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

Progressive fibrosis in major organs, including the heart, the kidney and the vascular tree, plays an important role in mediating chronic disease and atherosclerosis. Production of extracellular matrix proteins, in many cases regulated by the growth factor TGF-beta is an essential component of this process. In a parallel manner to TGF-beta, the cyclin kinase inhibitors (CKIs; which are induced by TGF-beta) regulate transit through the cell cycle, and their effect on growth has been shown to be bimodal in the case of vascular smooth muscle (VSM) cells. Using an antisense oligodeoxynucleotide to the CKI p21(Waf1/Cip1), developed in our laboratory and shown to specifically inhibit p21(Waf1/Cip1) protein levels, we asked whether attenuation of the CKI p21(Waf1/Cip1) by transfection of this oligodeoxynucleotide results in the abolition of TGF-beta-mediated growth inhibition and/or diminished matrix protein production and secretion in the presence or absence of TGF-beta. Specific inhibition of p21(Waf1/Cip1) protein with the antisense oligodeoxynucleotide markedly reduces the production and secretion of the matrix proteins fibronectin and laminin, both in the presence and absence of TGF-beta stimulation, in VSM cells as observed by Western blotting of cell lysate and conditioned medium. In addition, TGF-beta-mediated cell growth inhibition, though attenuated by this oligo, is preserved. Due to the relative ease and safety of transfecting antisense oligodeoxynucleotides into VSM, we believe that this work unmasks a potentially powerful technique for inhibition of matrix protein synthesis in VSM and related cell lines, and may lead to new treatment strategies for atherosclerotic as well as other systemic diseases characterized by aberrant matrix protein secretion.
Atherosclerosis 2002 Mar
PMID:Attenuation of matrix protein secretion by antisense oligodeoxynucleotides to the cyclin kinase inhibitor p21(Waf1/Cip1). 1188 22

Vascular smooth muscle cell (VSMC) proliferation after arterial injury is playing a pivotal role in the pathogenesis of a number of vascular proliferative disorders including atherosclerosis and restenosis after balloon-mediated angioplasty. Thus, a better understanding of the molecular mechanisms underlying VSMC proliferation in response to injury would have important therapeutic implications. Cell proliferation is controlled by an intricate network of extracellular and intracellular signaling pathways which are processing various growth regulatory signals and integrating them into the basic cell-cycle regulatory machinery through control of cyclin dependent kinases (CDK). CDK are positively regulated by cyclins and negatively regulated by CDK inhibitory proteins (CKI). To dissect the role of CKI in VSMC proliferation, we prepared the replication-deficient adenovirus constructs expressing p21 family members (Ad-CKI), p21Waf1, p27Kip1 and p57Kip2, respectively, and investigated the effect of CKI overexpression on the proliferation of vascular smooth muscle cells. The overexpression of each CKI protein in cultured VSMC was confirmed by western blot analysis. Flowcytometric analysis revealed that the Ad-CKI infected VSMC were largely retained in G1 phase, and had significantly less G2/M fraction than control cells. The extent of DNA synthesis in VSMC was assessed by [3H]-thymidine uptake, and shown to be inhibited by Ad-CKI dose dependently. Among three CKIs tested in this study, p57Kip2 showed the most significant suppression of DNA synthesis. In order to investigate in vivo effect of p57Kip2 overexpression, Ad-p57 was locally delivered to the luminal wall of rabbit carotid arteries after balloon angioplasty. Histological examinations revealed that the local infection of Ad-p57 significantly suppressed the neointimal formation at the site of vascular injury. These results clearly demonstrated the antiproliferative role of p57Kip2 in VSMC, and also proposed a possibility of gene therapy approach for vascular proliferative disorders.
 ...
PMID:Adenovirus-mediated overexpression of a cyclin-dependent kinase inhibitor, p57Kip2, suppressed vascular smooth muscle cell proliferation. 1205 49

Excessive cell proliferation contributes to the pathobiology of human diseases with a high health and socio-economic impact, including cancer and vascular occlusive diseases (e. g., atherosclerosis, in-stent restenosis, transplant vasculopathy, and vessel bypass graft failure). Recent advances in the understanding of the molecular networks governing the hyperplastic growth of tumors and vascular obstructive neointimal lesions have provided new perspectives for preventive and therapeutic strategies against these disorders. Mammalian cell proliferation requires the activation of several cyclin-dependent protein kinases (CDKs). Postranslational activation of CDKs is a complex process that involves their association with regulatory subunits called cyclins. The activity of CDK/cyclin holoenzymes is negatively regulated through their interaction with members of the CDK family of inhibitory proteins (CKIs). Moreover, over fifty low molecular weight pharmacological CDK inhibitors that target the ATP-binding pocket of the catalytic site of CDKs have been identified. In this review, we will discuss the use of pharmacological and gene therapy strategies against CDK/cyclins in animal models and clinical trials of cancer and cardiovascular disease.
 ...
PMID:Inhibiting cyclin-dependent kinase/cyclin activity for the treatment of cancer and cardiovascular disease. 1257 Jun 80

