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  • 1. Gidlöf, Andreas C.
    et al.
    Ocaya, Pauline
    Örebro University, School of Health and Medical Sciences.
    Krivospitskaya, Olesya
    Örebro University, Department of Clinical Medicine.
    Sirsjö, Allan
    Örebro University, School of Health and Medical Sciences.
    Vitamin A: a drug for prevention of restenosis/reocclusion after percutaneous coronary intervention?2008In: Clinical Science, ISSN 0143-5221, E-ISSN 1470-8736, Vol. 114, no 1, p. 19-25Article in journal (Refereed)
    Abstract [en]

    The re-establishment of adequate blood flow in a vessel with a reduced lumen due to an atherosclerotic plaque by percutaneous vascular intervention is a well established procedure. However, the long-term outcome of such interventions is negatively influenced by the development of intimal hyperplasia/restenosis. Although extensively researched, this still represents a significant clinical problem. Retinoids, i.e. natural and synthetic derivates of vitamin A, represent a potential therapeutic compound, since they have been shown to influence the vast majority of processes that ultimately lead to reocclusion of the injured vessel. Retinoids exert their effects at the transcriptional level through their nuclear receptors. Targeting multiple processes, i.e. proliferation, migration, extracellular matrix composition and cell differentiation, as well as coagulation/fibrinolysis, should increase their future role in the prevention of restenosis. The purpose of this review is to summarize the diverse effects of retinoids on pathobiological and biological processes activated at sites of vascular injury with particular emphasis on intimal hyperplasia/restenosis after endovascular interventions.

  • 2. Gidlöf, Andreas C.
    et al.
    Ocaya, Pauline
    Örebro University, Department of Clinical Medicine.
    Olofsson, Peder S.
    Törmä, Hans
    Sirsjö, Allan
    Örebro University, Department of Clinical Medicine.
    Differences in retinol metabolism and proliferative response between neointimal and medial smooth muscle cells2006In: Journal of Vascular Research, ISSN 1018-1172, E-ISSN 1423-0135, Vol. 43, no 4, p. 392-398Article in journal (Refereed)
    Abstract [en]

    Vascular disease is multifactorial and smooth muscle cells (SMCs) play a key role. Retinoids have been shown to influence many disease-promoting processes including proliferation and differentiation in the vessel wall. Phenotypic heterogeneity of vascular SMCs is a well-known phenomenon and phenotypic modulation of SMCs precedes intimal hyperplasia. The SMCs that constitute the intimal hyperplasia demonstrate a distinct phenotype and differ in gene expression compared to medial SMCs. Cellular retinol-binding protein-1 (CRBP-I), involved in retinoid metabolism, is highly expressed in intimal SMCs, indicating altered retinoid metabolism in this subset of cells. The aim of this study was to evaluate the metabolism of all-trans ROH (atROH), the circulating prohormone to active retinoids, in vascular SMCs of different phenotypes. The results show an increased uptake of atROH in intimal SMCs compared to medial SMCs as well as increased expression of the retinoid-metabolizing enzymes retinol dehydrogenase-5 and retinal dehydrogenase-1 and, in conjunction with this gene expression, increased production of all-trans retinoic acid (atRA). Furthermore, the retinoic acid-catabolizing enzyme CYP26A1 is expressed at higher levels in medial SMCs compared to intimal SMCs. Thus, both retinoid activation and deactivation processes are in operation. To analyze if the difference in ROH metabolism was also correlated to differences in the biological response to retinol, the effects of ROH on proliferation of SMCs with this phenotypic heterogeneity were studied. We found that intimal SMCs showed a dose- and time-dependent growth inhibition when treated with atROH in contrast to medial SMCs, in which atROH had a mitogenic effect. This study shows, for the first time, that (1) vascular SMCs are able to synthesize biologically active atRA from the prohormone atROH, (2) intimal SMCs have a higher capacity to internalize atROH and metabolize atROH into atRA compared to medial SMCs and (3) atROH inhibits growth of intimal SMCs, but induces medial SMC growth.

