Inhibition of coronary artery transplant atherosclerosis in rabbits with angiopeptin, an octapeptide

Foegh, Marie L.; Khirabadi, Bijan S.; Chambers, E. D.; Amamoo, Samia; Ramwell, Peter W.

doi:10.1016/0021-9150(89)90228-1

Cited by 84 publications

(20 citation statements)

References 6 publications

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“…This feature was also appreciated in our studies using the TNF-␣sr (18) and CS-1 peptide (12), but not in studies with other agents used to reduce graft arteriopathy (63,78). This reinforces a selective effect of elafin on the pathophysiology of graft arteriopathy.…”

Section: Discussionsupporting

confidence: 53%

Elafin, a serine elastase inhibitor, attenuates post-cardiac transplant coronary arteriopathy and reduces myocardial necrosis in rabbits afer heterotopic cardiac transplantation.

Cowan¹,

Bar-On²,

Crack³

et al. 1996

J. Clin. Invest.

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We have related experimentally induced post-cardiac transplant coronary arteriopathy to increased elastolytic activity, IL-1 ␤ , fibronectin-mediated inflammatory and smooth muscle cell (SMC) migration, and SMC proliferation. Since our in vitro studies show that a serine elastase releases SMC mitogens and facilitates IL-1 ␤ induction of fibronectin, we hypothesized that administration in vivo of the specific serine elastase inhibitor, elafin, would decrease the post-cardiac transplant coronary arteriopathy. Cholesterol-fed rabbits underwent a heterotopic cardiac transplant without immunosuppression and received elafin (1.79 mg/kg per d continuous infusion after a 9 mg bolus, n ϭ 6) or vehicle ( n ϭ 6). 1 wk later, hearts were harvested for morphometric, immunohistochemical, and biochemical analyses. A Ͼ 70% decrease in the total number of coronary arteries with intimal thickening in elafin-treated compared to control donor hearts ( P Ͻ 0.002) was associated with reduced vascular elastolytic activity judged by fewer breaks in the internal elastic lamina ( P Ͻ 0.03), less accumulation of immunoreactive fibronectin ( P Ͻ 0.02), and reduced cell proliferation quantified by proliferating cell nuclear antigen ( P Ͻ 0.0001). Despite myocardial lymphocytic infiltration, wet weight of elafin-treated donor hearts was reduced by 50% compared to untreated controls ( P Ͻ 0.002) and associated with relative preservation of myocyte integrity, instead of extensive myocardial necrosis ( P Ͻ 0.004). This protective effect correlated with decreased myocardial elastolytic activity ( P Ͻ 0.0001) and inflammatory cell proliferation ( P Ͻ 0.0001) and with an elafin-inhibitable elastase in lymphocytes. Serine elastase activity thus appears an important therapeutic target for post-cardiac transplant coronary arteriopathy and myocardial necrosis induced by rejection. ( J. Clin. Invest. 1996. 97:2452-2468.)

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Section: Discussionsupporting

confidence: 53%

Elafin, a serine elastase inhibitor, attenuates post-cardiac transplant coronary arteriopathy and reduces myocardial necrosis in rabbits afer heterotopic cardiac transplantation.

Cowan¹,

Bar-On²,

Crack³

et al. 1996

J. Clin. Invest.

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“…However, human studies should be performed to elucidate the possible changes in serum IGFBP-3 within the first hours after octreotide administration, with measurement of serum IGFBP-3 both by specific RIA and WLB. As already emphasized in the previous studies on this topic (Ezzat et al 1991, 1992, Orskov et al 1994, Wolthers et al 1994, the octreotide-induced increases in IGFBP-1, and the IGFBP-3 increase described in the present study, may have clinical implications in the use of octreotide and lanreotide in acromegaly (Heron et al 1993), diabetes mellitus (Hyer et al 1989, Sem et al 1991, some cancers (Pannar et al 1989), and in treatment trials as antiproliferative agents after balloon catherization of coronary arteries (Foegh et al 1989). The biological roles of IGFBPs, especially as local modulators of IGF action, are not fully understood.…”

Section: Discussionmentioning

confidence: 61%

“…Further¬ more, octreotide has been shown to increase IGFBP-1 mRNA in human hepatoma cells in vitro within 24 h, indicative of a direct stimulatory effect on IGFBP-1 synthesis (Ren et al 1992). This newly discovered stimulating effect is interesting as long-acting somatostatin analogues have recently been introduced in clinical therapy trials of acromegaly (Heron et al 1993), diabetes mellitus (Hyer et al 1989, Serri et al 1991, certain cancer forms (Pannar et al 1989) and in attempts to reduce the incidence of restenosis after balloon catherization of coronary arteries (Foegh et al 1989). …”

Section: Introductionmentioning

confidence: 97%

Stimulation of hepatic insulin-like growth factor-binding protein-1 and -3 gene expression by octreotide in rats

