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Biomedical subjects

G A Stouffer

Publications and source records attributed to G A Stouffer.

At least 55 records · Page 3Linked to original sources
PubMed1998

The role of secondary growth factor production in thrombin-induced proliferation of vascular smooth muscle cells.

Alpha-thrombin is a multifunctional serine proteinase that is concentrated at sites of vascular injury and has been implicated in vascular healing responses following balloon injury. In addition to its well-known hemostatic effects, thrombin stimulates smooth muscle cell (SMC) proliferation via binding of protease activated receptor-1 (PAR-1), a seven transmembrane, G-protein-coupled cell surface receptor. Following activation of this receptor, SMC produce and secrete various autocrine growth factors, including platelet-derived growth factor-AA (PDGF-AA), basic fibroblast growth factor (bFGF), heparin binding epidermal growth factor (HBEGF), and transforming growth factor-beta (TGFbeta). The role that autocrine growth factors play in alpha-thrombin-induced proliferation will be discussed in this review.

Angina, Unstable↗
PubMed1998

Use of stress testing to evaluate patients with recurrent chest pain after percutaneous coronary revascularization.

Controversy exists regarding the diagnostic accuracy, optimal technique, and timing of noninvasive stress testing after percutaneous transluminal coronary angioplasty (PTCA). Many patients return with chest pain after PTCA, and because the incidence of restenosis has been reported to be as high as 50%, a noninvasive test with a high predictive value is needed to reduce the need for unnecessary coronary angiography. Studies have shown that the sensitivity and specificity of stress testing varies depending on the amount of time elapsed since the procedure. Soon after a successful PTCA, perfusion defects on nuclear imaging following exercise or pharmacologic stress may be detected in asymptomatic patients without angiographic restenosis. In many patients, abnormal stress myocardial perfusion scans will normalize spontaneously, and thus stress testing with nuclear imaging within 4 to 6 weeks of PTCA lacks specificity for detecting restenosis. In contrast, stress echocardiography which detects wall motion abnormalities rather than perfusion mismatch has been reported to offer more specific information on myocardial ischemia and restenosis early after PTCA. In patients who develop chest pain more than 6 weeks after PTCA, the ability to accurately identify restenosis is shared by both echocardiographic and nuclear imaging methods. The purpose of this review is to clarify the strengths, pitfalls, and prognostic value of different stress modalities and cardiac imaging techniques in patients who develop chest pain within 6 months of undergoing PTCA.

Angioplasty, Balloon, Coronary↗
PubMed1997

Hypertrophic cardiomyopathy: presentation and pathophysiology.

HCM is a heterogeneous disease with various clinical presentations. Recent advances in understanding the genetic abnormalities responsible for ventricular hypertrophy promise to improve our ability to diagnose this condition and to identify subgroups who are at the highest risk of cardiovascular mortality. Numerous difficulties remain in treating patients with HCM, including obtaining relief of symptoms and preventing SCD, but several new treatment options are currently being evaluated. In the future, randomized trials comparing the major treatment options (eg, pharmacologic therapy, myotomy/myectomy, mitral valve replacement, pacemaker implantation, and nonsurgical septal reduction) will be needed to provide guidance concerning the optimal treatment of patients with HCM.

Adult↗
PubMed1997

Hemodynamic changes of aortic regurgitation.

Hemodynamic changes associated with acute AR include a rapid increase in LV pressures during diastole, markedly elevated pressures at end diastole, and premature closure of the mitral valve. Systemic diastolic pressures may be low, but there is a minimal increase in pulse pressure. In very severe cases of acute AR, cardiac output may decrease, leading to hypotension. In chronic AR, the LV remodels to accommodate the regurgitant volume flow, and stroke volume increases to maintain effective forward blood flow. These adaptations lead to a dilated LV, a widened pulse pressure, and a low diastolic blood pressure, which are the classic findings of chronic AR.

Aortic Valve Insufficiency↗
PubMed1996

Effect of thrombin inhibition with desulfatohirudin on early kinetics of cellular proliferation after balloon angioplasty in atherosclerotic rabbits.