  • 3.
    Ocaya, Pauline
    Örebro University, Department of Clinical Medicine.
    Retinoid metabolism and signalling in vascular smooth muscle cells2007Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Smooth muscle cells (SMCs) play a major role in cardiovascular diseases. In advanced atherosclerosis, blood flow is impaired due to reduced luminal diameter. Percutaneous vascular interventions, including balloon angioplasty and stent-application are commonly used for the re-establishment of luminal size and improvement of tissue perfusion. However, the benefit of vascular interventions is hampered by re-stenosis. The molecular basis of re-stenosis is not fully elucidated and so far, no successful treatment is clinically available. Re-stenosis, which is proposed to be a response to mechanical injury, involves the activation of multiple processes including inflammation, SMC migration and proliferation, and is characterized by vessel remodelling and intimal hyperplasia.

    Retinoids have been shown to regulate several processes activated at site of vascular injury including inflammation, SMC migration and proliferation, and have been demonstrated to inhibit SMC proliferation and reduce intimal hyperplasia. Thus, retinoids are potential candidates in the treatment of certain vascular disorders. Retinoid metabolism is complex and involves a repertoire of proteins including retinoic acid synthesizing and catabolizing enzymes. The purpose of this study was to investigate retinoid metabolism in vascular cells, more specifically to find key points in the regulation of retinoid metabolism in vascular SMCs and atherosclerotic lesions.

    We demonstrate that different phenotypes of SMCs exhibit differences in retinoid metabolism, which suggests a link between retinoid metabolism and the SMC phenotype. Vascular SMCs and atherosclerotic lesions expressed cytochrome P450 isoform 26 (CYP26) enzymes, which are involved in retinoid catabolism. Our studies reveal the presence of a negative feedback loop, in which retinoids induce its inactivation by inducing CYP26 expression in vascular SMCs and atherosclerotic lesions. Moreover, inhibition of CYP26 potently blocked retinoid catabolism and resulted in retinoid-like effects in SMCs, indicating that CYP26 is an important endogenous modulator of retinoid metabolism in vascular cells. In atherosclerotic lesions and vascular SMCs, decreased retinoid catabolism and hence, increased retinoid availability, resulted in increased expression of retinoid-responsive genes.

    Since retinoids reduce intimal hyperplasia in animal models, our studies suggest that CYP26 inhibitors may provide an alternative to exogenous retinoid administration. Thus, CYP26 inhibitors may offer a new therapeutic approach to vascular proliferative disorders.

    List of papers
    1. Differences in retinol metabolism and proliferative response between neointimal and medial smooth muscle cells
    Open this publication in new window or tab >>Differences in retinol metabolism and proliferative response between neointimal and medial smooth muscle cells
    Show others...
    2006 (English)In: Journal of Vascular Research, ISSN 1018-1172, E-ISSN 1423-0135, Vol. 43, no 4, p. 392-398Article in journal (Refereed) Published
    Abstract [en]