Cardiovascular diseases are the leading cause of morbidity and mortality in industrialized countries. Most cardiovascular diseases result from complications of atherosclerosis, which is a chronic and progression inflammatory condition characterized by excessive cellular proliferation of vascular smooth muscle cells, endothelial cells and inflammatory cells leading to occlusive vascular disease, myocardial infarction and stroke. Recent studies have revealed the important role of the cyclins, the cyclin-dependent kinases (CDKs), and the cyclin-dependent kinase inhibitors (CKIs) in vascular and cardiac tissue injury, inflammation and wound repair. Tissue remodeling in the cardiovascular system is a regulated balance between pro- and anti-proliferative molecules, and this balance becomes derailed in cardiovascular pathology. Understanding the circuitry of the cyclin-CDK-CKI interactions in normal physiology and disease pathology allows a better understanding of the molecular mechanisms of cardiovascular diseases and permits the rationale design of new classes of therapeutic agents for these diseases.
 ...
PMID:The cell cycle and cardiovascular diseases. 1459 97

Increased aortic smooth muscle cell (SMC) proliferation is a key event in the pathogenesis of atherosclerosis. Transforming growth factor-beta (TGF-beta) is one of the potent inhibitors of SMC proliferation. The purpose of this study was 1) to explore the effect of TGF-beta inhibition on proliferation of SMC and expression of growth regulatory molecules like p21 and c-myc and 2) to determine whether restoration of cell cycle regulatory molecules normalizes the altered proliferation. To test the role of TGF-beta in SMC proliferation, using antisense plasmid DNA, we inhibited TGF-beta gene from aortic SMC, which resulted in a significant increase (P < 0.03) in proliferation (studied by quantifying new DNA synthesis with [(3)H]thymidine uptake assay). In TGF-beta-altered SMC (TASMC), the mRNA expression (studied by RT-PCR) of c-myc was increased whereas that of the cyclin inhibitor p21 was completely inhibited. Using p21 sense plasmid DNA, we transfected p21 gene in TASMC, which restored p21 mRNA and protein expression and decreased proliferation (P < 0.002) in TASMC. Similar treatment with c-myc antisense oligonucleotides significantly (P < 0.001) decreased the proliferation of TASMC. TASMC also exhibited alteration in morphological changes in SMC but returned to normal with treatment of p21 and TGF-beta sense plasmid DNA. Two-dimensional gel electrophoresis analysis of SMC and TASMC demonstrated differential expression of proteins relevant to cellular proliferation and atherosclerosis. This study uniquely analyzes the effect of TGF-beta at the molecular level on proliferation of SMC and on cell cycle regulatory molecules, implicating their potential role in the pathogenesis of atherosclerosis.
 ...
PMID:Concerted effect of transforming growth factor-beta, cyclin inhibitor p21, and c-myc on smooth muscle cell proliferation. 1476 78

Excessive cellular proliferation contributes to the pathobiology of vascular obstructive diseases (e.g., atherosclerosis, in-stent restenosis, transplant vasculopathy, and vessel bypass graft failure). Therefore, anti-proliferative therapies may be a suitable approach in the treatment of these disorders. Candidate targets for such strategies include the cyclin-dependent kinase/cyclin holoenzymes, members of the cyclin-dependent kinase family of inhibitory proteins, tumor suppressors, growth factors and transcription factors that control cell cycle progression. In this review, we will discuss the use of pharmacological agents and gene therapy approaches targeting cellular proliferation in animal models and clinical trials of cardiovascular disease.
 ...
PMID:Antiproliferative strategies for the treatment of vascular proliferative disease. 1532 Aug 55

The abnormal proliferation of vascular smooth muscle cells (VSMCs) in arterial walls is an important pathogenetic factor of vascular disorders such as atherosclerosis and restenosis after angioplasty. Epothilone B, a novel potential antitumor compound, has a potent effect on preventing postangioplasty restenosis. Therefore, we established an in vivo rat carotid injury model and examined the potential effects of epothilone B on cardiovascular disease. We found that epothilone B potently prevented neointimal formation and in vivo VSMCs proliferation. In addition, we also showed that epothilone B significantly inhibited 5% fetal bovine serum (FBS)- and 50 ng/ml platelet-derived growth factor (PDGF)-BB-induced proliferation and cell cycle progression in rat aortic VSMCs. Furthermore, FBS and PDGF-BB induced the activations of extracellular signal-regulated kinases 1 and 2, Akt, phospholipase C gamma 1, and PDGF-receptor beta chain tyrosine kinase were not changed by epothilone B. However, epothilone B treatment caused a significant decrease in the level of cyclin-dependent protein kinase (CDK) 2, whereas it caused no change in the levels of cyclin E and down-regulated the phosphorylation of retinoblastoma, which plays a critical role in cell cycle regulation. Furthermore, levels of p27, an inhibitor of cyclin E/CDK2 complex, were significantly increased in VSMCs treated with epothilone B, indicating that this might be a major molecular mechanism for the inhibitory effects of epothilone B on the proliferation and cell cycle of VSMCs. These findings suggest that epothilone B can inhibit neointimal formation via the cell cycle arrest by the regulation of the cell cycle-related proteins in VSMCs.
 ...
PMID:Epothilone B inhibits neointimal formation after rat carotid injury through the regulation of cell cycle-related proteins. 1728 37