BACKGROUND: Thrombin may have a pivotal role in restenosis after angioplasty. Hirudin, a potent thrombin inhibitor, reduces luminal narrowing by plaque after angioplasty in a rabbit model of atherosclerosis. Because cellular proliferation is believed to be an important mechanism for restenosis and thrombin has been shown to be a potent smooth muscle cell mitogen in vitro, we hypothesized that the mechanism of the effect of hirudin on limiting luminal narrowing by plaque occurs via inhibition of cellular proliferation. METHODS AND RESULTS: Femoral atherosclerosis was induced in 108 rabbits, and balloon angioplasty was performed. At angioplasty, group 1 rabbits (n=38) were treated with a 2-hour infusion of hirudin, and group 2 rabbits (n=41) were treated with heparin. Group 3 rabbits (n=29) were treated with hirudin (n=15) or heparin (n=14) and killed at 7 or 28 days to determine cross-sectional area narrowing by plaque and cellular proliferation with the use of bromodeoxyuridine labeling. At 29, 71, or 167 hours after angioplasty, group 1 and 2 rabbits were injected with 3H-thymidine and killed 1 hour later, and labeling indexes were determined. A significant increase in the index of 3H-thymidine-labeled nuclei was observed in the intima of "ballooned" arteries compared with "nonballooned" atherosclerotic arteries at both 30 hours (0.06+/-0.05 versus 0.01+/-0.01, P<.01) and 72 hours (0.10+/-0.06 versus 0.004+/-0.004, P<.01). By 7 days, the index of labeled cells was similar to baseline (0.04+/-0.03 versus 0.01+/-0.01, P=.12). Hirudin had no effect on the 3H-thymidine labeling indexes at any of the time points studied despite the fact that hirudin treatment in group 3 rabbits resulted in less cross-sectional area narrowing by plaque at both 7 and 28 days after angioplasty (41+/-16 versus 24+/-12 at 7 days and 60+/-21 versus 44+/-17 at 28 days, heparin versus hirudin; P<.03). CONCLUSIONS: Balloon angioplasty resulted in a marked increase in cellular proliferation that peaked at 72 hours. A 2-hour infusion of hirudin failed to reduce early 3H-thymidine labeling, suggesting that inhibition of cell proliferation within the first 7 days after angioplasty is not the predominant mechanism by which hirudin exerts its effect on limiting luminal narrowing by plaque 28 days after balloon angioplasty in this animal model.

Angioplasty, Balloon↗
PubMed1996

Thrombin and vascular smooth muscle cell proliferation: implications for atherosclerosis and restenosis.

Despite long-standing knowledge about the relationship between thrombosis and atherosclerosis, the specific role of thrombin in modulating atherosclerosis and the response to vascular injury is not well understood. Thrombin receptor stimulation in vitro signals many cellular events that are associated with the response to vascular injury (atherosclerosis) in vivo. Proliferation of smooth muscle cells (SMCs) is an important component of the response to vascular injury. We have previously shown that human alpha-thrombin and the 14-amino acid human thrombin receptor-activating peptide (huTRAP-14) stimulate proliferation of cultured rat aortic SMCs. However, thrombin-induced SMC proliferation demonstrates delayed kinetics relative to platelet-derived growth factor (PDGF-BB, another potent SMC mitogen). Several mechanisms may be responsible for these delayed kinetics in vitro, including production of necessary secondary growth factors and thrombin-induced upregulation of its receptor. In vivo studies have demonstrated that thrombin inhibition limits the response to vascular injury in a hypercholesterolemic rabbit model of focal femoral atherosclerosis. However, this effect does not appear to be mediated by effects on early SMC proliferation. In this discussion, we will address the mechanisms of thrombin-induced SMC proliferation in vitro and apply this knowledge to our understanding of the role of thrombin inhibition in limiting the response to vascular injury in vivo.

Animals↗
PubMed1996

Restenosis following percutaneous revascularization--the potential role of thrombin and the thrombin receptor.

