without exception, fibrillogenesis of these peptides involved an oligomeric alpha-helix-containing intermediate and the kinetics of formation of the intermediate and of fibrils was temporally correlated. The kinetics varied depending on amino acid sequence and the extent of peptide N- and C-terminal truncation. The pH dependence of helix formation suggested that Asp and His exerted significant control over this process and over fibrillogenesis in general. Consistent with this idea, Abeta peptides containing Asp-->Asn or His-->Gln substitutions showed altered fibrillogenesis kinetics. These data emphasize the importance of the dynamic interplay between Abeta monomer conformation and oligomerization state in controlling fibrillogenesis kinetics.
J Mol Biol 2001 Oct 05
PMID:Identification and characterization of key kinetic intermediates in amyloid beta-protein fibrillogenesis. 1158 Feb 53

Molecular defects in genes encoding enzymes involved in homocysteine metabolism may account for mild hyperhomocysteinemia, an independent and graded risk factor for cardiovascular disease (CVD). We examined the relationship of two polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene, the 677C-->T and 1298A-->C variants, to MTHFR activity, homocysteine concentrations, and risk of CVD in a population of 190 vascular disease patients and 601 apparently healthy controls. The mean specific and residual MTHFR activities were significantly lower in 677CT and 677TT individuals (both P<0.001). The 1298A-->C mutation alone showed no effect on MTHFR activities. However, when the 677C-->T genotype was taken into account, the 1298A-->C mutation also caused a significant decrease in MTHFR activities, which was observed in both the homozygous 1298CC (P<0.001) and the heterozygous 1298AC states (P=0.005). Both the 677TT as the 677CT genotypes were associated with significantly higher fasting and postload homocysteine levels than 677CC (P<0.001 and P=0.003, respectively). The 1298A-->C mutation had no effect on fasting or postload homocysteine levels. Since homocysteine itself is considered to be positively associated with the risk of CVD, these findings indicate that the 1298A-->C mutation cannot be considered a major risk factor for CVD.
J Mol Med (Berl) 2001 Sep
PMID:A second common variant in the methylenetetrahydrofolate reductase (MTHFR) gene and its relationship to MTHFR enzyme activity, homocysteine, and cardiovascular disease risk. 1169 65

Tenascin-C (TN-C) expression and matrix metalloproteinase (MMP) activity are induced within remodeling pulmonary arteries (PAs), where they promote cell growth. Because pulmonary vascular disease in children with congenital heart defects is commonly associated with changes in pulmonary hemodynamics, we hypothesized that changes in pulmonary blood flow regulate TN-C and MMPs. To test this, we ligated the left PAs of neonatal pigs. After 12 wk, we evaluated the levels of TN-C and MMPs in control and ligated lung tissue. Modifying pulmonary hemodynamics increased TN-C mRNA and protein expression, MMP activity, and the DNA-binding activity of Egr-1, a transcription factor that has been shown to activate TN-C expression. To link MMP-mediated remodeling of the extracellular matrix to increased TN-C expression and Egr-1 activity, porcine PA smooth muscle cells were cultivated either on denatured type I collagen, which supported TN-C expression and Egr-1 activity, or on native collagen, which had the opposite effect. These data provide a framework for understanding how changes in pulmonary blood flow in the neonate modify the tissue microenvironment and cell behavior.
Am J Physiol Lung Cell Mol Physiol 2002 Jan
PMID:Altered hemodynamics controls matrix metalloproteinase activity and tenascin-C expression in neonatal pig lung. 1174 12

It is well established that prolonged hyperglycemia may be a key contributor in the development of vascular complications in diabetes leading to vascular disease. An important feature of vascular disease is abnormal growth, proliferation, migration and hypertrophy of vascular smooth muscle cells (VSMC). However, the precise molecular events linking hyperglycemia with the abnormal VSMC functions remain poorly characterized. Interestingly, recent work has shown that exposure of VSMC with high glucose activates signal transduction networks responsible for mediating the proliferative and growth promoting responses. These include activation of specific isoforms of protein kinase C (PKC), mitogen-activated protein kinases (MAPKs), nuclear transcription factors, Janus-family of activated kinases (JAKs) and signal transducers and activators of transcription (STAT). Since reactive oxygen species (ROS) which are generated in response to hyperglycemia stimulate signaling pathways similar to hyperglycemia and many of the growth promoting effects of hyperglycemia are blocked by antioxidant, a key role of ROS in mediating the cellular responses of hyperglycemia has been suggested. Therefore, this article aims to summarize some of the key studies on hyperglycemia-induced cell signaling pathways in VSMC in relation to their potential role in the development of vascular disease in diabetes.
Int J Mol Med 2002 Jan
PMID:High glucose-induced activation of protein kinase signaling pathways in vascular smooth muscle cells: a potential role in the pathogenesis of vascular dysfunction in diabetes (review). 1174 3

