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)

Interaction between cultured endothelial cells (EC) and pericytes (PC) was studied in vitro to clarify the mechanism of diabetic proliferative retinopathy. Conditioned medium (CM) from retinal PC strongly increased the proliferation and moderately stimulated migration of retinal EC. Moreover, CM from PC caused stimulation of angiogenesis of retinal EC and umbilical cord vein EC in vitro at the same extent as basic fibroblast growth factor (bFGF). PC also stimulated angiogenesis by EC in mixed cultures. The angiogenic, proliferative and migration activities in CM from PC were inhibited by an antibody to bFGF. These data suggest that PC play an important role in angiogenesis through secretion of an FGF-like molecule.
Atherosclerosis 1997 Apr
PMID:Cultured retinal pericytes stimulate in vitro angiogenesis of endothelial cells through secretion of a fibroblast growth factor-like molecule. 912 53

Basic fibroblast growth factor (bFGF) is a mitogenic factor that is implicated in smooth muscle cell growth in atherosclerosis and vascular restenosis. In this study, we examined the effect of bFGF on the expression of the interstitial collagenase gene in human vascular smooth muscle cells. Results from Northern transfer analysis showed that bFGF increased collagenase mRNA levels greater than threefold as early as 24 h. Collagenase pre-mRNA levels were elevated approximately threefold by bFGF, according to RT-PCR analysis. Transient transfections of the smooth muscle cells with a 4.4-kb human collagenase promoter-CAT reporter gene, however, failed to show upregulation of the promoter activity by bFGF. Interestingly, transfections with deleted fragments containing promoter sequences from -1047 to -2271 resulted in modest stimulation of the collagenase-CAT promoter activity by bFGF, bFGF did not alter the stability of the collagenase mRNA, as demonstrated by degradation studies. The enhanced collagenase mRNA levels elicited by bFGF were reflected in increased amounts of collagenase protein that were detected by Western blot analysis. In summary, bFGF upregulates the interstitial collagenase expression, resulting in turnover of the extracellular matrix, an event that could facilitate smooth muscle cell migration and proliferation during the early stages of atherosclerosis and restenosis.
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PMID:Basic FGF regulates interstitial collagenase gene expression in human smooth muscle cells. 913 78

A cyclic peptide analogue of platelet-derived growth factor-BB (PDGF-BB), P1 [77IVRKK81-C-73RKIE76], has recently been shown to inhibit specifically [125I]PDGF-BB/receptor binding, and PDGF-BB-induced DNA synthesis in cells expressing PDGF receptors. Here we demonstrate that P1 induces apoptosis in exponentially growing human fibroblasts as confirmed by characteristic changes in cell and nuclear morphology, by TUNEL staining and by flow cytometry. Following incubation with P1 (100 microM), the percentage of cells exhibiting DNA fragmentation increased from 24% after 8 h to 76% after 28 h as exponentially growing cells progressed through the cell cycle. We conclude from these findings taken together that apoptosis accounts for the major proportion of P1-induced cell death. Omission of the Cys residue from P1 or replacement by Ser did not alter the potency of the peptide confirming that peptide dimerisation is not important for its activity. PDGF-BB, EGF, FGF, thrombin and foetal bovine serum were not able to rescue cells from the effects of P1. P1 is a useful tool for investigation of the balance of cellular proliferation/apoptosis in wound healing, atherosclerosis and restenosis, and constitutes a basis from which to design compounds with greater potency.
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PMID:A cyclic peptide analogue of loop III of PDGF-BB causes apoptosis in human fibroblasts. 942 27

The vasoactive hormone angiotensin II (Ang II) can stimulate vascular smooth muscle cell (SMC) hypertrophy and proliferation; thus, it may have an important role in the pathogenesis of hypertension, atherosclerosis and restenosis. Several studies have indicated that Ang II bioactivity on SMC may depend, at least in part, on its ability to induce the expression of polypeptide growth factors that can function in an autocrine manner. Here we report that Ang II treatment of rat aortic SMC increases fibroblast growth factor-2 (FGF-2) but not FGF-1 mRNA levels. Increased FGF-2 mRNA expression is first detectable at 30 min after Ang II addition and maximal levels are present at 8 hr. Ang II induction of FGF-2 mRNA levels is dependent on de novo RNA and protein synthesis. The Ang II effect can be blocked by treatment with either the Ang II type 1 receptor-selective antagonist CI-996 or the tyrosine kinase inhibitor genistein. The potent vasoconstrictor and SMC mitogen endothelin-1 can also induce FGF-2 mRNA levels in rat aortic SMC. These results indicate that FGF-2 gene expression is up-regulated by two distinct vasoactive peptides implicated in vascular SMC growth control in vivo.
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PMID:Angiotensin II and endothelin-1 increase fibroblast growth factor-2 mRNA expression in vascular smooth muscle cells. 943 36

