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Biomedical subjects

J S Forrester

Publications and source records attributed to J S Forrester.

At least 19 recordsLinked to original sources
PubMed1992

Angiotensin II regulates tenascin gene expression in vascular smooth muscle cells.

Angiotensin II, a vasoactive peptide, has been implicated in the pathophysiology of a number of vascular wall abnormalities. Since aberrant extracellular matrix deposition contributes to the pathogenesis of vessel wall disease, we examined the potential involvement of angiotensin II in the regulation of extracellular matrix synthesis by vascular smooth muscle cells. Immunoprecipitation of newly synthesized matrix proteins showed that, under serum-free conditions, cultured vascular smooth muscle cells constitutively produced high levels of fibronectin, small amounts of laminin, and a barely detectable amount of tenascin. Angiotensin II treatment increased synthesis of a 230-kDa tenascin glycoprotein by 9-fold and fibronectin synthesis by only 30-40% during a 24-h treatment period, without stimulating laminin production or a general increase in the synthesis of secreted proteins. Concomitant treatment with saralasin, a competitive inhibitor of angiotensin II, prevented the stimulation observed with angiotensin II. The stimulation of immunoprecipitable tenascin was preceded by an increase in tenascin mRNA. Levels of tenascin transcripts (8.4 and 7.0 kilobase) were significantly increased within 2 h after angiotensin II treatment, reached a maximum (10- to 12-fold) by 4 h, and remained elevated after 18 h. The induction was completely blocked by actinomycin D. Serum also induced tenascin mRNA, but with a different time course. Serum induction of tenascin mRNA was also evident at 2 h, maximal at 4 h, but declined to control levels at 8 h. These results indicate that angiotensin II exerts a rapid and selective stimulation of tenascin biosynthesis, at least in part at a transcriptional level. This suggests that angiotensin II may alter the composition of the extracellular matrix of the vessel wall by stimulating synthesis of the antiadhesive protein tenascin.

Angiotensin II↗
PubMed1992

Effects of hypophysectomy on vascular insulin-like growth factor-I gene expression after balloon denudation in rats.

Insulin-like growth factor-I (IGF-I) is a widely distributed mediator of the growth promoting effects of growth hormone (GH). We sought to determine whether the relationship between GH and IGF-I extends to the vascular system, where IGF-I is proposed to participate in the process of neointimal proliferation after balloon denudation. We show that in hypophysectomized rats basal aortic IGF-I mRNA is one-tenth that of normal rats and is increased after balloon denudation. The induction peaks at 7 days after balloon denudation at about 10-fold control levels, similar to normal rats. Treatment with GH restores basal IGF-I mRNA content to approximately half that of normal rats, without further increase in the relative magnitude of induction after balloon denudation. This local induction of IGF-I gene expression in the vessel wall following injury might explain why neointimal proliferation is not inhibited more profoundly after hypophysectomy.

Animals↗
PubMed1992

A human immunodeficiency virus-resistant airway for cardiopulmonary resuscitation.

Due to fear of transmitted disease, mouth-to-mouth cardiopulmonary resuscitation (CPR) is now rare, even though early CPR is associated with a fivefold to 30-fold increase in survival. The authors have devised a one-piece silicone mask (Kiss of Life [KOL], Brunswick Biomedical Technologies, Inc, Warehom, MA) with a one-way valve and circular recess to form a no-contact lip seal, enabling mouth-to-mouth CPR to be given. The ventilatory volume during mannequin CPR using the KOL mask was 0.75 +/- 0.235 L. This volume was significantly (P less than .05) greater than that generated by alternate widely used airways (range, 0.195 +/- 0.147 to 0.617 +/- 0.208 L). To assess mask performance in vivo, the authors measured exhaled volumes in 10 apneic anesthetized patients under three conditions: with the KOL mask, a standard anesthetic mask and bag, and an anesthetic mask with an endotracheal tube. The results were: anesthetic mask and tube, 1.5 L (range, 1.2 to 1.7 L); KOL mask, 1.1 L (range, 1.0 to 1.3 L); anesthetic mask alone, 0.7 L (range, 0.5 to 0.8 L). To test permeability, we exposed two KOL masks to a high titer of human immunodeficiency virus (HIV)-1 soup (10(6) culture infection doses/mL) for 10 and eight masks for 60 minutes, respectively, and cultured swabs of the interior of the valve for 1 month. There was no growth in any culture. These data suggest that the KOL mask has excellent ventilating characteristics, is practical (pocket-portable, disposable), experimentally impermeable to HIV-1, and inexpensive.(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiopulmonary Resuscitation↗
PubMed1992

