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)

There is currently intense interest in the development of gene therapy for cardiovascular disease. The stimulation of therapeutic angiogenesis for ischemic heart disease has been one of the areas of greatest promise. Encouraging results have been obtained with the angiogenic cytokines vascular endothelial growth factor (VEGF) and basic fibroblast growth factor in animal models, leading to clinical trials in ischemic heart disease. VEGF also has therapeutic potential in a second area of cardiovascular gene therapy, the enhancement of arterioprotective endothelial functions to prevent postangioplasty restenosis and bypass graft arteriopathy. The endothelial cell growth and survival functions of VEGF promote endothelial regeneration, whereas VEGF-induced endothelial production of NO and prostacyclin inhibits vascular smooth muscle cell proliferation. Inhibition of neointimal hyperplasia may also be achieved by gene transfer of endothelial NO synthase (eNOS), PGI synthase, or cell cycle regulators (retinoblastoma, cyclin or cyclin-dependent kinase inhibitors, p53, growth arrest homeobox gene, fas ligand) or antisense oligonucleotides to c-myb, c-myc, proliferating cell nuclear antigen, and transcription factors such as nuclear factor kappaB and E2F. An improved understanding of etiologically complex pathologies involving the interplay of genes and the environment, such as atherosclerosis and systemic hypertension, has led to the identification of new targets for gene therapy, with the potential to alleviate inherited genetic defects such as familial hypercholesterolemia. The use of vasodilator gene overexpression and antisense knockdown of vasoconstrictors to reduce blood pressure in animal models of systemic and pulmonary hypertension offers the prospect of gene therapy for human hypertensive disease. The renin-angiotensin system has been the target of choice for antihypertensive strategies because of its wide distribution and additional effects on fibrinolytic and oxidative stress pathways. Gene therapy in cardiovascular disease has an exciting future but remains at an early stage. Further developments in gene transfer vector technology and the identification of additional target genes will be required before its full therapeutic potential can be realized.
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PMID:Gene therapy for cardiovascular disease: a case for cautious optimism. 1171 25

We recently demonstrated that ceramide-coated balloon catheters limit vascular smooth muscle cell (VSMC) growth after stretch injury in vivo. In that study, inhibition of VSMC growth was correlated with a decrease in phosphorylation of the cell survival kinase Akt (protein kinase B). Utilizing cultured A7r5 VSMCs, we have now examined the mechanism by which ceramide inhibits Akt phosphorylation/activation. Our initial studies showed that ceramide-induced inhibition of Akt phosphorylation was not mediated through diminution in phosphoinositide 3-kinase activity. As we have previously demonstrated that protein kinase Czeta (PKCzeta) is a target of ceramide, we proposed an alternative signaling mechanism by which ceramide induces inhibition of Akt through activation of PKCzeta. We demonstrate that C(6)-ceramide (but not the inactive analog dihydro-C(6)-ceramide) induced PKCzeta activity and also caused a selective increase in the association between Akt and PKCzeta, without affecting PKCepsilon, in A7r5 cells. In addition, the ability of ceramide to significantly decrease platelet-derived growth factor-induced Akt phosphorylation or cell proliferation was abrogated in A7r5 cells overexpressing a dominant-negative mutant of PKCzeta. Taken together, these data suggest that ceramide-mediated activation of PKCzeta leads to diminished Akt activation and consequent growth arrest in VSMCs. The therapeutic potential for ceramide to limit dysregulated VSMC growth has direct applicability to vascular diseases such as restenosis and atherosclerosis.
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PMID:Ceramide-induced inhibition of Akt is mediated through protein kinase Czeta: implications for growth arrest. 1172 39

