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Biomedical subjects

G H Gibbons

Publications and source records attributed to G H Gibbons.

At least 19 recordsLinked to original sources
PubMed2002

Apolipoprotein E-deficient mice created by systemic administration of antisense oligodeoxynucleotides: a new model for lipoprotein metabolism studies.

Atherosclerotic cardiovascular disease results from complex interactions among multiple genetic and environmental factors. Thus, it is important to elucidate the influence of each factor on cholesterol metabolism. For this purpose, transgenic/gene-targeting technology is a powerful tool for studying gene functions. However, this technology has several disadvantages such as being time consuming and expensive. Accordingly, we established new animal models using in vivo gene transfer technology. In this study, we examined the feasibility of the creation of a new animal model for the study of atherosclerosis. We hypothesized that apolipoprotein (apo) E-deficient mice can be created by systemic administration of antisense apo E oligodeoxynucleotides (ODN) coupled to the HVJ-liposome complex. Initially, we examined the localization and cellular fate of FITC-labeled antisense ODN administered intravenously. FITC-labeled ODN transfection by the HVJ-liposome method resulted in fluorescence in the liver, spleen and kidney, but not in other organs such as brain. Moreover, fluorescence with the HVJ-liposome method was sustained for up to 2 weeks after transfection, which resulted in a striking difference from transfection of ODN alone or ODN in liposomes without HVJ, which showed rapid disappearance of fluorescence (within 1 day). Given these unique characteristics of the HVJ-liposome method, we next examined transfection of antisense apo E ODN by intravenous administration. Transfection of antisense apo E ODN resulted in a marked reduction of apo E mRNA levels in the liver, but no change in apo B and beta-actin mRNA levels. In mice fed a normal diet, a transient increase in cholesterol and triglyceride levels was observed in the antisense apo E-treated group, but they returned to normal levels by 6 days after transfection. Similar findings were also found in mice fed a high cholesterol diet. Neither scrambled nor mismatched ODN resulted in any increase in cholesterol. To make chronic hypercholesterolemic mice, we therefore performed repeated injections of apo E antisense ODN. Whenever antisense apo E ODN were injected, mice showed a transient increase in cholesterol and triglyceride. Cumulative administration of antisense apo E ODN resulted in a sustained increase in cholesterol for up to 3 weeks after the last transfection. Finally, mice treated with repeated injections of antisense apo E every week developed sustained hypercholesterolemia and hypertriglyceridemia until withdrawal of injections. Apolipoprotein-deficient mice created by intravenous administration of antisense ODN are a promising new animal model to help understand the role of apolipoprotein in vivo and develop a new drug therapy targeting apolipoprotein.

Animals↗
PubMed2001

Overexpression of Ref-1 inhibits hypoxia and tumor necrosis factor-induced endothelial cell apoptosis through nuclear factor-kappab-independent and -dependent pathways.

We hypothesized that a redox-sensitive transcription factor, redox factor-1 (Ref-1) (HAP1, APE, and APEX), was critical in the regulation of endothelial cell survival in response to hypoxia and cytokines, including tumor necrosis factor (TNF)-alpha. Hypoxia resulted in a significant decrease in Ref-1 protein expression in both human umbilical vein endothelial cells and calf pulmonary artery endothelial cells. The hypoxia-induced decrease in Ref-1 expression was followed by a significant induction of apoptosis as measured by caspase 3 activity and nuclear morphology. Transient upregulation of Ref-1 significantly inhibited hypoxia-induced apoptosis. However, deletion of the redox-sensitive domain of Ref-1 abolished the antiapoptotic effect. We postulated that the antiapoptotic effects of Ref-1 were mediated through nuclear factor-kappaB (NF-kappaB). However, blockade of NF-kappaB with a dominant-negative IkappaB (S32A/S36A) expression vector had no effect on Ref-1-mediated survival under hypoxic conditions. The second aim of this study was to test the cytoprotective ability of Ref-1 upregulation in response to TNF-induced apoptosis. Ref-1 inhibition of TNF-induced death was associated with a significant potentiation of NF-kappaB activity. Deletion of the redox-sensitive domain of Ref-1 significantly inhibited TNF-induced NF-kappaB activation. Moreover, loss of the redox-sensitive domain also abolished the antiapoptotic effect of Ref-1 in response to TNF. To test whether Ref-1 induced activation of NF-kappaB was necessary to promote survival, we blocked NF-kappaB activity with a dominant-negative IkappaB (S32A/S36A). Indeed, blockade of NF-kappaB activity abolished the ability of Ref-1 to rescue TNF-induced apoptosis. In conclusion, upregulation of Ref-1 promotes endothelial cell survival in response to hypoxia and TNF through NF-kappaB-independent and NF-kappaB-dependent signaling cascades, respectively. Moreover, it seems that Ref-1 may act as a critical cofactor, mediating the TNF-induced NF-kappaB response in the vascular endothelium.