Platelet-derived growth factor isoforms decrease insulin-like growth factor I gene expression in rat vascular smooth muscle cells and selectively stimulate the biosynthesis of insulin-like growth factor binding protein 4.

Platelet-derived growth factor (PDGF) is believed to be a critical mediator of vascular smooth muscle cell (SMC) proliferation. Because insulin-like growth factor (IGF) I (IGF-I) functions as a progression factor for the mitogenic effects of PDGF, we hypothesized that IGF-I gene expression and the production of IGF binding proteins (IGFBPs) by cultured rat aortic SMCs might be regulated by one or more of the three isoforms of PDGF: PDGF-AA, -BB, and -AB. IGF-I gene expression was highly dependent on cell density: IGF-I mRNA transcripts decreased markedly as a function of cell confluence. IGF-I mRNA content was inhibited to a similar degree by PDGF-AA, -BB, and -AB through a mechanism requiring protein synthesis. The inhibition was readily apparent at 4 hours, reaching approximately 25% of control levels after 24 hours. Radioimmunoassayable IGF-I was only barely detectable in SMC-conditioned serum-free medium and not significantly modulated by PDGF. Western ligand blot revealed that vascular SMCs release 30-kd and 24-kd IGFBP into serum-free conditioned medium. PDGF isoforms did not significantly alter release of the 30-kd IGFBP but evoked a fivefold to sixfold increase in the 24-kd IGFBP. The 24-kd IGFBP was found to comigrate with IGFBP-4, a recently identified binding protein that inhibits IGF action. The 30-kd protein was not merely a glycosylated form of IGFBP-4, because it was not sensitive to N-glycanase digestion. PDGF-AA, -BB, and -AB markedly induced expression of IGFBP-4 mRNA in a time- and concentration-dependent fashion. Vascular SMCs also express IGFBP-2 mRNA, but its abundance was not induced by PDGF. In conclusion, PDGF evokes a complex pattern of regulation of genes in the IGF/IGFBP system. By inhibiting IGF-I production and specifically inducing biosynthesis of the inhibitory binding protein IGFBP-4, PDGF may set in motion mechanisms to limit the final magnitude of the mitogenic response.

Animals↗
PubMed1992

Regulation of insulin-like growth factor-I and its receptor in rat aorta after balloon denudation. Evidence for local bioactivity.

Local production of growth factors may play a major role in vascular repair after injury. We examined the regulation of insulin-like growth factor-I (IGF-I) and its specific membrane receptor in balloon-denuded rat aorta. Aortic IGF-I mRNA and radioimmunoassayable IGF-I content increased severalfold after balloon denudation with a peak at 7 d after injury. This coincided with a reciprocal 25% decrease in IGF-I receptor mRNA content and a 40% decrease in total 125I-IGF-I binding. Scatchard analysis indicated a single class of binding sites, with a decrease in receptor number at 7 d compared to control and no change in affinity. By in situ hybridization the predominant site of IGF-I expression in the normal and the denuded vessel wall was the medial smooth muscle cell. After denudation there was a relative decrease in IGF-I receptor mRNA in the medial cells as compared to the neointima, suggesting that the site of IGF-I action was predominantly in the medial layer. These data suggest that local expression and action of IGF-I are significant in the promotion of smooth muscle cell proliferation after arterial injury.

