ISSN:0009-7330    

出版商:OVID    

年代:1998

数据来源: OVID

ISSN:0009-7330    

出版商:OVID    

年代:1998

数据来源: OVID

ISSN:0009-7330    

出版商:OVID    

年代:1998

数据来源: OVID

ISSN:0009-7330    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

&NA;Intensive work over the past decade has been directed to the study of vascular gene transfer as an approach to the unresolved problem of restenosis. This effort has resulted in a significant foundation of knowledge relative to the activities of potentially therapeutic gene products as well as the capabilities and limitations of vector systems and mechanical delivery modalities available for effecting the vascular expression of these gene products. In several instances, significant progress has been made by experiments highlighting unexpected difficulties and the need for more comprehensive understanding. It is thus now possible to clearly define and address specific challenges that must be overcome in order to make feasible progress from the preclinical to the clinical arena. The key challenges at present appear to include the evolution of clinically practical delivery methods that meet the kinetic requirements of achieving efficient gene transduction and the availability of vectors that maximize efficiency while minimizing undesirable host responses. Emerging data suggest that approaches to solving each of these issues may have recently been developed. Basic research evaluating these new delivery mechanisms and molecular vectors is essential to establish their true potential for use in the clinical arena. (Circ Res. 1998;82:295‐305.)

ISSN:0009-7330    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

&NA;The application of gene therapy techniques to the clinical problem of coronary restenosis has generated tremendous attention and enthusiasm. Use of gene transfer technology to prevent a common intractable illness would represent a watershed event for human gene therapy. However, the time is not yet right to initiate gene therapy trials for restenosis. The biology of restenosis is incompletely understood, catheter‐based gene delivery is poorly adapted to the coronary circulation, and current gene transfer vectors are ill‐suited for safe and effective gene delivery to the coronary artery wall. Basic research designed to overcome these obstacles is currently more appropriate than the initiation of clinical trials. (Circ Res. 1998;82:306‐313.)

ISSN:0009-7330    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

&NA;The transcriptional regulatory protein nuclear factor‐kappa B (NF‐kappa B) participates in the control of gene expression of many modulators of the inflammatory and immune responses, including the adhesion molecules E‐selectin and intercellular adhesion molecule‐1 (ICAM‐1). NF‐kappa B is found in the cytoplasm complexed with its inhibitory protein I kappa B. On activation, I kappa B is phosphorylated and degraded, thereby freeing NF‐kappa B for translocation to the nucleus. We have generated populations of endothelial cells expressing wild‐type and a proteolysis‐resistant mutation of I kappa B that is lacking the 36 N‐terminal amino acids (I kappa B Delta N) in order to examine the effects of expression of the mutated I kappa B on tumor necrosis factor‐alpha (TNF‐alpha)‐induced E‐selectin and ICAM‐1 expression. Wild‐type and I kappa B Delta N were introduced into primary endothelial cells using retrovirus infection followed by selection with G418. The I kappa B Delta N protein remained at untreated control levels in endothelial cells treated with TNF‐alpha and also remained complexed with the NF‐kappa B family member p65. Furthermore, TNF‐alpha‐induced NF‐kappa B DNA binding activity was inhibited in the population of endothelial cells expressing I kappa B Delta N. That population of cells was also refractory to upregulation of E‐selectin and ICAM‐1 after treatment with TNF‐alpha. The use of a truncated I kappa B alpha protein to prevent NF‐kappa B‐mediated gene expression provides a novel and specific approach for investigating the role of NF‐kappa B in processes associated with adhesion molecule expression during inflammation. (Circ Res. 1998;82:314‐320.)