Animals↗
PubMed2001

Upregulation of glucose metabolism during intimal lesion formation is coupled to the inhibition of vascular smooth muscle cell apoptosis. Role of GSK3beta.

The purpose of this study was to define the role of metabolic regulatory genes in the pathogenesis of vascular lesions. The glucose transporter isoform, GLUT1, was significantly increased in the neointima after balloon injury. To define the role of GLUT1 in vascular biology, we established cultured vascular smooth muscle cells (VSMCs) with constitutive upregulation of GLUT1, which led to a threefold increase in glucose uptake as well as significant increases in both nonoxidative and oxidative glucose metabolism as assessed by 13C-nuclear magnetic resonance spectroscopy. We hypothesized that the differential enhancement of glucose metabolism in the neointima contributed to formation of lesions by increasing the resistance of VSMCs to apoptosis. Indeed, upregulation of GLUT1 significantly inhibited apoptosis induced by serum withdrawal (control 20 +/- 1% vs. GLUT1 11 +/- 1%, P < 0.0005) as well as Fas-ligand (control 12 +/- 1% vs. GLUT1 6 +/- 1.0%, P < 0.0005). Provocatively, the enhanced glucose metabolism in GLUT1 overexpressing VSMC as well as neointimal tissue correlated with the inactivation of the proapoptotic kinase, glycogen synthase kinase 3beta (GSK3beta). Transient overexpression of GSK3beta was sufficient to induce apoptosis (control 7 +/- 1% vs. GSK3beta 28 +/- 2%, P < 0.0001). GSK3beta-induced apoptosis was significantly attenuated by GLUT1 overexpression (GSK3beta 29 +/- 3% vs. GLUT1 + GSK3beta 6 +/- 1%, n = 12, P < 0.001), suggesting that the antiapoptotic effect of enhanced glucose metabolism is linked to the inactivation of GSK3beta. Taken together, upregulation of glucose metabolism during intimal lesion formation promotes an antiapoptotic signaling pathway that is linked to the inactivation of GSK3beta.

Animals↗
PubMed2000

Hyperglycemia inhibits vascular smooth muscle cell apoptosis through a protein kinase C-dependent pathway.

We hypothesized that the pathogenesis of diabetic vasculopathy involves the abnormal regulation of vascular smooth muscle cell (VSMC) apoptosis. In nondiabetic mice, a reduction in carotid artery blood flow resulted in a significant loss of medial VSMCs via apoptosis (normal flow 84+/-1 viable VSMCs, reduced flow 70+/-5 viable VSMCs; n=12, P:<0.01). In contrast, flow-induced VSMC apoptosis was markedly attenuated in streptozotocin-induced diabetic mice (normal flow 85+/-2 viable VSMC, reduced flow 82+/-4 viable VSMC; n=13, NS). In accord with our in vivo findings, the exposure of cultured rat and human VSMCs to high glucose (17.5 mmol/L) significantly attenuated the induction of apoptosis in response to serum withdrawal (rat VSMCs in normal [5.5 mmol/L] glucose 28+/-1%, high D-glucose 19+/-2%; P:<0.0001). High glucose also inhibited apoptosis induced by Fas ligand (100 ng/mL) (normal 23+/-2%, high D-glucose 13+/-2%; P:<0.006). Supplementation with the nonmetabolized enantiomer L-glucose had no effect. We confirmed reports that high glucose activates protein kinase C (PKC) and demonstrated that PKC blockade with long-term phorbol ester treatment or calphostin C prevented the antiapoptotic effect (P:<0. 001). Moreover, the upregulation of either PKCalpha or PKCbetaII expression was sufficient to inhibit serum withdrawal-induced apoptosis (control 25+/-2%, PKCalpha 11+/-2%, PKCbetaII 8+/-2%; P:<0. 0001), whereas the upregulation of PKCdelta had no significant effect. Taken together, these findings demonstrate that hyperglycemia inhibits VSMC apoptosis via a PKC-dependent pathway.