Vascular smooth muscle cells (SMCs), the major cellular constituent of an artery, synthesize the bulk of fibrillar collagens, including type V/XI, which regulates heterotypic collagen fibril assembly. Basic fibroblast growth factor (bFGF) is a heparin-binding polypeptide growth factor that has been implicated in important events during the development of atherosclerosis, such as early intimal SMC proliferation. Here we have investigated the effects of bFGF on aortic SMC expression of type V/XI collagen. Treatment of exponentially growing or serum-deprived subconfluent cultures of bovine aortic SMCs with bFGF decreased the steady-state levels of the mRNAs for collagen type V/XI, including alpha 1(V), alpha 2(V), and alpha 1(XI). The effect of bFGF was time dependent with a two- and a fourfold decrease in alpha 2(V) mRNA observed after treatment for 24 and 48 h, respectively. This decrease resulted from a drop in the rate of alpha 2(V) gene transcription; no change was observed in the stability of the alpha 2(V) mRNA. Furthermore, accumulation of collagen protein decreased upon bFGF treatment. As expected, treatment with bFGF increased the rate of proliferation of serum-deprived SMCs, as judged by DNA content in the cultures, thymidine incorporation, and steady-state mRNA levels of the S-phase-expressed histone H3.2. These results suggest that bFGF plays an important role in the regulation of collagen fibril structure, with potential implications for the development and organization of an atherosclerotic lesion.
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PMID:Basic fibroblast growth factor decreases type V/XI collagen expression in cultured bovine aortic smooth muscle cells. 944 80

Recombinant FGF-2-SAP is a mitotoxin consisting of the plant-derived ribosome-inactivating toxin saporin (SAP) fused to basic fibroblast growth factor (FGF-2). FGF-2-SAP targets and kills cells bearing upregulated FGF receptors. In vivo, FGF-2-SAP inhibits smooth muscle cell hyperplasia in models of restenosis. The present study examined the potential for a differential effect of FGF-2-SAP on canine vascular endothelial cells (EC) and smooth muscle cells (SMC) separately as well as in a novel co-culture model. Canine vascular SMC and EC cultures were established separately and made quiescent once cells reached 80% confluence. Following the release from growth arrest, both cell types were treated with FGF-2-SAP, or FGF-2, or SAP alone for 48 h. [3H]TdR incorporation was used to determine the growth response of SMC and EC. The co-culture system was created by plating canine vascular SMC and EC on either side of a microporous 13 microm thick polyester membrane insert. Both cell types were grown to 80% confluence and independently made quiescent. Following the release from growth arrest, cells were treated with FGF-2-SAP, or FGF-2, or SAP alone. Negative and positive control groups were untreated wells containing phosphate buffered saline and complete growth media, respectively. After 48 h, both [3H]TdR incorporation and total DNA content, by fluorometric measurement, were quantitated in SMC and EC independently. FGF-2-SAP showed a concentration-dependent cytotoxicity in both canine SMC and EC but cytotoxicity for EC required substantially higher concentrations. In co-cultured SMC, FGF-2-SAP significantly decreased both [3H]TdR uptake and total DNA content at 0.5, 5, 50, and 500 ng/ml (0.01-10 nM) compared to positive controls. In co-cultured EC, FGF-2-SAP decreased [3H]TdR uptake at 50 and 500 ng/ml and total DNA content at 500 ng/ml compared to positive controls. Neither SAP alone nor FGF-2 alone showed a significant effect on [3H]TdR uptake or DNA content of either SMC or EC. In this unique co-culture model, which better replicates the relationship between SMC and EC in vivo, we demonstrated a dose-response range of FGF-2-SAP at which both the proliferation and total cell number of SMC, but not EC, is significantly reduced. These data suggest that FGF-2-SAP may have therapeutic utility in inhibiting myointimal hyperplasia in the absence of a deleterious effect on regenerating endothelium following vascular reconstructions.
Atherosclerosis 1998 Apr
PMID:Fibroblast growth factor-2-toxin induced cytotoxicity: differential sensitivity of co-cultured vascular smooth muscle cells and endothelial cells. 962 71