ISSN:0009-7330    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

&NA;In this study, anti‐basic fibroblast growth factor (anti‐bFGF) antibody was used to determine whether the mitogenic effect of angiotensin II in vivo could be blocked by neutralizing bFGF in the vessel wall. Animals, divided into six experimental groups, were given (1) angiotensin II, (2) angiotensin II+anti‐bFGF antibody, (3) angiotensin II+normal goat IgG (ngIgG), (4) anti‐bFGF antibody, (5) ngIgG, and (6) Ringer's solution. Angiotensin II at 435 ng [center dot] kg‐1[center dot] min (‐1) was infused into rats continuously for 1 week to induce smooth muscle cell replication, and anti‐bFGF antibody or ngIgG was injected intravenously 4 times over the 1‐week period at a dose of 60 mg/injection. Bromodeoxyuridine (30 mg/mL) was also continuously infused during the 1‐week period. The left carotid artery of all animals was balloon‐injured on day 4 of the treatment, and all groups were killed for study on day 7. The results showed that angiotensin II significantly stimulated smooth muscle replication in the balloon‐injured carotid artery, intact carotid artery, and three branch levels of the mesenteric vascular tree. Anti‐bFGF was able to block the mitogenic effect of angiotensin II in larger vessels but not the smallest (type I) microvessels of the mesenteric arterial tree. This differential response may be attributable to the nature of the lesions in type I vessels versus larger vessels: the type I vascular lesion has a large component of proliferating macrophages, whereas the larger vessels show less injury, few macrophages, and varying levels of smooth muscle replication. Our data suggest that the vessel wall remodeling in the angiotensin II‐treated larger vessels involves DNA replication that is dependent on the presence of bFGF. (Circ Res. 1998;82:321‐327.)

ISSN:0009-7330    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

&NA;The elastic properties of extensible tissues such as arteries and skin are mainly due to the presence of elastic fibers whose major component is the extracellular matrix protein elastin. Pathophysiological degradation of this protein leads to the generation of elastin peptides that have been identified in the circulation in the ng/mL to [micro sign]g/mL range. Similar concentrations of an elastin peptide preparation (kappa‐elastin) were previously demonstrated to induce, among other biological actions, a dose‐ and endothelium‐dependent vasorelaxation mediated by the elastin/laminin receptor and by endothelial NO production. To determine the elastin sequence(s) responsible for vasomotor activity and to learn more about possible signaling pathways, we have compared the action of different concentrations (10‐13to 10‐7mol/L) of recombinant human tropoelastin, eight synthetic elastin peptides, and a control peptide (VPVGGA) on both rat aortic ring tension and [Ca2+]iof cultured human umbilical vein endothelial cells. No vasoactivity could be detected for VPVGGA and for the elastin‐related sequences VGVGVA, PGVGVA, and GVGVA. Tropoelastin, VGV, PGV, and VGVAPG were found to induce an endothelium‐ and dose‐dependent vasorelaxation and to increase endothelial [Ca2+]i, whereas PVGV and VGVA produced these effects only at low concentration (10‐11mol/L). A likely candidate for mediating the elastin peptide‐related effects is the elastin/laminin receptor, since the presence of lactose strongly inhibited the vasoactivity associated with these compounds. Our results show that although the flanking amino acids modulate its activity, VGV seems to be the core sequence recognized by the elastin receptor. (Circ Res. 1998;82:328‐336.)

ISSN:0009-7330    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

&NA;Angiotensin II (Ang II) induces hypertrophy of cardiac myocytes and hyperplasia of cardiac fibroblasts. To determine the molecular mechanism by which Ang II displayed different effects on cardiac myocytes and fibroblasts, we examined signal transduction pathways leading to activation of extracellular signal‐regulated kinases (ERKs). Ang II‐induced ERK activation was abolished by pretreatment with pertussis toxin and by overexpression of the Gbetagamma subunit‐binding domain of the beta‐adrenergic receptor kinase 1 in cardiac fibroblasts but not in cardiac myocytes. Inhibition of protein kinase C strongly inhibited activation of ERKs by Ang II in cardiac myocytes, whereas inhibitors of tyrosine kinases but not of protein kinase C abolished Ang II‐induced ERK activation in cardiac fibroblasts. Overexpression of C‐terminal Src kinase (Csk), which inactivates Src family tyrosine kinases, suppressed the activation of transfected ERK in cardiac fibroblasts. Ang II rapidly induced phosphorylation of Shc and association of Shc with Grb2. Cotransfection of the dominant‐negative mutant of Ras or Raf‐1 kinase abolished Ang II‐induced ERK activation in cardiac fibroblasts. Overexpression of Csk or the dominant‐negative mutant of Ras had no effects on Ang II‐induced ERK activation in cardiac myocytes. These findings suggest that Ang II‐evoked signal transduction pathways differ among cell types. In cardiac fibroblasts, Ang II activates ERKs through a pathway including the Gbetagamma subunit of Giprotein, tyrosine kinases including Src family tyrosine kinases, Shc, Grb2, Ras, and Raf‐1 kinase, whereas Gqand protein kinase C are important in cardiac myocytes. (Circ Res. 1998;82:337‐345.)

ISSN:0009-7330    

出版商:OVID    

年代:1998

数据来源: OVID