Animals↗
PubMed1992

Proliferating cell nuclear antigen immunohistochemistry in rat aorta after balloon denudation. Comparison with thymidine and bromodeoxyuridine labeling.

The authors compared detection of proliferating vascular smooth muscle cells (SMC) in vitro and in vivo with proliferating cell nuclear antigen (PCNA) immunohistochemistry and two established methods: [3H]thymidine autoradiography and bromodeoxyuridine immunohistochemistry. Labeling with [3H]thymidine and bromodeoxyuridine of rat vascular SMC in culture stained 11% +/- 2% and 11% +/- 1% of cells, and PCNA immunohistochemistry 22% +/- 2% of cells. Proliferation in the media of the denuded rat aortae was highest 3 days after denudation: 4.2%, 3.8%, and 4.7% of labeled cells with [3H]thymidine, bromodeoxyuridine, and PCNA, respectively. In the intima, proliferation was highest 7 days after denudation with 42% [3H]thymidine, 40% bromodeoxyuridine, and 46% PCNA-positive cells. With double labeling, all [3H]thymidine-positive cells were PCNA positive, whereas some cells were only positive for PCNA. The authors conclude that PCNA immunohistochemistry compares favorably with [3H]thymidine autoradiography, and bromodeoxyuridine immunohistochemistry.

Animals↗
PubMed1991

Pathophysiology of acute coronary syndromes.

The natural history of coronary artery disease is punctuated by clinical manifestations of unstable angina, acute myocardial infarction, and ischemic sudden death. These acute coronary syndromes share common pathophysiologic mechanisms that include fissuring of a plaque followed by varying degrees of dynamic coronary obstruction, which is due to vasoconstriction and coronary thrombosis. The response to plaque fissure is likely to be modulated by local and/or systemic procoagulant and anticoagulant-fibrinolytic activities. The key role of coronary thrombosis in acute coronary syndromes has substantial implications for prevention and treatment of complications of coronary atherosclerosis.

Animals↗
PubMed1991

Growth factors in pathogenesis of coronary arterial restenosis.

Restenosis occurs in 25% to 55% of patients within 6 months of successful angioplasty. The major histologic component of the restenotic lesion is intimal hyperplasia, which is almost certainly driven by growth factors. After vascular injury, smooth muscle cells proliferate, reaching a maximum rate at day 2. Smooth muscle cell proliferation diminishes as the vessel surface is re-endothelialized at about day 7, and by week 4 the smooth muscle cell mitotic rate returns to baseline of less than 1% per day. The events of the histologic evolution of arterial injury can be used to create a hypothetical paradigm for the role of growth factors in restenosis. Restenosis might logically be prevented by an inhibitory intervention at any of the various steps in the healing process.

Animals↗
PubMed1991

A paradigm for restenosis based on cell biology: clues for the development of new preventive therapies.

Angioplasty causes substantial injury to the coronary artery intima and media that is unrecognizable by angiography. On the basis of a substantial body of research in oncology and wound healing, it is hypothesized that restenosis is a manifestation of the general wound healing response expressed specifically in vascular tissue. The temporal response to injury occurs in three characteristic phases: inflammation, granulation and extracellular matrix remodeling. The specific expression of these phases in the coronary artery leads to intimal hyperplasia at 1 to 4 months. The major milestones in the temporal sequence of restenosis are platelet aggregation, inflammatory cell infiltration, release of growth factors, medial smooth muscle cell modulation and proliferation, proteoglycan deposition and extracellular matrix remodeling. Each step has potential inhibitors that could be used for preventive therapy. Resolution of restenosis, however, probably requires both creation of the largest possible residual lumen and substantial inhibition of intimal hyperplasia.

Angioplasty, Balloon, Coronary↗
PubMed1991

Initiating events of acute coronary arterial occlusion.