Thrombin is present at sites of vascular injury and elicits many effects which may contribute to neointimal growth. Further studies are needed to order to determine steps involved in thrombin-induced effects and to identify potential sites to regulate these effects. The failure of the Helvetica trial to demonstrate an effect of treatment with hirudin on restenosis may relate more to our inability to safely inhibit thrombin than to a lack of a role for thrombin in restenosis. A therapy which enables safe and effective control of thrombin-induced responses following vascular injury may yet prove effective at reducing restenosis following percutaneous coronary revascularization.

Angioplasty, Balloon, Coronary↗
PubMed1994

TGF-beta promotes proliferation of cultured SMC via both PDGF-AA-dependent and PDGF-AA-independent mechanisms.

Transforming growth factor-beta 1 (TGF-beta 1) has been implicated in mediating smooth muscle cell (SMC) growth after vascular injury. Studies examining TGF-beta-induced growth of cultured SMC have identified only modest mitogenic effects which are largely dependent on autocrine production of platelet-derived growth factor-AA (PDGF-AA). Recent studies have suggested, however, that TGF-beta also may have delayed growth effects independent of PDGF-AA. The aims of the present studies were to examine the effects of TGF-beta on chronic growth responses of cultured SMC. Results demonstrated that TGF-beta elicited a delayed growth response (24 fold increase in 3H-TdR incorp. from 48-72 h) and enhanced SMC production of PDGF-AA (eightfold increase at 24 h). Neutralizing antibodies to PDGF-AA, however, inhibited only 10-40% of delayed TGF-beta-induced growth. Co-treatment with TGF-beta transiently delayed epidermal growth factor (EGF)-, basic fibroblast growth factor (bFGF)-, or PDGF-BB-induced entry into S phase but enhanced the delayed growth responses to these growth factors by 16.0-, 5.8-, or 4.2-fold, respectively. Neutralizing antibodies to PDGF-AA had no effect on these synergistic responses and exogenous PDGF-AA did not increase growth responses to EGF, bFGF, or PDGF-BB. In summary, TGF-beta induces marked delayed growth responses, alone and in combination with EGF, bFGF or PDGF-BB, that are largely independent of PDGF-AA.

Animals↗
PubMed1993

Activated alpha 2-macroglobulin and transforming growth factor-beta 1 induce a synergistic smooth muscle cell proliferative response.

The role that soluble binding proteins might play in regulating transforming growth factor-beta 1 (TGF-beta 1)-induced growth of smooth muscle cells (SMC) is unknown. alpha 2-Macroglobulin (alpha 2M) is the major plasma binding protein for TGF-beta. Reaction of alpha 2M with methylamine (alpha 2M-MA) forms "activated" alpha 2M which binds TGF-beta and specific cell surface receptors. The objectives of these studies were to determine whether native alpha 2M or alpha 2M-MA influences growth responses of cultured rat aortic SMC to TGF-beta 1. Results demonstrated that native alpha 2M was not mitogenic. Treatment with alpha 2M-MA or TGF-beta 1 stimulated a 3- or 3.5-fold increase in [3H]thymidine incorporation, respectively. Cotreatment with TGF-beta 1 and alpha 2M-MA resulted in a 70-fold increase in [3H]thymidine incorporation. SMC bound alpha 2M-MA in a specific and saturable manner and expressed alpha 2M receptor/low density lipoprotein receptor-related protein (LRP). A modified form of alpha 2M-MA (alpha 2M-MA-cis-dichlorodiammine platinum), which bound TGF-beta 1 but did not bind alpha 2M receptors, failed to enhance TGF-beta 1-induced growth. In summary, results demonstrated that alpha 2M-MA enhanced TGF-beta 1-induced growth responses and that this effect was dependent on alpha 2M-MA binding to alpha 2M receptor/LRP.

Animals↗
PubMed1993

ANG II- or AVP-induced increases in protein synthesis are not dependent on autocrine secretion of PDGF-AA.