Animals↗
PubMed2000

Systemic administration of HVJ viral coat-liposome complex containing human insulin vector decreases glucose level in diabetic mouse: A model of gene therapy.

In this study, we examined the feasibility of a systemic administration of HVJ-liposome complex containing human insulin construct into the blood in mice via the tail vein. Transfection of human insulin vector resulted in a transient decrease in serum glucose in streptozotocin (SZT)-induced diabetic mice, accompanied by the detection of human insulin in the liver and spleen. In accordance with the decreased glucose, plasma immunoreactive insulin could be detected up to 14 days after a single transfection in mice transfected with insulin vector. Repeated intravenous injection of human insulin vector every week resulted in a sustained decrease in serum glucose over a 4-week period, accompanied by the detection of C-peptide fragments and a significant decrease in BUN and creatinine. Here, we demonstrated the feasibility of intravenous systemic administration of an insulin vector that results in a sustained improvement of diabetic glucose metabolism.

Animals↗
PubMed2000

Transcription factor decoy for NFkappaB inhibits TNF-alpha-induced cytokine and adhesion molecule expression in vivo.

The expression of several cytokines and adhesion molecules is regulated by the transcription factor NFkappaB, which is activated by tumor necrosis factor alpha (TNF-alpha). In this study, we employed a mouse model of nephritis induced by TNF-alpha to examine whether inhibition of NFkappaB activity using transcription factor decoy oligonucleotides (ODN) blocks cytokine and adhesion molecule expression and attenuates the renal inflammatory response. First, we developed a method for delivering FITC-ODN in vivo into mouse kidney glomeruli by employing HVJ-liposome. Then, in order to study the feasibility of decoy strategy in vivo, the reporter gene chloramphenicol acetyltransferase (CAT) driven by three tandemly repeated NFkappaB binding sequences was transfected into the kidney. Intrapenetorial injection of TNF-alpha stimulated CAT expression in vivo, and the increase in CAT expression was completely abolished by NFkappaB decoy ODN, but not scrambled ODN. Therefore, we examined the effect of NFkappaB decoy ODN transfection on TNF-alpha-induced endogenous interleukin (IL)-1alpha, IL-1beta, IL-6, ICAM-1 and VCAM-1 gene expression as assessed by RT-PCR and Northern blotting. Our present data showed that NFkappaB decoy, but not scrambled, ODN abolished TNF-alpha induced gene expression in vivo, as well as glomerular inflammation as assessed by CD45 staining. Taken together, our results suggest the potential utility of NFkappaB decoy strategy for molecular therapy to glomerular inflammatory diseases.

Animals↗
PubMed2000

Antisense oligodeoxynucleotide inhibition of vascular angiotensin-converting enzyme expression attenuates neointimal formation: evidence for tissue angiotensin-converting enzyme function.

It has been proposed that vascular angiotensin-converting enzyme (ACE) plays an important role in regulating vascular growth. Indeed, ACE inhibitors have been reported to prevent neointimal formation after vascular injury in a rat carotid artery model. However, classic pharmacological experiments cannot exclude the potential contributions of hemodynamics and the circulating renin-angiotensin system (RAS). In this study, we used antisense oligodeoxynucleotide (ODN) to obtain local blockade of vascular ACE expression without effects on systemic hemodynamics and circulating RAS. To increase the effectiveness of antisense action, we modified the hemagglutinating virus of Japan-liposome ODN delivery method by cotransfection with nuclear protein (high mobility group 1 [HMG-1]) and RNase H. In vitro experiments showed the enhanced efficacy of antisense ODN by cotransfection of HMG-1 and RNase H compared with ODN alone. In vivo transfection of antisense ACE ODNs into intact uninjured rat carotid artery resulted in a significant reduction of vascular ACE activity, and cotransfection of HMG-1 and RNase H showed further reduction. We examined the effects of local blockade of vascular ACE expression on neointimal formation after vascular injury. Transfection of antisense ACE ODNs resulted in the attenuation of neointimal formation, whereas sense and scrambled ODNs did not. Blood pressure, heart rate, and serum ACE activity were not affected by antisense treatment. The magnitude of vascular ACE inhibition correlated with the suppression of the neointimal size. Overall, this study demonstrates that local antisense ODN inhibition of vascular ACE expression attenuates neointimal formation independent of hemodynamics and circulating RAS. The results support the existence of a functional tissue angiotensin system in the rat vessel wall.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1999

Regulation of vascular smooth muscle cell apoptosis. Modulation of bad by a phosphatidylinositol 3-kinase-dependent pathway.