Acute myocardial infarction is caused by coronary thrombosis on an ulcerated atheroma. We now believe that the predominant cause of this intimal disruption is the rupture of the atheroma through the intimal surface, caused by enzymes released by activated macrophages. The subsequent clinical course following atheroma disruption is determined by the rate and size of thrombus formation. Partially occlusive thrombi produce unstable angina; completely occlusive thrombi produce myocardial infarction; clot embolization can produce sudden death. The localized thrombus lyses within days. The healing process, however, is frequently accompanied by rapid local progression of the size of the atheroma at the site of intimal disruption. With healing of the intimal surface, the patient's clinical status stabilizes. Thus coronary disease is a cyclical phenomenon driven by cellular events within the atheroma and by the interaction of the atheroma with circulating blood elements.

Angina Pectoris↗
PubMed1991

Histopathologic validation of angioscopy and intravascular ultrasound.

BACKGROUND: To establish a histopathologic basis for angioscopic and ultrasound image interpretation we studied 70 postmortem human arterial segments in vitro. METHODS AND RESULTS: We used 7- to 9-French fiber-optic angioscopes and 20- to 30-MHz intravascular ultrasound imaging catheters. Three observers assigned an angioscopic and ultrasound image classification to each vessel segment. The image and histological classification categories were then compared. The sensitivity, specificity, and accuracy of both methods separately or in combination for normal vessels were each greater than or equal to 95%. The predictive value was better for angioscopy than for ultrasound due to incorrect ultrasound interpretations of normal anatomy in the presence of thrombus. For stable atheroma the sensitivity, specificity, and accuracy of the individual methods were each greater than 90%. However, both angioscopy and ultrasound had classification errors in that disrupted atheroma was identified and classified as stable atheroma. Consequently, the predictive value was 74% for angioscopy and 78% for ultrasound. For disrupted atheroma the sensitivities for angioscopy and ultrasound were only moderate (73% and 81%, respectively), whereas the specificity, accuracy, and predictive value were each high (greater than 90%). For thrombus detection, the specificity, accuracy, and predictive value were high (greater than 93%) for each method. The sensitivity of angioscopy was 100%. However, sensitivity was lower for ultrasound (57%) due to false-negative interpretation of laminar clots in normal vessels and an inability to distinguish disrupted or stable atheroma from intraluminal thrombus. CONCLUSIONS: Contingency analyses showed that each imaging method alone or combined had significant agreement with the results obtained from histology (p less than 0.001). When assessing all cases in which angioscopy and ultrasound were concordant, there was a 92% agreement with the histological classification.

Coronary Artery Disease↗
PubMed1991

Percutaneous excimer laser coronary angioplasty of lesions not ideal for balloon angioplasty.

BACKGROUND: Excimer laser coronary angioplasty is a new, investigational technique for treating coronary artery stenoses. Initial reports have demonstrated acute efficacy and relative safety of this procedure, but have not addressed the effect of lesion type on acute success and complication rates. METHODS AND RESULTS: In the first 100 patients undergoing percutaneous excimer laser coronary angioplasty at our institution, acute laser success was obtained in 84% and procedural success was obtained in 94%. There were six acute closures during laser angioplasty and one myocardial infarction. Two patients required emergency coronary bypass surgery. Sixty-five percent of patients had lesions not ideal for balloon angioplasty because of lesion morphology (tubular, diffuse, or chronic total occlusion) or ostial location. There were 10 tubular stenoses, 29 diffuse lesions, 18 chronic total occlusions, and eight ostial lesions, including five aorto-ostial lesions. In this nonideal subgroup, the acute success rate with laser was 86% (72% of chronic total occlusions and 91% of non-totally occluded lesions), and the procedural success rate was 94%. There were three acute occlusions during laser angioplasty but no myocardial infarctions, emergency bypass surgeries, or deaths. One coronary artery perforation occurred without clinical sequelae. Laser angioplasty was successful in four of six lesions (67%) in which balloon angioplasty had failed. Laser success was obtained in 10 of 11 (91%) moderately or heavily calcified stenoses. Eight eccentric lesions and two lesions on bends were successfully treated without dissection or perforation. No side branch occlusions occurred in the 15 patients in whom one or more major branches originated within the lesion treated. Adjunctive balloon angioplasty was performed in 47% of cases, usually to obtain a larger final luminal diameter. Need for adjunctive balloon angioplasty decreased to 36% after a larger (2.0 mm) laser catheter became available. Twenty-eight percent of the 105 lesions treated were American College of Cardiology/American Heart Association classification type A, 47% were type B, and 25% were type C. Laser and procedural successes were obtained in 83% and 97% of type A, 88% and 96% of type B, and 85% and 88% of type C lesions, respectively. CONCLUSIONS: In our initial experience, excimer laser angioplasty was found to be acutely effective and safe therapy for lesions identified as not ideal for balloon angioplasty. This technique may provide a useful adjunct or alternative to balloon angioplasty in selected patients.