    Vascular disease is multifactorial and smooth muscle cells (SMCs) play a key role. Retinoids have been shown to influence many disease-promoting processes including proliferation and differentiation in the vessel wall. Phenotypic heterogeneity of vascular SMCs is a well-known phenomenon and phenotypic modulation of SMCs precedes intimal hyperplasia. The SMCs that constitute the intimal hyperplasia demonstrate a distinct phenotype and differ in gene expression compared to medial SMCs. Cellular retinol-binding protein-1 (CRBP-I), involved in retinoid metabolism, is highly expressed in intimal SMCs, indicating altered retinoid metabolism in this subset of cells. The aim of this study was to evaluate the metabolism of all-trans ROH (atROH), the circulating prohormone to active retinoids, in vascular SMCs of different phenotypes. The results show an increased uptake of atROH in intimal SMCs compared to medial SMCs as well as increased expression of the retinoid-metabolizing enzymes retinol dehydrogenase-5 and retinal dehydrogenase-1 and, in conjunction with this gene expression, increased production of all-trans retinoic acid (atRA). Furthermore, the retinoic acid-catabolizing enzyme CYP26A1 is expressed at higher levels in medial SMCs compared to intimal SMCs. Thus, both retinoid activation and deactivation processes are in operation. To analyze if the difference in ROH metabolism was also correlated to differences in the biological response to retinol, the effects of ROH on proliferation of SMCs with this phenotypic heterogeneity were studied. We found that intimal SMCs showed a dose- and time-dependent growth inhibition when treated with atROH in contrast to medial SMCs, in which atROH had a mitogenic effect. This study shows, for the first time, that (1) vascular SMCs are able to synthesize biologically active atRA from the prohormone atROH, (2) intimal SMCs have a higher capacity to internalize atROH and metabolize atROH into atRA compared to medial SMCs and (3) atROH inhibits growth of intimal SMCs, but induces medial SMC growth.

    National Category
    Medical and Health Sciences
    Research subject
    Biomedicine
    Identifiers
    urn:nbn:se:oru:diva-2840 (URN)10.1159/000094415 (DOI)
    Available from: 2007-05-11 Created: 2007-05-11 Last updated: 2017-12-14Bibliographically approved
    2. CYP26 inhibitor R115866 increases retinoid signaling in intimal smooth muscle cells
    Open this publication in new window or tab >>CYP26 inhibitor R115866 increases retinoid signaling in intimal smooth muscle cells
    Show others...
    2007 (English)In: Arteriosclerosis, Thrombosis and Vascular Biology, ISSN 1079-5642, E-ISSN 1524-4636, Vol. 27, no 7, p. 1542-1548Article in journal (Refereed) Published
    Abstract [en]

    OBJECTIVE: Intimal smooth muscle cells (SMCs) are dedifferentiated SMCs that have a powerful ability to proliferate and migrate. This cell-type is responsible for the development of intimal hyperplasia after vascular angioplasty. Retinoids, especially all-trans retinoid acid, are known to regulate many processes activated at sites of vascular injury, including modulation of SMC phenotype and inhibition of SMC proliferation. Intracellular levels of active retinoids are under firm control. A key enzyme is the all-trans retinoic acid-degrading enzyme cytochrome p450 isoform 26 (CYP26). Thus, an alternative approach to exogenous retinoid administration could be to increase the intracellular level of all-trans retinoic acid by blocking CYP26-mediated degradation of retinoids.

    METHODS AND RESULTS: Vascular intimal and medial SMCs expressed CYP26A1 and B1 mRNA. Although medial cells remained unaffected, treatment with the CYP26-inhibitor R115866 significantly increased cellular levels of all-trans retinoic acid in intimal SMCs. The increased levels of all-trans retinoic acid induced retinoid-regulated genes and decreased mitogenesis.

    CONCLUSIONS: Blocking of the CYP26-mediated catabolism mimics the effects of exogenously administrated active retinoids on intimal SMCs. Therefore, CYP26-inhibitors offer a potential new therapeutic approach to vascular proliferative disorders.