Our objective was to define the signaling mechanisms by which mitogens such as insulin-like growth factor-I (IGF-I) regulate vascular smooth muscle cell (VSMC) apoptosis. We confirmed that IGF-I inhibits serum withdrawal-induced apoptosis of cultured VSMCs in a dose-dependent and time-dependent fashion. To test the hypothesis that the phosphatidylinositol (PI) 3-kinase signaling pathway regulates VSMC survival, we examined the relationship between PI 3-kinase activity and cell fate. PI 3-kinase was elevated in viable VSMCs maintained in serum-containing medium, declined significantly in response to serum withdrawal, and increased in response to IGF-I-induced survival. Moreover, blockade of PI 3-kinase with 2 structurally dissimilar inhibitors (wortmannin or LY294002) abolished the capacity of IGF-I to maintain VSMC viability. Similarly, transient transfection of a dominant-negative Deltap85 PI 3-kinase mutant construct abrogated the capacity of IGF-I to prevent VSMC death. Thus, PI 3-kinase is a critical antiapoptotic signal in VSMCs. To define the distal element of the antiapoptotic cascade, we tested the hypothesis that IGF-I inhibits the influence of the proapoptotic gene Bad. Indeed, IGF-I stimulates increased expression of the inactive, phosphorylated form of Bad by a PI 3-kinase-dependent pathway. Moreover, the proapoptotic effect of Bad was attenuated by the stimulation of IGF-I. Thus, growth factors appear to prevent VSMC death by activating signal transduction pathways linked to apoptotic regulatory genes.

Animals↗
PubMed1999

Pressure-mediated oligonucleotide transfection of rat and human cardiovascular tissues.

The application of gene therapy to human disease is currently restricted by the relatively low efficiency and potential hazards of methods of oligonucleotide or gene delivery. Antisense or transcription factor decoy oligonucleotides have been shown to be effective at altering gene expression in cell culture expreriments, but their in vivo application is limited by the efficiency of cellular delivery, the intracellular stability of the compounds, and their duration of activity. We report herein the development of a highly efficient method for naked oligodeoxynucleotide (ODN) transfection into cardiovascular tissues by using controlled, nondistending pressure without the use of viral vectors, lipid formulations, or exposure to other adjunctive, potentially hazardous substances. In this study, we have documented the ability of ex vivo, pressure-mediated transfection to achieve nuclear localization of fluorescent (FITC)-labeled ODN in approximately 90% and 50% of cells in intact human saphenous vein and rat myocardium, respectively. We have further documented that pressure-mediated delivery of antisense ODN can functionally inhibit target gene expression in both of these tissues in a sequence-specific manner at the mRNA and protein levels. This oligonucleotide transfection system may represent a safe means of achieving the intraoperative genetic engineering of failure-resistant human bypass grafts and may provide an avenue for the genetic manipultation of cardiac allograft rejection, allograft vasculopathy, or other transplant diseases.

Aged↗
PubMed1999

Vascular cell apoptosis: cell type-specific modulation by transforming growth factor-beta1 in endothelial cells versus smooth muscle cells.

