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P Häyry

Publications and source records attributed to P Häyry.

At least 19 recordsLinked to original sources
PubMed2001

Structure of carotid artery in baboon and rat and differences in their response to endothelial denudation angioplasty.

BACKGROUND: Most studies dealing with vascular response to injury have been conducted using rodent and rabbit models, although it is expected that the response to injury in these species is dissimilar from man. AIMS: Here we compare the structure of native carotid artery in rat and baboon and the response of these vessels to endothelial denudation angioplasty. METHODS: In both species, the carotid is a musculoelastic artery. Only baboon carotid has a distinct intima, correlating in size with the weight of male baboons. Complete endothelial denudation of left carotid was performed on eight male baboons and 24 male rats by applying an equivalent pull force with a Fogarthy catheter. The animals were sacrificed prior to and 15 min and 2, 3, 4, 7, 14 and 28 days postinjury, one baboon and three rats per time point. RESULTS: Re-endothelialization in the baboon was complete already on day 4, whereas in the rat it was still incomplete on day 28. The proliferative response to injury was far smaller in the baboon than in the rat, the intimal area increased only by 5-fold in baboon compared with 25-fold in rat, and the number of intimal nuclei by 4-fold in baboon compared with 12-fold in rat. Complete compensatory remodelling of the lumen size occurred in the baboon, whereas in the rat remodelling remained incomplete. The cell types participating in the response were, however, similar: deposition of thrombocytes on denuded luminal surface, expression of alpha-actin by intimal cells, and lack of any significant white cell infiltration in the denuded intima. CONCLUSIONS: Baboon carotids are very different from rat carotids both in their native structure and in their response to injury. With the limited amount of information available from human vessels, baboon carotids closely resemble human carotids in both respects.

Angioplasty, Balloon↗
PubMed1999

Differentiation and maturation of porcine fetal islet cells in vitro and after transplantation.

BACKGROUND: Porcine fetal pancreas is a potential source of beta cells for transplantation. The immaturity of the cells is a problem. We have defined the optimal conditions for in vitro propagation of this tissue before transplantation. METHODS: Porcine fetal pancreas tissue was obtained for tissue culture at various stages of development. Serum-containing and serum-free media and a variety of potential differentiation factors were tested. In vitro, the numbers of endocrine islet cells and their proliferation were quantified and functional maturity of the beta cells was assessed by perifusion. Growth and maturation of the cells was assessed 3 months after transplantation into nude mice. RESULTS: Highest beta cell mass was obtained from end-gestational, as compared with early fetal or neonatal, pancreas. Nicotinamide and sodium butyrate effectively increased the insulin content and the number of endocrine cells in culture. In combination, these factors led up to a 90-fold increase in the insulin content of islet-like cell clusters (ICC) as compared with untreated controls. However, a high level of cell death through apoptosis was observed in these maximally stimulated endocrine cells, and they did not survive as grafts when transplanted into nude mice. Instead, a serum-free culture medium containing 10 mM nicotinamide and 0.1 mM isobutylmethylxanthine was found to support both differentiation and proliferation of endocrine cells as loose ICCs. Insulin release from these ICCs was sensitive to glucose. When transplanted under the kidney capsule of normoglycemic nude mice, a high level of beta cell differentiation and function was evident only in the ICCs cultured in the serum-free medium, and in freshly isolated ICCs. When transplanted to hyperglycemic nude recipients, the cells cultured in serum-free medium for 3 weeks reversed hyperglycemia more consistently and rapidly than freshly isolated ICCs. CONCLUSIONS: Optimal maturation of porcine fetal pancreatic cells is obtained in serum-free medium supplemented with nicotinamide. Butyrate is a potent stimulus for beta cell differentiation but leads to increased apoptotic cell death.

Animals↗
PubMed1999

Differentiation between vasculoprotective and uterotrophic effects of ligands with different binding affinities to estrogen receptors alpha and beta.

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 (ERalpha) is constitutively expressed at a low level whereas the expression of the novel ERbeta mRNA increases >40-fold. Under in situ hybridization and immunohistochemistry, ERbeta 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 ERbeta than to ERalpha, or with 17beta-estradiol, which does not differentiate between the two receptors, provides similar dose-dependent vasculoprotective effect in rat carotid injury model. In addition in concentrations <10 microM, both ligands are equally inhibitory to the replication and migration of smooth muscle cells in vitro. However, only treatment with 17beta-estradiol, but not with genistein, is accompanied with a dose-dependent uterotrophic effect. The results suggest that preferential targeting to ERbeta will provide vasculoprotective estrogen analogs devoid of effects to the reproductive system.

Animals↗
PubMed1999

Prevention of cardiac allograft arteriosclerosis by protein tyrosine kinase inhibitor selective for platelet-derived growth factor receptor.

BACKGROUND: Increased immunoreactivity of platelet-derived growth factor (PDGF)-AA, -Ralpha, and -Rbeta in intimal cells correlates with the development of cardiac allograft arteriosclerosis, a condition for which there is little or no current therapy. Therefore, we hypothesized that PDGF may have a rate-limiting role in the development of this disease. METHODS AND RESULTS: The hypothesis was tested in a rat model of heterotopic cardiac and aortic allografts using dark agouti (AG-B4, RT1(a)) donors and Wistar-Furth (AG-B2, RT1(u)) recipients. The recipients received CGP 53716, a selective PDGF-R protein tyrosine kinase inhibitor, 50 mg. kg-1. d-1, or vehicle for 60 days. Cardiac allograft recipients also received background cyclosporin A immunosuppression. Our results demonstrate that CGP 53716 significantly reduced the incidence and intensity of arteriosclerotic lesions in rat cardiac and aortic allograft recipients. When rat coronary smooth muscle cells were stimulated in vitro with PDGF-AA or -BB in the presence of interleukin-1beta or tumor necrosis factor-alpha, CGP 53716 significantly inhibited only AA-ligand-induced but not BB-ligand-induced replication. Concomitantly, in quantitative reverse transcriptase-polymerase chain reaction, interleukin-1beta or tumor necrosis factor-alpha stimulation specifically upregulated the expression of PDGF-Ralpha mRNA but not of other ligand or receptor genes in cultured smooth muscle cells. CONCLUSIONS: We conclude that a PDGF-AA/Ralpha-dependent cycle is induced in the generation of allograft arteriosclerosis that may be inhibited by blocking of signaling downstream of PDGF-R.