    Place, publisher, year, edition, pages
    Baltimore, Md: Lippincott Williams & Wilkins, 2007
    National Category
    Medical and Health Sciences
    Research subject
    Biomedicine
    Identifiers
    urn:nbn:se:oru:diva-2841 (URN)10.1161/ATVBAHA.106.138602 (DOI)
    Available from: 2007-05-11 Created: 2007-05-11 Last updated: 2017-12-14Bibliographically approved
    3. The importance of CYP26 in the regulation of atRA metabolism in human atherosclerotic lesions and aortic smooth muscle cells
    Open this publication in new window or tab >>The importance of CYP26 in the regulation of atRA metabolism in human atherosclerotic lesions and aortic smooth muscle cells
    Show others...
    (English)Manuscript (Other academic)
    National Category
    Medical and Health Sciences
    Research subject
    Biomedicine
    Identifiers
    urn:nbn:se:oru:diva-2842 (URN)
    Available from: 2007-05-11 Created: 2007-05-11 Last updated: 2017-10-18Bibliographically approved
    4. Expression of IL-1β, IL-1 receptor type I and IL-1 receptor antagonist in human aortic smooth muscle cells: effects of all-trans-retinoic acid
    Open this publication in new window or tab >>Expression of IL-1β, IL-1 receptor type I and IL-1 receptor antagonist in human aortic smooth muscle cells: effects of all-trans-retinoic acid
    Show others...
    2006 (English)In: Journal of Vascular Research, ISSN 1018-1172, E-ISSN 1423-0135, Vol. 43, no 4, p. 377-382Article in journal (Refereed) Published
    Abstract [en]

    The proinflammatory cytokine interleukin (IL)-1β and the IL-1 receptor antagonist are expressed by atherosclerotic plaques and may be linked to the development of atherosclerosis. Existing evidence shows that retinoids and their receptors are involved in inflammatory response and that they are found in atherosclerotic plaques. In all-trans-retinoic acid (atRA)-treated human aortic smooth muscle cells (AOSMC), significant increases in IL-1β levels were observed, compared with untreated cells. Examination of IL-1 receptor antagonist and IL-1 receptor type I levels did not show any difference between atRA-treated and -untreated AOSMC. The results show that atRA-treated AOSMC express both the precursor (33 kDa) and the active form (17 kDa) of the IL-1β protein. atRA-treated carotid lesions showed significantly elevated IL-1β mRNA levels (2.9 ± 2.33) compared with untreated lesions (2.0 ± 1.77; p < 0.05). These results support the role of atRA as a regulator of inflammation such as in atherosclerosis.

    National Category
    Medical and Health Sciences
    Research subject
    Biomedicine
    Identifiers
    urn:nbn:se:oru:diva-2843 (URN)10.1159/000094258 (DOI)
    Available from: 2007-05-11 Created: 2007-05-11 Last updated: 2017-12-14Bibliographically approved
  • 4.
    Ocaya, Pauline A.
    et al.
    Örebro University, Department of Clinical Medicine.
    Gidlöf, Andreas C.
    Olofsson, Peder S.
    Norgren, Lars
    Törmä, Hans
    Sirsjö, Allan
    Örebro University, Department of Clinical Medicine.
    The importance of CYP26 in the regulation of atRA metabolism in human atherosclerotic lesions and aortic smooth muscle cellsManuscript (Other academic)
  • 5.
    Ocaya, Pauline Ajok
    et al.
    Örebro University, School of Health and Medical Sciences.
    Elmabsout, Ali Ateia
    Örebro University, School of Health and Medical Sciences.
    Olofsson, Peder Stefan
    Dept Anesthesiol & Intens Care Med, Ctr Mol Med, Karolinska Univ Hosp, Karolinska Inst, Stockholm, Sweden .
    Törmä, Hans
    Dept Med Sci Dermatol, Uppsala Univ, Uppsala, Sweden.
    Gidlöf, Andreas Carl
    Dept Anesthesiol & Intens Care Med, Ctr Mol Med, Karolinska Univ Hosp, Karolinska Inst, Stockholm, Sweden.
    Sirsjö, Allan
    Örebro University, School of Health and Medical Sciences.
    CYP26B1 plays a major role in the regulation of all-trans-retinoic acid metabolism and signaling in human aortic smooth muscle cells2011In: Journal of Vascular Research, ISSN 1018-1172, E-ISSN 1423-0135, Vol. 48, no 1, p. 23-30Article in journal (Refereed)
    Abstract [en]

    Aim: The cytochrome P450 enzymes of the CYP26 family are involved in the catabolism of the biologically active retinoid all-trans-retinoic acid (atRA). Since it is possible that an increased local CYP26 activity would reduce the effects of retinoids in vascular injury, we investigated the role of CYP26 in the regulation of atRA levels in human aortic smooth muscle cells (AOSMCs).