Vascular smooth muscle cell (VSMC) proliferation is a key feature in the development of atherosclerosis and restenosis after angioplasty, which can occur in response to many different humoral and mechanical stimuli. We investigated the growth promoting activities of two potent vasoactive substances, angiotensin II (Ang II) and serotonin (5-HT), on cultured rabbit VSMCs. Growth-arrested VSMCs were incubated with serum-free medium containing different concentrations of Ang II in the presence or absence of 5-HT. [3H]thymidine incorporation into VSMC DNA was measured as an index of cell proliferation. Ang II and 5-HT stimulated DNA synthesis in a dose-dependent manner with a maximal effect at 1.75 microM for Ang II (202%) and 50 microM for 5-HT (205%). When added together, low concentrations of Ang II (1 microM) and 5-HT (5 microM) synergistically induced DNA synthesis (363%). Candesartan (1 microM), an AT(1) receptor antagonist, but not PD 123319 (1 microM), an AT(2) receptor antagonist, inhibited the mitogenic effect on Ang II and its interaction with 5-HT. Sarpogrelate (10 microM), a 5-HT(2A) receptor antagonist, and pertussis toxin (10 ng/ml) inhibited the mitogenic effect of 5-HT and its interaction with Ang II. The protein kinase C inhibitor Ro 31-8220 (0.1 microM), the Raf-1 inhibitor radicicol (10 microM), and the MAPK kinase inhibitor PD 098059 (10 microM) abolished mitogenic effects of Ang II and 5-HT, and also their synergistic interaction. The JAK2 inhibitor AG 490 (10 microM) had only a minimal inhibitory effect of Ang II-induced DNA synthesis but significantly inhibited the interaction of Ang II with 5-HT. The synergistic effect on Ang II (1 microM) with 5-HT (5 microM) on DNA synthesis was completely reversed by the combined use of both candesartan (1 microM) and sarpogrelate (10 microM). Our results suggest that Ang II and 5-HT exert a synergistic interaction on VSMC proliferation via AT(1) and 5-HT(2A) receptors. The activation of MAPK and JAK/STAT pathways may explain the synergistic interaction between Ang II and 5-HT.
Atherosclerosis 2001 Dec
PMID:Serotonin potentiates angiotensin II--induced vascular smooth muscle cell proliferation. 1173 Aug 6

Dehyroepiandrosterone (DHEA), an adrenal-derived steroid, has been clinically implicated in protection against coronary artery disease and experimentally in inhibition of atherosclerosis and plaque progression. Because DHEA is enzymatically metabolized to androgens or estrogens, it is not clear whether DHEA exerts effects directly or after conversion to these hormones, both of which are associated with well-characterized pathways of action. We therefore examined the effects of DHEA on proliferation of human vascular smooth muscle cells (VSMCs) in culture in the presence or absence of the ER antagonist ICI 182,780 and the AR antagonist flutamide and compared them with the effects of 17beta-estradiol, androstenedione, and T. We also determined the affinity of DHEA for ERs and ARs in VSMC and its specific binding in intact cells. To explore a possible mechanism for DHEA action in these cells, we measured the phosphorylation of ERK-1, c-jun N-terminal protein kinase, and p38 (three members of the MAPK superfamily). Both DHEA and 17beta-estradiol significantly inhibited platelet derived growth factor (PDGF)-BB-induced increases in VSMC proliferation, whereas androstenedione and T increased proliferation. Although E2-induced inhibition of the PDGF effect was abolished by ICI 182,780 and T-induced stimulation was abolished by flutamide, neither receptor antagonist altered the inhibitory effect of DHEA. Binding studies confirmed the presence of both ERs and ARs; DHEA showed minimal affinity for either receptor but bound specifically and with high affinity to putative receptors in intact cells. Following 4-h incubation with DHEA (1-100 nM), ERK1 phosphorylation was significantly reduced in a dose-dependent manner, whereas neither c-jun N-terminal protein kinase nor p38 kinase activity was altered by either PDGF-BB or DHEA. DHEA inhibits human VSMC proliferation by a mechanism independent of either ARs or ERs, presumably via a DHEA-specific receptor that involves ERK1 signaling pathways.
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PMID:Dehydroepiandrosterone inhibits human vascular smooth muscle cell proliferation independent of ARs and ERs. 1178 44