Animals↗
PubMed1999

Endothelial L-selectin ligands are likely to recruit lymphocytes into rejecting human heart transplants.

L-selectin-dependent lymphocyte extravasation is a hallmark of acute heart allograft rejection in rats. On screening over 600 endomyocardial biopsies (EMBs), taken at different time points after heart transplantation in man, we identified 91 samples with histological signs of acute rejection. Rejection and nonrejection EMBs were analyzed for the presence of properly glycosylated, ie, sulfated sialyl Lewis-x (sLex) decorated L-selectin ligands. Two anti-sLex (2F3 and HECA-452) and one anti-6- or 6'-sulfated and/or 6, 6'-bisulfation (MECA-79) monoclonal antibodies were used. Nonrejecting heart endothelium did not express, or expressed only weakly, sulfated and or sLex decorations of L-selectin ligands. On the contrary, these epitopes were readily detectable on endothelium of capillaries and venules at the onset and during acute rejection episodes. The more intense the sulfated sLex expression was, the more severe the rejection episode was in histological grading. The endothelial expression of L-selectin ligands decreased to background levels as the rejection resolved. Our data demonstrate a complete correlation between the level of expression of the sulfated sLex-decorated ligands on the one hand and the histological severity of acute heart allograft rejection on the other hand. These data suggest that functionally active endothelial L-selectin ligands are instrumental in lymphocyte extravasation into the human heart allografts at the onset and during acute rejection episodes.

Antibodies, Monoclonal↗
PubMed1999

Selective tyrosine kinase inhibitor for the platelet-derived growth factor receptor in vitro inhibits smooth muscle cell proliferation after reinjury of arterial intima in vivo.

The long-term success of coronary angioplasty is limited by restonosis. This study was undertaken to investigate whether and to what extent the enhanced proliferative response observed in a balloon reinjury model of rat aorta is regulated by the PDGF receptor (PDGF-R). Balloon injury was performed to 14-day-old pre-existing neointimal lesion in rat aorta. PDGF receptor and ligand immunoreactivity were measured at several time points after the first and second injury, and PDGF-R signaling was blocked with a selective inhibitor of PDGF-R tyrosine kinase. In the neointima, after repeated injury, upregulation of PDGF-AA was seen to coincide with a prompt proliferative response of smooth muscle cells (SMC). Administration of the PDGF-R tyrosine kinase inhibitor in vivo, tested and found to inhibit the proliferation of SMC induced by PDGF-AA and PDGF-BB, but not by IGF-1, EGF, or bFGF, resulted in a 60% reduction in the absolute number and percentage of BrdU + cells after the second balloon injury to pre-existing neointima, but had no significant effect on proliferation after the first injury. Endpoint lesion area was reduced by 50% in the treated group at 14 days after the second injury. The results suggest that systemic administration of a tyrosine kinase inhibitor specific for the PDGF-R can be useful in the prevention of restenosis.

Angioplasty, Balloon, Coronary↗
PubMed1998

Eotaxin and capping protein in experimental vasculopathy.

Ischemia-induced tissue activation may contribute to the pathogenesis of graft vasculopathy, but the mediators implicated have only partially been characterized. To gain further insight into the molecular mechanisms involved, syngeneic rat aortic transplants with cold-storage-induced vasculopathy were studied for differentially expressed mRNA transcripts. Vessel segments were exposed to either 1 or 18 hours of cold ischemia, followed by transplantation into syngeneic recipients. After 3 days or 4 weeks, the grafts were removed and total mRNA was isolated and used for differential display to identify modulation of transcript expression related to prolonged storage. Using 15 sets of random primers, 17 polymerase chain reaction products were up-regulated and 2 were downregulated in grafts exposed to 18 hours of ischemia. Sequencing of these amplicons showed that 6 had a high degree of homology to known sequences whereas 13 had no homology to any of the genes in the database. Two of the differentially displayed amplicons (capping protein and eotaxin) were cloned, re-amplified, and used as probes for Northern blot analysis to confirm their differential expression. Immunohistochemistry using monoclonal antibodies against capping protein-alpha and eotaxin confirmed that both proteins are expressed in the media of normal aortas and that there was an increased expression in vessels exposed to prolonged ischemia albeit that the increase at the protein level seemed less compared with changes in transcript expression. Northern blots with RNA from aortic allografts exposed to prolonged ischemic storage also showed increased levels of capping protein and eotaxin mRNA whereas there was a decrease in the relative amount of these transcripts in vessels exposed to balloon denudation, suggesting that the increase after prolonged ischemic exposure is not the result of a nonspecific response to injury. Based on the biological characteristics of capping protein and eotaxin it is conceivable that they play a pathogenetic role in ischemia-induced vessel wall remodeling. It remains to be established whether these genes or their products serve as target molecules for therapeutic interventions to prevent or treat cold-storage-induced graft vasculopathy.

Actin Depolymerizing Factors↗