BACKGROUND: It is postulated that vascular lesion formation and remodeling involves a balance between vascular cell death and cell proliferation. Transforming growth factor-beta1 (TGF-beta1) is a pleiotropic factor expressed within vascular cells that regulates cell growth in a tissue-specific manner. This study tested the hypothesis that the control of vascular cell apoptosis involves cell type-specific regulation by TGF-beta1. METHODS AND RESULTS: In response to serum withdrawal, cultured endothelial cells and vascular smooth muscle cells exhibited apoptosis as evidenced by DNA laddering and quantitated by analysis of nuclear chromatin morphology. Addition of TGF-beta1 to endothelial cells in serum-free media further potentiated the induction of apoptosis in a dose-dependent fashion. Moreover, TGF-beta1 promoted endothelial cell death despite the presence of 10% serum. However, endothelial cells plated on collagen I were resistant to TGF-beta1-induced apoptosis. This antiapoptotic influence of the matrix was mimicked by integrin activation with anti-beta1 antibodies and associated with increased expression of the antiapoptotic factor bcl-2. In accord with the hypothesis that the modulation of antiapoptotic gene expression may mediate the effects of TGF-beta1 and beta1 integrins on cell fate, we observed that endothelial cells with constitutive upregulation of bcl-2 remained viable despite exposure to TGF-beta1 in serum-free conditions. In contrast to the proapoptotic effect of TGF-beta1 in endothelial cells, addition of TGF-beta1 to vascular smooth muscle cells in serum-free media inhibited apoptosis. CONCLUSIONS: These findings suggest that the effect of cytokines such as TGF-beta1 on cell fate is contextual and is modulated by cell-matrix interactions in a cell type-specific manner.

Animals↗
PubMed1999

Regression of atherosclerosis: role of nitric oxide and apoptosis.

BACKGROUND: We have recently found that administration of L-arginine to hypercholesterolemic rabbits induces regression of preexisting lesions. Others have previously shown that activation of the L-arginine/nitric oxide (NO) synthase pathway can induce apoptosis of vascular cells in vitro. Accordingly, the current study was designed to determine if dietary supplementation of L-arginine induces apoptosis of intimal lesions and if this effect is mediated through the NO synthase pathway. METHODS AND RESULTS: Male New Zealand White rabbits were fed a 0.5% cholesterol diet for 10 weeks and subsequently placed on 2.5% L-arginine HCl in the drinking water, and the cholesterol diet was continued for 2 weeks, at which time the aortas were harvested for histological studies. L-Arginine treatment increased the number of apoptotic cells (largely macrophages) in the intimal lesions by 3-fold (11.9+/-3.9 vs 3.9+/-1. 4 apoptotic cells/mm2, P<0.01). In subsequent studies, aortas were harvested for ex vivo studies. Aortic segments were incubated in cell culture medium for 4 to 24 hours with modulators of the NO synthase pathway. The tissues were then collected for histological studies and the conditioned medium collected for measurement of nitrogen oxides by chemiluminescence. Addition of sodium nitroprusside (10(-5) mol/L) to the medium caused a time-dependent increase in apoptosis of vascular cells (largely macrophages) in the intimal lesion. L-Arginine (10(-3) mol/L) had an identical effect on apoptosis, which was associated with an increase in nitrogen oxides released into the medium. These effects were not mimicked by D-arginine, and they were antagonized by the NO synthase inhibitor L-nitro-arginine (10(-4) mol/L). The effect of L-arginine was not influenced by an antagonist of cGMP-dependent protein kinase, nor was the effect mimicked by the agonist of protein kinase G or 8-BR cGMP. CONCLUSIONS: These results indicate that supplemental L-arginine induces apoptosis of macrophages in intimal lesions by its metabolism to NO, which acts through a cGMP-independent pathway. These studies are consistent with our previous observation that supplementation of dietary arginine induces regression of atheroma in this animal model. These studies provide a rationale for further investigation of the therapeutic potential of manipulating the NO synthase pathway in atherosclerosis.

Animals↗
PubMed1999

Endothelial cell apoptosis in capillary network remodeling.

We hypothesized that the regulation of apoptosis is an important determinant of capillary network structure. Using human umbilical vein endothelial cells (HUVEC) in in vitro model systems of capillary tube formation, we initially documented that apoptosis is a prominent feature of network formation. Perturbations of integrin-matrix signaling by the administration of either colchicine or an anti-alpha(v)beta3 antibody resulted in the dissolution of the tubular network in association with increased apoptosis. The activation of the alpha(v)beta3 integrin induced increased expression of the anti-apoptotic gene bcl-2 and conferred resistance to the proapoptotic effect of TGF-beta1. In contrast to the stable networks formed by HUVEC, bovine aortic endothelial cells (BAEC) exhibited a more dynamic process of network formation and spontaneous involution. The inhibition of BAEC apoptosis by stable transfection of bcl-2 prevented the involution of the network. We hypothesized that TGF-beta1 present within the model system mediated network involution by inducing BAEC death. Indeed, blockade of TGF-beta1 with neutralizing antibodies reduced BAEC apoptosis and preserved the network structure. As observed with HUVEC networks, stable BAEC networks formed during blockade of TGF-beta1 were also dependent on the survival-promoting effects of matrixintegrin interactions. This study suggests that capillary network structure is determined by the balance of proapoptotic vs. anti-apoptotic signals mediated by the engagement of cytokine and integrin receptors within the milieu.