Atherosclerosis preferentially occurs in areas of turbulent flow and low fluid shear stress, whereas laminar flow and high shear stress are atheroprotective. Inflammatory cytokines, such as tumor necrosis factor-alpha (TNF), have been shown to stimulate expression of endothelial cell (EC) genes that may promote atherosclerosis. Recent data suggest that steady laminar flow decreases EC apoptosis and blocks TNF-mediated EC activation. EC apoptosis is likely important in the process termed "plaque erosion" that leads to platelet aggregation. Steady laminar flow inhibits EC apoptosis by preventing cell cycle entry, by increasing antioxidant mechanisms (e.g., superoxide dismutase), and by stimulating nitric oxide-dependent protective pathways that involve enzymes PI3-kinase and Akt. Conversely, our laboratory has identified nitric oxide-independent mechanisms that limit TNF signal transduction. TNF regulates gene expression in EC, in part, by stimulating mitogen-activated protein kinases (MAPK) which phosphorylate transcription factors. We hypothesized that fluid shear stress modulates TNF effects on EC by inhibiting TNF-mediated activation of MAP kinases. To test this hypothesis, we determined the effects of steady laminar flow (shear stress = 12 dynes/cm2) on TNF-stimulated activity of two MAP kinases: extracellular signal regulated kinase (ERK1/2) and c-Jun N-terminal kinase (JNK). Flow alone stimulated ERK1/2 activity, but decreased JNK activity compared to static controls. TNF (10 ng/ml) alone activated both ERK1/2 and JNK maximally at 15 minutes in human umbilical vein EC (HUVEC). Pre-exposing HUVEC for 10 minutes to flow inhibited TNF activation of JNK by 46%, but it had no significant effect on ERK1/2 activation. Incubation of EC with PD98059, a specific mitogen-activated protein kinase kinase inhibitor, blocked the flow-mediated inhibition of TNF activation of JNK. Flow-mediated inhibition of JNK was unaffected by 0.1 mM L-nitroarginine, 100 pM 8-bromo-cyclic GMP, or 100 microM 8-bromo-cyclic AMP. Transfection studies with dominant negative constructs of the protein kinase MEK1 and MEK5 suggested an important role for BMK1 in flow-mediated regulation of TNF signals. In summary, the atheroprotective effects of steady laminar flow on the endothelium involve multiple synergistic mechanisms.
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PMID:Endothelial atheroprotective and anti-inflammatory mechanisms. 1179 13

Lipid oxidation products promote atherosclerosis and may also affect osteoporosis. We showed previously that oxidized lipids including 8-isoprostaglandin E2 (isoPGE2) inhibit osteoblastic differentiation of preosteoblasts. Since osteoporosis is mediated both by decreased osteoblastic bone formation and by increased osteoclastic bone resorption, we assessed whether oxidized lipids regulate the osteoclastic potential of marrow hematopoietic cells. Treatment of marrow-derived preosteoclasts with isoPGE2 enhanced osteoclastic differentiation as evidenced by increased tartrate-resistant acid phosphatase (TRAP) activity and multinucleation, which were inhibited by calcitonin, and increased numbers of resorption pits. The enhanced osteoclastic differentiation by isoPGE2 was observed whether preosteoclasts were in coculture with stromal cells or in monoculture in the presence of receptor-activated NFkappaB ligand (RANKL) and macrophage colony-stimulating factor. Receptor antagonist studies suggest that isoPGE2 effects were mediated by prostaglandin receptor subtypes EP2/DP on preosteoclasts and subtype EP1 and thromboxane receptors on stromal/osteoblast cells. The enhanced TRAP activity was also inhibited by cAMP-dependent protein kinase inhibitors, and isoPGE2 elevated intracellular cAMP levels of preosteoclast monocultures. Other oxidized lipids also enhanced the TRAP activity of preosteoclast monocultures. These data suggest that isoPGE2 enhances osteoclastic differentiation of marrow preosteoclasts and that this regulation occurs via the cAMP-dependent protein kinase pathway.
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PMID:8-Isoprostaglandin E2 enhances receptor-activated NFkappa B ligand (RANKL)-dependent osteoclastic potential of marrow hematopoietic precursors via the cAMP pathway. 1182 70

Interactions among growth factors, cells, and extracellular matrix regulate proliferation during normal development and in pathologies such as atherosclerosis. SPARC (secreted protein, acidic, and rich in cysteine) is a matrix-associated glycoprotein that modulates the adhesion and proliferation of vascular cells. In this study, we demonstrate that SPARC inhibits human arterial smooth muscle cell proliferation stimulated by platelet-derived growth factor or by adhesion to monomeric type I collagen. Binding studies with SPARC and SPARC peptides indicate specific and saturable interaction with smooth muscle cells that involves the C-terminal Ca2+-binding region of the protein. We also report that SPARC arrests monomeric collagen-supported smooth muscle cell proliferation in the late G1-phase of the cell cycle in the absence of an effect on cell shape or on levels of cyclin-dependent kinase inhibitors. Cyclin-dependent kinase-2 activity, p107 and cyclin A levels, and retinoblastoma protein phosphorylation are markedly reduced in response to the addition of exogenous SPARC and/or peptides derived from specific domains of SPARC. Thus, SPARC, previously characterized as an inhibitor of platelet-derived growth factor binding to its receptor, also antagonizes smooth muscle cell proliferation mediated by monomeric collagen at the level of cyclin-dependent kinase-2 activity.
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PMID:Inhibition of PDGF-stimulated and matrix-mediated proliferation of human vascular smooth muscle cells by SPARC is independent of changes in cell shape or cyclin-dependent kinase inhibitors. 1183 1