Piceatannol (3,5,3',4'-tetrahydroxy- trans-stilbene), a resveratrol analogue, is a polyphenol present in the skins of grapes and in wine and other foods. The present study aimed to investigate for the first time the cardioprotective effects of piceatannol on vascular smooth muscle cells (VSMC). The treatment of cells with piceatannol inhibited cell proliferation by reducing extracellular signal-regulated kinase (ERK) 1/2 and JNK activity in cultured VSMC in the presence of tumor necrosis factor-alpha (TNF-alpha). These inhibitory effects were also associated with G1 cell cycle arrest, and resulted in a decrease in cyclin-dependent kinases (CDKs) and cyclins. Piceatannol treatment strongly induced the expression of p21WAF1 via independence of p27KIP and p53 expression. The effect of piceatannol was not restricted to cell proliferation, as TNF-alpha-induced invasion and migration was also suppressed in VSMC. Moreover, piceatannol treatment strongly decreased matrix metalloproteinase-9 (MMP-9) expression and promoter activity in a dose-dependent manner in response to TNF-alpha. It was further demonstrated that piceatannol abrogated the transcriptional activity of nuclear factor kappa B (NF-kappaB), an important nuclear transcription factor involved in MMP-9 expression. Overall, these results demonstrate that piceatannol inhibits proliferation and migration of VSMC treated with TNF-alpha. Therefore, piceatannol may be an effective therapeutic approach to treat atherosclerosis.
 ...
PMID:Inhibition of proliferation and migration by piceatannol in vascular smooth muscle cells. 1963 Dec 64

Blood cells participate in vital physiological processes, and their numbers are tightly regulated so that homeostasis is maintained. Disruption of key regulatory mechanisms underlies many blood-related Mendelian diseases but also contributes to more common disorders, including atherosclerosis. We searched for quantitative trait loci (QTL) for hematology traits through a whole-genome association study, because these could provide new insights into both hemopoeitic and disease mechanisms. We tested 1.8 million variants for association with 13 hematology traits measured in 6015 individuals from the Australian and Dutch populations. These traits included hemoglobin composition, platelet counts, and red blood cell and white blood cell indices. We identified three regions of strong association that, to our knowledge, have not been previously reported in the literature. The first was located in an intergenic region of chromosome 9q31 near LPAR1, explaining 1.5% of the variation in monocyte counts (best SNP rs7023923, p=8.9x10(-14)). The second locus was located on chromosome 6p21 and associated with mean cell erythrocyte volume (rs12661667, p=1.2x10(-9), 0.7% variance explained) in a region that spanned five genes, including CCND3, a member of the D-cyclin gene family that is involved in hematopoietic stem cell expansion. The third region was also associated with erythrocyte volume and was located in an intergenic region on chromosome 6q24 (rs592423, p=5.3x10(-9), 0.6% variance explained). All three loci replicated in an independent panel of 1543 individuals (p values=0.001, 9.9x10(-5), and 7x10(-5), respectively). The identification of these QTL provides new opportunities for furthering our understanding of the mechanisms regulating hemopoietic cell fate.
 ...
PMID:Sequence variants in three loci influence monocyte counts and erythrocyte volume. 1985 36

Excessive hyperplastic cell growth within occlusive vascular lesions has been recognized as a key component of the inflammatory response associated with atherosclerosis, restenosis post-angioplasty, and graft atherosclerosis after coronary artery bypass. Understanding the molecular mechanisms that regulate arterial cell proliferation is therefore essential for the development of new tools for the treatment of these diseases. Mammalian cell proliferation is controlled by a large number of proteins that modulate the mitotic cell cycle, including cyclin-dependent kinases, cyclins, and tumour suppressors. The purpose of this review is to summarize current knowledge about the role of these cell cycle regulators in the development of native and graft atherosclerosis that has arisen from animal studies, histological examination of specimens from human patients, and genetic studies.
 ...
PMID:Control of cell proliferation in atherosclerosis: insights from animal models and human studies. 1990 Sep 64


<< Previous 1 2 3 4 Next >>