Animals↗
PubMed1998

Role of AP-1 complex in angiotensin II-mediated transforming growth factor-beta expression and growth of smooth muscle cells: using decoy approach against AP-1 binding site.

The cis element double-stranded oligodeoxynucleotides (ODN) ("decoy") approach has enabled us to clarify the responsible elements. Using this approach, we transfected AP-1 decoy ODN into VSMC cultured from WKY rats (WKY Adu) which produce latent TGF-beta, but not active TGF-beta, and Sprague-Dawley rats (CNC) which produce active and latent TGF-beta under Ang II-stimulation. AP-1, but not mismatched, decoy ODN abolished Ang II-stimulated TGF-beta gene expression and production in both Adu and CNC. However, AP-1 decoy did not alter DNA, RNA, and protein synthesis in Adu. In contrast, cell number was increased under Ang II stimulation by AP-1 decoy ODN in CNC without significant change in RNA and protein synthesis. These results showed that Ang II stimulated TGF-beta production through the AP-1 complex. In VSMC that produce active TGF-beta (CNC), the AP-1 complex stimulated by Ang II may inhibit cell growth through active TGF-beta production. Overall, this study demonstrates the utility of the decoy approach to study the specific function of cis elements in endogenous gene regulation such as Ang II-induced TGF-beta expression.

Angiotensin II↗
PubMed1998

Angiotensin II type 2 receptor mediates vascular smooth muscle cell apoptosis and antagonizes angiotensin II type 1 receptor action: an in vitro gene transfer study.

Angiotensin II type 2 (AT2) receptor is expressed abundantly in the fetal vasculature with rapid decline after birth and re-expressed in the adult vasculature after injury, whereas angiotensin II type 1 (AT1) receptor is expressed. We studied their effects on apoptosis in cultured rat vascular smooth muscle cells (VSMC). Serum starvation induced VSMC DNA fragmentation and the stimulation of AT1 receptor inhibited this apoptotic change. We transfected rat AT2 receptor cDNA, since cultured adult VSMCs show very low level of endogenous AT2 receptor. In AT2 receptor transfected VSMC, selective stimulation of AT2 receptor facilitated serum-deprivation-induced apoptosis and AT1 receptor stimulation inhibited it. Moreover we observed that AT1 receptor stimulation activated extracellular signal-regulated kinase (ERK), whereas the AT2 receptor stimulation inhibited the activation of ERK. Taken together, our results suggest that AT1 and AT2 receptors exert counteracting effects on ERK activation and consequently VSMC apoptosis and differential expression of these receptors may participate in vascular development and vascular remodeling.

Animals↗
PubMed1998

The pathophysiology of hypertension: the importance of angiotensin II in cardiovascular remodeling.

Emerging data on the role of the tissue renin-angiotensin system are redefining our understanding of the pathophysiology of hypertension and other vascular disorders. Although the tissue renin-angiotensin system is quiescent after birth, it can be reactivated in response to tissue injury. Recent evidence suggests that this system is involved in maladaptive changes such as ventricular and vascular remodeling, alterations in renal function, and atherosclerosis. With increased recognition of the role of angiotensin II in these processes, new therapeutic opportunities are emerging. Blockade of angiotensin II will likely prove more effective than other vasodilator therapies in the setting of congestive heart failure and after acute myocardial infarction.

Angiotensin II↗
PubMed1998

Inhibition of neointimal cell bcl-x expression induces apoptosis and regression of vascular disease.

We postulated that activation of a genetic program that tonically inhibits intimal cell death is a necessary condition for the pathogenesis of vascular disease. Studies of vascular lesions in humans and animal models documented increased expression of the anti-apoptotic gene product Bcl-xL within intimal cells. Downregulation of intimal cell bcl-xL expression with the use of antisense oligonucleotides induced apoptosis and acute regression of vascular lesions. These findings indicate that apoptosis regulatory genes such as bcl-xL are critical determinants of intimal lesion formation and that targeted apoptosis may be a novel therapy for intimal vascular disease.

Animals↗