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.
Related Books
In Vitro Propagation and Secondary Metabolite Production from Medicinal Plants: Current Trends (Part 2)
Micropropagation of Medicinal Plants
Software and Programming Tools in Pharmaceutical Research
Biotechnology and Drug Development for Targeting Human Diseases
In Vitro Propagation and Secondary Metabolite Production from Medicinal Plants: Current Trends (Part 1)
Molecular and Physiological Insights into Plant Stress Tolerance and Applications in Agriculture- Part 2
Micropropagation of Medicinal Plants
Genome Editing in Bacteria (Part 1)
Data Science for Agricultural Innovation and Productivity
Animal Models In Experimental Medicine
30