Treatment with Dietary Cyclosporine has no Direct Effect on Myocardial Fibrosis and Hypertension in Mice

Cyclosporine, a potent immunosuppressive agent, is proved to be effective to reduce the incidence of acute organ rejection and increase early graft survival in patients who received kidney, liver, lung or heart transplant. However, the adverse effects associated with the use of cyclosporine such as nephrotoxicity and interstitial fibrosis in kidney transplant recipient have also been observed [1,2]. Although the mechanisms of action related to cyclosporine mediated transplant complications are still remained to be illustrated as a matter of debate [3], previous studies have demonstrated that activation of angiotensin II (Ang II) [4,5] and production of reactive oxygen species [6] might be primarily involved in the pathogenesis of chronic cyclosporine nephrotoxicity. In spontaneously hypertensive rats, a previous study has shown that cyclosporine treatment enhances angiotensin converting enzyme activity to produce Ang II, and cyclosporine-induced nephropathy can be attenuated by the Ang II AT1 receptor blocker [5]. Furthermore, chronic cyclosporine nephrotoxicity could also be relieved by anti-inflammatory drugs [7,8]. Under these conditions, inhibition of perivascular and interstitial fibrosis resulting from cyclosporine toxicity has been reported. In this regard, we have recently reported that the extravasation of macrophages and proliferation of myofibroblasts are the predominant features in stimulation of transforming growth factor-β mediated fibrotic signaling in response to Ang II stimulation and oxidant production [9,10]. However, it is unknown whether administration of cyclosporine has any toxic effects on the heart and blood vessels, and whether dietary cyclosporine could be selected as a conventional intervention for treatment of cardiovascular diseases. Therefore, the present study was designed to evaluate the direct effect of cyclosporine, which simulates the regimen of clinical treatment in patient, on the heart and blood pressure. To illustrate whether cyclosporine is associated with stimulation of Ang II AT1 receptor and induction of inflammation, telmisartan, the Ang II AT1 receptor blocker and curcumin, an anti-oxidant compound [10] were concomitantly administered during the treatment period with dietary cyclosporine. Expression of angiotensin converting enzyme 2 (ACE2), AT1/AT2 receptors, monocyte chemotactic protein-1 (MCP-1), transforming growth factor β1 (TGF-β1) and collagens was characterized to check the potential injurious mechanisms involved. Cardio toxicity likely-induced by cyclosporine was evaluated by accumulation of macrophages/myofibroblasts and interstitial/perivascular fibrosis. Blood pressure was measured noninvasively to check whether dietary cyclosporine induces hypertension. Volume 1 Issue 4 2017