Occlusive vascular disease most often results from thrombosis superimposed on atherosclerotic plaque. In the case of an acute coronary syndrome including an acute myocardium infarction or an unstable angina pectoris thrombus in coronary artery takes significant part as known. There are few reports about animal models of acute coronary artery thrombi, because of the difficulties of operative significance. We have succeeded in making thrombus at murine coronary arteries with ferric chloride. Slight or moderate IL-8 expressions were found in the endothelial cells in the thrombus formed vessel analyzed by immunohistochemistry. The interleukin-8 (IL-8) receptor knockout mice formed the slight thrombus in coronary arteries treated with ferric chloride. We propose a role for IL-8 in the pathogenesis of acute coronary artery thrombi. This hypothesis lends itself to testing using interventions to influence IL-8 secretion and actions in the early phase of coronary thrombotic formation.
Res Commun Mol Pathol Pharmacol
PMID:A new murine model of coronary artery thrombosis and role of interleukin-8 in the development of coronary thrombosis. 1175 67

The epsilon4 allele of apolipoprotein E (apoE) is a risk factor for Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA). The mechanism underlying this increased risk is not completely clear, yet mounting evidence supports the idea that the ability of apoE to interact with the amyloid-beta (Abeta) peptide and influence its conformation and clearance plays a major role. Evidence to support this concept comes from in vitro and in vivo studies of apoE/Abeta interactions and the effects of these interactions on Abeta conformation and cellular clearance. Recent studies on the effect of murine and human apoE in APP transgenic mice provide direct evidence that apoE is critically involved in the in vivo converstion of Abeta into forms which contain high 5-sheet content and associated cellular toxicity (neuritic plaques and CAA). These studies also suggest a role for human apoE in Abeta clearance in vivo.
J Mol Neurosci 2001 Oct
PMID:Role of apoe/Abeta interactions in the pathogenesis of Alzheimer's disease and cerebral amyloid angiopathy. 1181 88

Mutations in KRIT1, a protein initially identified based on a yeast two-hybrid interaction with the RAS-family GTPase RAP1A, are responsible for the development of the inherited vascular disorder cerebral cavernous malformations (CCM1). As the function of the KRIT1 protein and its role in CCM pathogenesis remain unknown, we performed yeast two-hybrid screens to identify additional protein binding partners. A fragment containing the N-terminal 272 amino acid residues of KRIT1, a region lacking similarity to any known protein upon database searches, was used as bait. From parallel screens of human fetal brain and HeLa cDNA libraries, we obtained multiple independent isolates of human integrin cytoplasmic domain-associated protein-1 (ICAP-1) as interacting clones. The interaction of KRIT1 and ICAP-1 was confirmed by GST-KRIT1 trapping of endogenous ICAP-1 from 293T cells. The alpha isoform of ICAP-1 is a 200 amino acid serine/threonine-rich phosphoprotein which binds the cytoplasmic tail of beta1 integrins. We show that mutagenesis of the N-terminal KRIT1 NPXY amino acid sequence, a motif critical for ICAP-1 binding to beta1 integrin molecules, completely abrogates the KRIT1/ICAP-1 interaction. The interaction between ICAP-1 and KRIT1, and the presence of a FERM domain in the latter, suggest that KRIT1 might be involved in the bidirectional signaling between integrin molecules and the cytoskeleton. Furthermore, these data suggest that KRIT1 might affect cell adhesion processes via integrin signaling in CCM1 pathogenesis.
Hum Mol Genet 2002 Feb 15
PMID:KRIT1 association with the integrin-binding protein ICAP-1: a new direction in the elucidation of cerebral cavernous malformations (CCM1) pathogenesis. 1185 71


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