    Methods: The expression of CYP26 was investigated in cultured AOSMCs using real-time PCR. The metabolism of atRA was analyzed by high-performance liquid chromatography, and the inhibitor R115866 or small interfering RNA (siRNA) was used to suppress CYP26 activity/expression.

    Results: AOSMCs expressed CYP26B1 constitutively and atRA exposure augmented CYP26B1 mRNA levels. Silencing of the CYP26B1 gene expression or reduction of CYP26B1 enzymatic activity by using siRNA or the inhibitor R115866, respectively, increased atRA-mediated signaling and resulted in decreased cell proliferation. The CYP26 inhibitor also induced expression of atRA-responsive genes. Therefore, atRA-induced CYP26 expression accelerated atRA inactivation in AOSMCs, giving rise to an atRA-CYP26 feedback loop. Inhibition of this loop with a CYP26 inhibitor increased retinoid signaling.

    Conclusion: The results suggest that CYP26 inhibitors may be a therapeutic alternative to exogenous retinoid administration. Copyright (C) 2010 S. Karger AG, Basel

  • 6.
    Ocaya, Pauline
    et al.
    Örebro University, Department of Clinical Medicine.
    Gidlöf, Andreas C.
    Olofsson, Peder S.
    Törmä, Hans
    Sirsjö, Allan
    Örebro University, School of Health and Medical Sciences.
    CYP26 inhibitor R115866 increases retinoid signaling in intimal smooth muscle cells2007In: Arteriosclerosis, Thrombosis and Vascular Biology, ISSN 1079-5642, E-ISSN 1524-4636, Vol. 27, no 7, p. 1542-1548Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Intimal smooth muscle cells (SMCs) are dedifferentiated SMCs that have a powerful ability to proliferate and migrate. This cell-type is responsible for the development of intimal hyperplasia after vascular angioplasty. Retinoids, especially all-trans retinoid acid, are known to regulate many processes activated at sites of vascular injury, including modulation of SMC phenotype and inhibition of SMC proliferation. Intracellular levels of active retinoids are under firm control. A key enzyme is the all-trans retinoic acid-degrading enzyme cytochrome p450 isoform 26 (CYP26). Thus, an alternative approach to exogenous retinoid administration could be to increase the intracellular level of all-trans retinoic acid by blocking CYP26-mediated degradation of retinoids.

    METHODS AND RESULTS: Vascular intimal and medial SMCs expressed CYP26A1 and B1 mRNA. Although medial cells remained unaffected, treatment with the CYP26-inhibitor R115866 significantly increased cellular levels of all-trans retinoic acid in intimal SMCs. The increased levels of all-trans retinoic acid induced retinoid-regulated genes and decreased mitogenesis.

    CONCLUSIONS: Blocking of the CYP26-mediated catabolism mimics the effects of exogenously administrated active retinoids on intimal SMCs. Therefore, CYP26-inhibitors offer a potential new therapeutic approach to vascular proliferative disorders.

  • 7. Olofsson, Peder S.
    et al.
    Söderström, Leif A.
    Wågsäter, Dick
    Örebro University, School of Health and Medical Sciences.
    Sheikine, Yuri
    Ocaya, Pauline
    Örebro University, Department of Clinical Medicine.
    Lang, François
    Rabu, Catherine
    Chen, Lieping
    Rudling, Mats
    Aukrust, Pål
    Hedin, Ulf
    Paulsson-Berne, Gabrielle
    Sirsjö, Allan
    Örebro University, School of Health and Medical Sciences.
    Hansson, Göran K.
    CD137 is expressed in human atherosclerosis and promotes development of plaque inflammation in hypercholesterolemic mice2008In: Circulation, ISSN 0009-7322, E-ISSN 1524-4539, Vol. 117, no 10, p. 1292-1301Article in journal (Refereed)
    Abstract [en]