Previous studies have demonstrated that angiotensin II (ANG II) and arginine vasopressin (AVP) stimulate increased protein synthesis and cellular hypertrophy in cultured rat aortic smooth muscle cells (SMC). The aim of this study was to explore the hypothesis that ANG II- and/or AVP-induced increases in protein synthesis are mediated by autocrine secretion of platelet-derived growth factor (PDGF)-AA. Results demonstrated that ANG II or AVP increased expression of PDGF-A, but not -B, chain mRNA. Additionally, conditioned media from ANG II- and AVP-treated SMC had increased mitogenic activity for Swiss 3T3 cells, which could be inhibited with a neutralizing antibody to PDGF-AA. However, PDGF-AA-neutralizing antibodies did not inhibit ANG II- or AVP-induced increases in protein synthesis, and exogenous PDGF-AA did not stimulate increased protein synthesis. Furthermore, no PDGF-alpha receptors were evident based on 125I-labeled PDGF-AA binding studies. In summary, results indicate that ANG II- or AVP-induced increases in protein synthesis were not dependent on autocrine secretion of PDGF-AA.

Angiotensin II↗
PubMed1993

Thrombin-induced mitogenesis of vascular SMC is partially mediated by autocrine production of PDGF-AA.

Previous studies have shown that alpha-thrombin (Thr) is a mitogen for cultured smooth muscle cells (SMC), but controversy exists concerning mechanisms of growth stimulation. The purpose of these studies was to determine whether autocrine production of platelet-derived growth factor-AA (PDGF-AA) mediated Thr-induced SMC mitogenesis. SMC derived from aortae of Sprague-Dawley rats were grown to confluence, growth arrested in serum-free medium, and treated. Conditioned medium (CM) was harvested by adding bovine serum albumin as a carrier and hirudin to neutralize residual Thr. Results demonstrated that CM from Thr-treated SMC (Thr CM) had increased mitogenic activity compared with control CM (Cnt CM) and that PDGF-AA levels were increased 12-fold in Thr CM compared with Cnt CM. The excess mitogenic activity in Thr CM was markedly inhibited by PDGF-AA-neutralizing antibodies. Cotreatment with Thr and PDGF-AA-neutralizing antibodies resulted in a 30% decrease in Thr-induced [3H]thymidine incorporation. These results demonstrate that autocrine production of PDGF-AA partially mediated Thr-induced SMC mitogenesis.

Animals↗
PubMed1992

Angiotensin II-induced mitogenesis of spontaneously hypertensive rat-derived cultured smooth muscle cells is dependent on autocrine production of transforming growth factor-beta.

Angiotensin II (Ang II) has been implicated in the regulation of smooth muscle cell proliferation after vascular injury, but the molecular mechanisms of this effect remain obscure. The aims of the present study were 1) to determine if Ang II was mitogenic (in a defined serum-free medium) for aortic smooth muscle cells derived from spontaneously hypertensive rats, either alone or in combination with epidermal growth factor, basic fibroblast growth factor, or platelet-derived growth factor-BB; and 2) to determine if the Ang II effects were mediated by autocrine production of transforming growth factor-beta (TGF-beta). Results demonstrated that Ang II increased the proliferative response of smooth muscle cells to epidermal growth factor or platelet-derived growth factor-BB. Ang II alone and in combination with basic fibroblast growth factor induced a small delayed increase (48-72 hours after treatment) in DNA synthesis and [3H]thymidine labeling indexes without an increase in cell number. Ang II effects were at least partially mediated by autocrine production of active TGF-beta in that 1) treatment with Ang II increased TGF-beta activity in conditioned media and 2) TGF-beta neutralizing antibody inhibited Ang II-induced increases in DNA synthesis. However, treatment with exogenous TGF-beta at concentrations induced by Ang II failed to elicit a mitogenic response, thus implicating other autocrine factors in mediation of Ang II effects. Results suggest a potential mechanism whereby Ang II might regulate smooth muscle cell mitogenesis after vascular injury.

Angiotensin II↗