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

Urotensin II (U II) is the most potent vasoconstrictor identified in vivo, which plays an important role in the smooth muscle cell proliferation in atherosclerosis. All available information suggests that focal adhesion kinase (FAK) is at the crossroads of multiple signaling pathways and is essential for cell proliferation. But the effect of U II on the FAK mediated signal transduction pathway is unclear. In this study, FAK content and tyrosine phosphorylation were assessed by Western blot and immunoprecipitation in cultured rat vascular smooth muscle cells. Increased protein tyrosine phosphorylation was observed within 5 min of U II 10(-7) (mol/L) addition and was maximal by 30 min, while FAK protein content showed no change during the first 30 min but it increased at 2 h reaching a plateau by 4 h, and decreased after 6 h. In addition, the elevated phosphorylation of FAK was detected upon U II stimulation at 10(-8) mol/L, being maximal at 10(-7) mol/L, but decreased at 10(-6) mol/L. Treatment of the cells with cytochalasin B (50 micromol/L), which disrupted the organization of cytoskeleton, had no influence on the increased FAK tyrosine phosphorylation in response to U sti II mulation. In order to study the relationship between FAK and mitogen-activated protein kinase, calmodulin and protein kinase C, selective inhibitors PD98059 (50 micromol/L), W7 (50 micromol/L) and H7 (50 micromol/L) were added following U II treatment. Neither PD98059 nor W7 influenced the increased FAK tyrosine phosphorylation, but H7 further increased it. These findings indicate that FAK activation is independent of the integrity of cytoskeleton and closely related to protein kinase C, but had no relation with mitogen activated protein kinase and calmodulin.
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PMID:[Content and activity of the focal adhesion kinase in cultured vascular smooth muscle cells enhanced by urotensin II]. 1194 6

Hyperinsulinemia has been shown to be associated with diabetic angiopathy. Migration and proliferation of vascular smooth muscle cells (VSMC) are the processes required for the development of atherosclerosis. In this study, we attempted to determine whether insulin affects mitogenic signaling induced by platelet-derived growth factor (PDGF) in a rat VSMC cell line (A10 cells). PDGF stimulated DNA synthesis which was totally dependent on Ras, because transfection of dominant negative Ras resulted in complete loss of PDGF-stimulated DNA synthesis. Initiation of DNA synthesis was preceded by activation of Raf-1, MEK and MAP kinases (Erk 1 and Erk2). Treatment of the cells with PD98059, an inhibitor of MAPK kinase (MEK) attenuated but did not abolish PDGF-stimulated DNA synthesis, suggesting that MAPK is required but not essential for DNA synthesis. PDGF also stimulated phosphorylation of protein kinase B (Akt/PKB) and p70 S6Kinase (p70S6K) in a wortmannin-sensitive manner. Rapamycin, an inhibitor of p70S6K, markedly suppressed DNA synthesis. Low concentrations of insulin (1-10 nmol/l) alone showed little mitogenic activity and no significant effect on MAPK activity. However, the presence of insulin enhanced both DNA synthesis and MAPK activation by PDGF. The enhancing effect of insulin was not seen in cells treated with PD98059. Insulin was without effect on PDGF-stimulated activations of protein kinase B (Akt/PKB) and p70S6K. We conclude that insulin, at pathophysiologically relevant concentrations, potentiates the PDGF-stimulated DNA synthesis, at least in part, by potentiating activation of the MAPK cascade. These results are consistent with the notion that hyperinsulinemia is a risk factor for the development of atherosclerosis.
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PMID:Potentiation of mitogenic activity of platelet-derived growth factor by physiological concentrations of insulin via the MAP kinase cascade in rat A10 vascular smooth muscle cells. 1199 Nov 99


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