Flyvbjerg¹,

Schuller²,

Neck³

et al. 1995

Journal of Endocrinology

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It has recently been demonstrated in various clinical experiments that native somatostatin and its long-acting analogues increase circulating levels of insulin-like growth factor-binding protein-1 (IGFBP-1) within 1-2 h, independent of effects on circulating insulin or glucose levels. Using human hepatoma cells in vitro the somatostatin analogue, octreotide, has been shown to increase IGFBP-1 mRNA within 24 h indicative of a direct stimulatory effect of octreotide on IGFBP-1 synthesis. In order to ascertain whether octreotide acutely stimulates IGFBP-1 mRNA in vivo, placebo or two doses of octreotide were injected subcutaneously into three groups of rats. One hour after saline or octreotide administration, liver, kidney and serum were obtained for the measurement of IGFBPs-1 to -6 mRNA in tissue and IGFBPs and IGF-I in serum. Octreotide increased liver IGFBP-1 (562%) and IGFBP-3 (23%) mRNA expression with a concomitant rise in the circulating 30 kDa (106%) and 38-42 kDa (23%) IGFBPs. No detectable changes were seen in other liver IGFBP transcripts, other circulating IGFBPs or in any of the kidney IGFBP transcripts. Serum IGF-I increased by 37% in the animals receiving the high octreotide dose. No concomitant changes were observed in glucose or insulin levels. These data show that octreotide acutely stimulates hepatic IGFBP-1 and -3 mRNA in vivo in rats. The stimulating effect on IGFBP-3 presents a possible hitherto unknown form of regulation of IGFBP-3 whilst the effect on IGFBP-1 indicates that the stimulatory effect of octreotide on circulating IGFBP-1 described in clinical trials may be due to increased hepatic production. The present findings may be of importance in the clinical use of octreotide.

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“…The smooth muscle cell proliferation stimulated by‘air‐drying’ of the endothelium can also be inhibited by angiopeptin and the somatostatin analogue BIM23034 (Lundergan et al , 1989). In addition to studies in rat animal models, the antiproliferative effects of SRIF and angiopeptin have been demonstrated in both rabbit (Foegh et al , 1989; Light et al , 1993; Howell et al , 1993; Foegh et al , 1994) and pig (Foegh, 1992) models of vascular smooth muscle cell proliferation.…”

Section: Introductionmentioning

confidence: 99%

Differential effects of somatostatin and angiopeptin on cell proliferation

Alderton

Lauder

Feniuk

et al. 1998

British J Pharmacology

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Somatostatin (SRIF) exerts antiproliferative effects, and angiopeptin (an sst2/sst5 receptor‐selective analogue) has recently been evaluated in clinical trials for the prophylaxis of restenosis following coronary angioplasty. Using an in vitro model of cell growth we have examined the effects of SRIF and angiopeptin on cell proliferation in CHO‐K1 cells stably transfected with the human or rat recombinant sst2 or sst5 receptor and compared these with their effects on rat aortic vascular smooth muscle cells (VSMC) expressing endogenous somatostatin receptors. In CHO‐K1 cells, expressing either human or rat recombinant sst2 or sst5 receptors, or in rat aortic VSMC, SRIF and angiopeptin (0.1–1000 nM) had no effect on basal re‐growth of cells into a denuded area of a previously confluent monolayer. In contrast, basic fibroblast growth factor (bFGF, 10 ng ml−1) stimulated re‐growth of these cells. SRIF (0.1–1000 nM) caused a concentration‐dependent inhibition of the bFGF‐stimulated re‐growth in CHO‐K1 cells expressing human sst2 (h sst2) or sst5 (h sst5) receptors (pIC50=8.05±0.03 and 8.56±0.12, respectively). In contrast, angiopeptin (0.1–1000 nM) acted as a partial agonist at the h sst2 receptor (44.6±2.7% inhibition of the bFGF‐stimulated re‐growth at 100 nM; pIC50=8.69±0.25) but was devoid of any agonist activity at the h sst5 receptor. In CHO‐K1 cells stably expressing rat recombinant sst2 (r sst2) or sst5 (r sst5) receptors, SRIF (0.1–1000 nM) was able to inhibit the bFGF‐stimulated re‐growth (pIC50=7.98±24 and 8.50±0.12, respectively). Angiopeptin (0.1–1000 nM) caused a concentration‐dependent inhibition of bFGF‐stimulated re‐growth at the r sst2 receptor (pIC50=8.08±0.24) but acted as a partial agonist at the r sst5 receptor (maximum response=57.7±3.6% inhibition of bFGF‐stimulated re‐growth at 100 nM; pIC50=8.60±0.16). Although angiopeptin was inactive as an agonist at the h sst5 receptor, 100 nM angiopeptin potently antagonized the SRIF‐induced inhibition of proliferation in CHO h sst5 (estimated pKB=10.4±0.3). 5‐Hydroxytryptamine (0.1 nM–10 μM) also inhibited bFGF‐stimulated re‐growth (pIC50=8.36±0.11) and angiopeptin had no effect on this response (pKB<7). SRIF (0.1–1000 nM) caused a concentration‐dependent (pIC50=8.04±0.08) inhibition of bFGF‐stimulated re‐growth in VSMC, whereas angiopeptin displayed weak agonist activity, only inhibiting bFGF‐stimulated re‐growth at concentrations greater than 100 nM. Angiopeptin (100 nM) caused a rightward displacement of the concentration‐effect curve to SRIF with an estimated pKB value of 7.70±0.12. These findings suggest that the low intrinsic activity of angiopeptin at the h sst2 receptor, combined with its lack of agonist activity at the h sst5 receptor, may explain the poor clinical efficacy of angiopeptin in trials for coronary artery restenosis, which contrasts with encouraging data found in equivalent in vivo animal studies.

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Inhibition of coronary artery transplant atherosclerosis in rabbits with angiopeptin, an octapeptide

Cited by 84 publications

References 6 publications

Elafin, a serine elastase inhibitor, attenuates post-cardiac transplant coronary arteriopathy and reduces myocardial necrosis in rabbits afer heterotopic cardiac transplantation.

Elafin, a serine elastase inhibitor, attenuates post-cardiac transplant coronary arteriopathy and reduces myocardial necrosis in rabbits afer heterotopic cardiac transplantation.

Stimulation of hepatic insulin-like growth factor-binding protein-1 and -3 gene expression by octreotide in rats

Differential effects of somatostatin and angiopeptin on cell proliferation

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