Abstract
Introduction: PAI-1 is a potent fibrosis promoting glycoprotein in a tissue dependent manner. We previously displayed that tacrolimus (FK506) toxicity increases vacuolar degeneration and arterial hyalinosis in cardiovascular tissue. FK506 toxicity induced transforming growth factor (TGF-β) expression. Renin angiotensin system (RAS) blockade partially reversed histopathological changes associated with FK506 toxicity. In the same model, we investigated the effects of FK506 and RAS blockade on PAI-1 expression.
Materials and Methods: We examined cardiac expression of PAI-1 in a chronic FK506 toxicity model in Wistar rats. Study animals were divided into 4 groups. FK506 group was treated with FK506 intraperitoneally, FK506+Quinapril and FK506+Valsartan groups were treated Quinapril or Valsartan orally in addition to FK506. Control group was treated with saline. Immunohistochemical staining of cardiovascular tissue was semiquantitatively scored for PAI-1 expression.
Results: FK506 significantly induced PAI-1 expression in the cardiovascular tissue compared to the control group (semiquantitative scores were 25±5 versus (vs) 49±21, p =0.01). Adding renin angiotensin system blockade with an angiotensin converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) to FK506 increased FK506 induced PAI-1 expression. Semiquantitative PAI-1 expression scores were 49±21, 87±14 and 95±10 for FK506, FK506+ACEI, and FK506+ARB groups respectively (p<0.01).
Conclusion: FK506 toxicity is associated with up-regulation of PAI-1 expression at the tissue level which is not attenuated after RAS blockade. These observations suggest that FK506 induces an angiotensin II independent increase on PAI-1 expression in cardiac tissue and/or elevated TGF-β and reduced BMP-7 levels with FK506 toxicity may reverse the inhibitory effects of RAS blockade on PAI-1 expression.
Keywords: Tacrolimus, cardiac toxicity, renin-angiotensin system, PAI-1.
Current Enzyme Inhibition
Title:Tacrolimus Toxicity Reverses the Inhibitory Effects of Renin Angiotensin System Blockade on PAI-1 Expression in Cardiac Tissue
Volume: 9 Issue: 2
Author(s): Mehmet Agirbasli, Emine Bas Bozkurtlar, Nurdan Papila-Topal, Hicran Deniz, Betul Ogutmen and Fulya Cakalagaoglu
Affiliation:
Keywords: Tacrolimus, cardiac toxicity, renin-angiotensin system, PAI-1.
Abstract: Introduction: PAI-1 is a potent fibrosis promoting glycoprotein in a tissue dependent manner. We previously displayed that tacrolimus (FK506) toxicity increases vacuolar degeneration and arterial hyalinosis in cardiovascular tissue. FK506 toxicity induced transforming growth factor (TGF-β) expression. Renin angiotensin system (RAS) blockade partially reversed histopathological changes associated with FK506 toxicity. In the same model, we investigated the effects of FK506 and RAS blockade on PAI-1 expression.
Materials and Methods: We examined cardiac expression of PAI-1 in a chronic FK506 toxicity model in Wistar rats. Study animals were divided into 4 groups. FK506 group was treated with FK506 intraperitoneally, FK506+Quinapril and FK506+Valsartan groups were treated Quinapril or Valsartan orally in addition to FK506. Control group was treated with saline. Immunohistochemical staining of cardiovascular tissue was semiquantitatively scored for PAI-1 expression.
Results: FK506 significantly induced PAI-1 expression in the cardiovascular tissue compared to the control group (semiquantitative scores were 25±5 versus (vs) 49±21, p =0.01). Adding renin angiotensin system blockade with an angiotensin converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) to FK506 increased FK506 induced PAI-1 expression. Semiquantitative PAI-1 expression scores were 49±21, 87±14 and 95±10 for FK506, FK506+ACEI, and FK506+ARB groups respectively (p<0.01).
Conclusion: FK506 toxicity is associated with up-regulation of PAI-1 expression at the tissue level which is not attenuated after RAS blockade. These observations suggest that FK506 induces an angiotensin II independent increase on PAI-1 expression in cardiac tissue and/or elevated TGF-β and reduced BMP-7 levels with FK506 toxicity may reverse the inhibitory effects of RAS blockade on PAI-1 expression.
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Agirbasli Mehmet, Bozkurtlar Bas Emine, Papila-Topal Nurdan, Deniz Hicran, Ogutmen Betul and Cakalagaoglu Fulya, Tacrolimus Toxicity Reverses the Inhibitory Effects of Renin Angiotensin System Blockade on PAI-1 Expression in Cardiac Tissue, Current Enzyme Inhibition 2013; 9 (2) . https://dx.doi.org/10.2174/1573408011309020002
DOI https://dx.doi.org/10.2174/1573408011309020002 |
Print ISSN 1573-4080 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-6662 |
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