Angiography↗
PubMed1991

Abundant expression of parathyroid hormone-related protein in primary rat aortic smooth muscle cells accompanies serum-induced proliferation.

Parathyroid hormone-related protein (PTHrP), which is responsible for producing hypercalcemia in patients with humoral hypercalcemia of malignancy, has recently been identified in several normal tissues. Because PTHrP, like parathyroid hormone (PTH), is known to exhibit vasodilatory properties, we investigated the expression and regulation of PTHrP mRNA in cultured rat aortic smooth muscle cells (SMC). We report here that PTHrP mRNA is expressed in SMC and is markedly induced by serum in a time- and concentration-dependent fashion. Addition of 10% fetal calf serum to serum-deprived, confluent cells, resulted in a marked induction of PTHrP mRNA by 2 h with a peak at 4-6 h. PTHrP was detected in SMC by immunocytochemistry and radioimmunoassay of conditioned medium, and was shown to be up-regulated within 24 h after the addition of serum. The serum induction of PTHrP mRNA was blocked by actinomycin D and by cycloheximide indicating the need for protein synthesis to evoke the serum effect on PTHrP gene transcription. In addition, treatment with dexamethasone, which has been previously shown to reduce the constitutive expression of PTHrP in human cancer cells, also blunted the serum induction of PTHrP mRNA in SMC. Treatment of quiescent cells with the serum mitogens platelet-derived growth factor or insulin-like growth factor-I had no effect on PTHrP, whereas the vasoactive peptides endothelin, norepinephrine and thrombin stimulated PTHrP expression. Exogenous addition of recombinant PTHrP-(1-141) had no significant effect on SMC DNA synthesis as measured by [3H]thymidine incorporation. In summary, the abundance of PTHrP mRNA and the characteristics of its regulation in SMC suggest a major role for PTHrP as a local modulator in vascular smooth muscle.

Animals↗
PubMed1991

XeCl excimer laser-induced fluorescence for selective ablation of atheromatous tissue.

In order to develop a reliable laser-induced fluorescence (LIF) guided laser angioplasty system, real time, pulse-by-pulse fluorescence spectra were recorded and the same fiberoptic was used for both detection of the fluorescence and for atheromatous tissue ablation. A 308 nm XeCl excimer laser served as the laser source for both the induction of fluorescence and the ablation. The fluorescence signal was induced at high laser energies during ablation without any serious change in the fluorescence pattern. A new characteristic fluorescence peak at 540 nm for atheromatous tissue was observed after treatment with chlortetracycline hydrochloride (CTC). This allowed the development of an algorithm and a subsequent index to discriminate the atheromatous tissue from the normal tissue. During atheromatous tissue ablation, this index changed as normal tissue was approached, thereby avoiding vessel perforation. Our results suggest that monitoring of this index through the catheter delivering the laser energy enhances selective ablation while simultaneously reducing the risk of vessel perforation.

Arteriosclerosis↗