Fibroblast growth factor 1 (FGF-1, also known as acidic FGF) is a mitogen for a variety of mesoderm- and neuroectoderm-derived cells, as well as an angiogenic factor in vivo. It has been implicated in angiogenic diseases including atherosclerosis, cancer and inflammatory diseases. In the present study, the entire transcriptional unit of the mouse FGF-1 gene, including four promoters, is characterized. By nucleotide sequence and RNase protection analyses, we have determined that its 3'-end resides 3.2 kilobase pairs downstream from the stop codon. We have previously cloned and characterized the mouse homologue of the human 1B promoter, as well as a novel upstream untranslated exon. In order to elucidate the regulatory mechanism of FGF-1 gene expression, the mouse promoter containing TATA and CAAT consensus sequences (FGF-1. A) was isolated from a P1 library and characterized. We further determined that the mouse heart is the most abundant source for the FGF-1.A mRNA. Finally, via both RNase protection analysis and 5'-rapid amplification of cDNA ends, we determined the transcription start site of the FGF-1.A mRNA.
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PMID:Characterization of the entire transcription unit of the mouse fibroblast growth factor 1 (FGF-1) gene. Tissue-specific expression of the FGF-1.A mRNA. 1020 15

Chronic rejection of transplanted organs is manifested as atherosclerosis of the blood vessels of the allograft. HLA class I Ags have been implicated to play a major role in this process, since signaling via HLA class I molecules can induce the proliferation of aortic endothelial as well as smooth muscle cells. In this study, we show that HLA class I-mediated induction of cell proliferation correlates with inactivation of the Rb protein in the T cell line Jurkat as well as human aortic endothelial cells. HLA class I-mediated inactivation of Rb can be inhibited specifically by neutralizing Abs to basic fibroblast growth factor (bFGF), suggesting a role for FGF receptors in the signaling process. Signaling through HLA class I molecules induced cyclin E-associated kinase activity within 4 h in quiescent endothelial cells, and appeared to mediate the inactivation of Rb. A cdk2 inhibitor, Olomoucine, as well as a dominant-negative cdk2 construct prevented HLA class I-mediated inactivation of Rb; in contrast, dominant-negative cdk4 and cdk6 constructs had no effect. Furthermore, there was no increase in cyclin D-associated kinase activity upon HLA class I ligation, suggesting that cyclin E-dependent kinase activity mediates Rb inactivation, leading to E2F activation and cell proliferation.
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PMID:HLA class I-mediated induction of cell proliferation involves cyclin E-mediated inactivation of Rb function and induction of E2F activity. 1022 11

Peptide growth factors such as PDGF, FGF, VEGF, and TGF-beta play a critical role in the pathogenesis of cardiovascular diseases. In addition to their pathophysiological role in atherosclerosis and myocardial remodeling, growth factors also promote beneficial effects such as stimulation of angiogenesis and formation of collateral vessels in ischemic tissue. This review focuses on the mechanisms of action and signal relay cascades of peptide growth factors, and summarizes novel therapeutic approaches in cardiovascular medicine. These approaches include both inhibition of growth factors in order to suppress pathogenic processes, and stimulation of growth factors to promote their beneficial effects.
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PMID:[Pathophysiologic significance of growth factors and new therapeutic concepts in cardiovascular disease]. 1054 12

Gene therapy for the treatment of atherosclerosis and related diseases has shown its potential in animal models and in the first human trials. Gene transfer to the vascular system can be performed both via intravascular and extravascular periadventitial routes. Intravascular gene transfer can be done with several types of catheters under fluoroscopic control. Extravascular gene transfer, on the other hand, provides a well-targeted gene delivery route available during vascular surgery. It can be done with direct injection or by using perivascular cuffs or surgical collagen sheets. Ex vivo gene delivery via transfected smooth muscle cells or endothelial cells might be useful for the production of secreted therapeutic compounds. Gene transfer to the liver has been used for the treatment of hyperlipidemia. The first clinical trials for the induction of therapeutic angiogenesis in ischemic myocardium or peripheral muscles with VEGF or FGF gene transfer are under way and preliminary results are promising. VEGF has also been used for the prevention of postangioplasty restenosis because of its capability to induce endothelial repair and production of NO and prostacyclin. However, further basic research is needed to fully understand the pathophysiological mechanisms involved in conditions related to atherosclerosis. Also, further development of gene transfer vectors and gene delivery techniques will improve the efficacy and safety of human gene therapy.
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PMID:Insights into the molecular pathogenesis of atherosclerosis and therapeutic strategies using gene transfer. 1073 55


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