    Background— Atherosclerosis is a multifactorial disease in which inflammatory processes play an important role. Inflammation underlies lesion evolution at all stages, from establishment to plaque rupture and thrombosis. Costimulatory molecules of the tumor necrosis factor superfamily such as CD40/CD40L and OX40/OX40L have been implicated in atherosclerosis. Methods and Results— This study shows that the tumor necrosis factor superfamily members CD137 and CD137 ligand (CD137L), which play a major role in several autoimmune diseases, may constitute a pathogenic pair in atherogenesis. We detected CD137 protein in human atherosclerotic lesions not only on T cells but also on endothelial cells and showed that CD137 in cultured endothelial cells and smooth muscle cells was induced by proinflammatory cytokines implicated in atherosclerosis. Activation of CD137 by CD137L induced adhesion molecule expression on endothelial cells and reduced smooth muscle cell proliferation. In addition, treatment of atherosclerosis-prone apolipoprotein E–deficient mice with a CD137 agonist caused increased inflammation. T-cell infiltration, mainly of CD8+ cells, and expression of the murine major histocompatibility complex class II molecule I-Ab increased significantly in atherosclerotic lesions, as did the aortic expression of proinflammatory cytokines. Conclusions— Taken together, these observations suggest that CD137-CD137L interactions in the vasculature may contribute to the progression of atherosclerosis via augmented leukocyte recruitment, increased inflammation, and development of a more disease-prone phenotype.

  • 8.
    Wågsäter, Dick
    et al.
    Örebro University, Department of Clinical Medicine.
    Jatta, Ken
    Örebro University, Department of Clinical Medicine.
    Ocaya, Pauline
    Örebro University, Department of Clinical Medicine.
    Dimberg, Jan
    Sirsjö, Allan
    Örebro University, Department of Clinical Medicine.
    Expression of IL-1b, IL-1R1 I and IL-1Ra in human aortic smooth muscle cells: effects of all-trans retinoic acid2006Manuscript (preprint) (Other academic)
  • 9.
    Wågsäter, Dick
    et al.
    Örebro University, Department of Clinical Medicine.
    Jatta, Ken
    Örebro University, Department of Clinical Medicine.
    Ocaya, Pauline
    Örebro University, Department of Clinical Medicine.
    Dimberg, Jan
    Sirsjö, Allan
    Örebro University, Department of Clinical Medicine.
    Expression of IL-1β, IL-1 receptor type I and IL-1 receptor antagonist in human aortic smooth muscle cells: effects of all-trans-retinoic acid2006In: Journal of Vascular Research, ISSN 1018-1172, E-ISSN 1423-0135, Vol. 43, no 4, p. 377-382Article in journal (Refereed)
    Abstract [en]

    The proinflammatory cytokine interleukin (IL)-1β and the IL-1 receptor antagonist are expressed by atherosclerotic plaques and may be linked to the development of atherosclerosis. Existing evidence shows that retinoids and their receptors are involved in inflammatory response and that they are found in atherosclerotic plaques. In all-trans-retinoic acid (atRA)-treated human aortic smooth muscle cells (AOSMC), significant increases in IL-1β levels were observed, compared with untreated cells. Examination of IL-1 receptor antagonist and IL-1 receptor type I levels did not show any difference between atRA-treated and -untreated AOSMC. The results show that atRA-treated AOSMC express both the precursor (33 kDa) and the active form (17 kDa) of the IL-1β protein. atRA-treated carotid lesions showed significantly elevated IL-1β mRNA levels (2.9 ± 2.33) compared with untreated lesions (2.0 ± 1.77; p < 0.05). These results support the role of atRA as a regulator of inflammation such as in atherosclerosis.

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