Alterations induced by cyclosporine A in myocardial fibers and extracellular matrix in rat

Abstract

Cyclosporine A (CsA) is the first choice immunosuppressant universally used in allotransplantation. However, it has been demonstrated that this drug produces unwanted side effects in several organs and in particular in the kidney and in the heart. While the cardiac toxicity, due to alteration of myocardial prostanoid has been reported, no data are available about the effects of CsA on myocardial cytoarchitecture. We studied the CsA induced alterations of the myocardial structure and of the extracellular matrix components (ECM). To test the ECM enzymatic changes we studied a family of enzymes (matrix metalloproteinase-MMP), responsible for the degradation of extracellular matrix components. In particular we investigated MMP1, MMP2 and MMP9. The study was carried out on two groups of Wistar rats. The group I animals served as a control and were injected subcutaneously daily with castor oil for 21 days. Group II: animals were subcutaneously injected daily with CsA (dose: 15 mg/Kg in castor oil) for 21 days. The group I animals (control) had normal heart architecture and low levels of MMP1, MMP2 and MMP9. The group II animals showed degenerative changes with myocardial fibrosis, low levels of MMP1 and MMP9 but a clear increase in MMP2. We suggest that the myocardial fibrosis was a consequence of the cardiotoxic effect of CsA determining the alteration of the balance between synthesis and degradation of ECM. The increase in MMP2 suggests that this enzyme could play a protective role during myocardial damage and represent a compensatory mechanism for the excessive accumulation of collagen.