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Estrogen-based drug therapy in cardiovascular diseases has been difficult because it has not been possible to separate the wanted vasculoprotective effect from the unwanted effects of the hormone to the reproductive system. Here, we demonstrate that, after endothelial denudation of rat carotid artery, the mRNA of the classical estrogen receptor (ER[Alpha]) is constitutively expressed at a low level whereas the expression of the novel ER[Beta] mRNA increases >40-fold. Under in situ hybridization and immunohistochemistry, ER[Beta] mRNA and protein colocalize with the smooth muscle cells in the media and neointima. Treatment of ovariectomized female rats with the isoflavone phytoestrogen genistein, which shows 20-fold higher binding affinity to ER[Beta] than to ER[Alpha], or with 17[Beta]-estradiol, which does not differentiate between the two receptors, provides similar dosedependent vasculoprotective effect in rat carotid injury model. In addition in concentrations

Background: We have shown that the combination of sirolimus and imatinib synergistically inhibits denudation-induced neointimal hyperplasia in rats. We have now dissected the mechanisms behind this synergy and evaluated its long-term efficacy. Methods: After aortic denudation injury, rats received established submaximal doses of sirolimus (1.0 mg/kg/day), imatinib (10.0 mg/kg/day), the combination of these, or vehicle per os from 3 days before the operation until 14 days after injury. Vessel histology and complete blood counts were monitored until 90 days after injury. Neointimal cell outgrowth, migration and proliferation were evaluated in ex vivo vessel cultures. Quantitative real-time polymerase chain reaction and immunohistochemistry were used for gene and protein expression analysis. Results: The combination therapy caused a synergistic decrease in the number of neointimal nuclei and area throughout the observation period. It also prevented postinjury thrombocytosis and leukocytosis, and almost abolished neointimal cell outgrowth and migration. Furthermore, the combination therapy resulted in upregulation of smooth muscle cell (SMC) markers SM22α and cysteine and glycine-rich protein 2, and of the anti-apoptotic BCL2 mRNA. Conclusions: Combination therapy confers superior long-term vasculoprotection, possibly by inhibition of postoperative thrombocytosis and leukocytosis, inhibition of neointimal cell migration to the injury site and maintenance of cell integrity by inhibition of apoptosis and SMC dedifferentiation. Copyright © 2008 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Reports the increase of allografts rate due to the improvement of immunosuppression. Emphasis of the manifestation of chronic rejection; Characterization of fibrointimal dysplasia of the allograft arteries; Ways of generating immunosuppressants and anti-T cell drugs.

Background: Accelerated arteriosclerosis remains a major limitation to therapeutic interventions such as angioplasty, stent deployment, and solid organ transplantation. Rapamycin, a powerful new immunosuppressant set to replace calcineurin inhibitors in the transplant setting, and imatinib mesylate, a receptor tyrosine kinase inhibitor, are both angioprotective. Here, we explored the pharmacological and therapeutic interactions of these two agents in a rat model of neointimal hyperplasia., Methods: Wistar rats, subjected to balloon catheter-induced aortic injury, received daily drug treatment until postoperative day 14 and were subsequently sacrificed or followed up to day 40 without further treatment. Development of neointimal lesions was assessed histologically and immunohistochemically. Steady-state rapamycin levels in whole blood were determined by HPLC-UV., Results: Rapamycin and imatinib, administered individually or in combination, produced no signs of overt toxicity. Continuous postoperative therapy with either rapamycin (0.5-1.5 mg/kg/day) or imatinib (2- 50 mg/kg/day) dose-dependently suppressed neointimal hyperplasia on day 14. Combined treatment (0.5 or 1 + 10 mg/kg/day, respectively) showed a trend towards synergistic action on day 14. Withdrawal of medication on day 14 nullified the early therapeutic effect of either agent by day 40. In contrast, early combination therapy (1 + 10 mg/kg/day) achieved long-term suppression of neointimal hyperplasia by approximately 81%. Notably, coadministration of imatinib appeared to reduce exposure to rapamycin, although this finding did not reach statistical significance., Conclusions: Short-term combination therapy with rapamycin and imatinib is well tolerated and produces synergistic, sustained suppression of neointimal hyperplasia in rats. Subject to clinical evaluation, this new drug regimen may afford definitive prophylaxis against accelerated arteriosclerosis.

We describe here a mouse model of diffuse aortic remodelling triggered by combined endothelial denudation/vascular distension injury using a novel balloon microcatheter. We validated this model in both outbred (NMRI) and inbred (BALB/c, C57BL/6) mouse strains and found evidence for differential strain susceptibility to neointimal hyperplasia, possibly attributable to genetic factors. Neointimal lesions were approximately 50% smaller in the inbred strains, a finding associated with profound cell loss in the aortic media at the early stages of the response to injury. A further insight from this model suggests an essential role for platelets in the initiation of neointimal hyperplasia, which apparently progresses through monocyte influx from the peripheral circulation. Our findings are consistent with monocyte recruitment driving neointimal growth, a minority expressing the endothelial cell marker FVIII. Overall, the time course and gross histological features of vascular remodelling seen here resemble those seen in other rodent models. However, this new mouse model offers distinct advantages over existing ones in that it involves the actual use of a catheter in a clinical manner, and because it allows the recovery of intact RNA from injured vessels in sufficient quantities for downstream molecular analyses., (Copyright 2005 S. Karger AG, Basel.)

The somatostatin analogs octreotide and lanreotide, selective to receptor subtypes 2 and 5, failed clinical efficacy for the prevention of restenosis after percutaneous transluminal angioplasty. These findings might have been the result of targeting a wrong subset of receptors. In rat arteries, subtypes 1 and 4 are expressed 3-4 times more prominently than 2 and 5, and subtype 1 is the nearly exclusive subtype in atherosclerotic human vessels. Here, we demonstrate that daily s.c. injections (50-500 microg/kg/d) of CH275 (DesAA1,2,5(D-W8,IAmp9)Somatostatine-14), selective to subtypes 1 and 4, dose-dependently inhibited intimal hyperplasia 14 days after rat carotid denudation injury (for intimal area P=0.0002 across the dose range). CH275 was more effective than somatostatin-14 (equal affinity to all five subtypes, P=0.03), or octreotide (selective to subtypes 2 and 5, P=0.098). When rats were given the peptides for 14 days with end-point at 28 days, CH275 still significantly inhibited intimal area expansion. Both CH275 and octreotide inhibited the outgrowth of cells from postinjury aortic tissue punch-explants and the distance migrated in vitro, but not cell replication, which indicated that the effects of somatostatin analogs were directed on the migration of intimal cell progenitors rather than on their proliferation.