Danny Ramzy, Laura C. Tumiati, Ning Xu, Elissa Tepperman, Rohit Sheshgiri, Jessica Jackman, Vivek Rao; Cardiac Surgery, Toronto General Hospital, Toronto, ON, Canada
Objective: Endothelial dysfunction is a known etiologic cause of cardiac allograft vasculopathy. Cyclosporine (CyA) and corticosteroids are associated with many side effects such as endothelial dysfunction. However, the mechanisms of injury remain unclear. Our study examined the effects of CyA and corticosteroids on vasomotor dysfunction specifically nitric oxide (NO) and endothelin-1 (ET) homeostasis.Methods: Lewis rats were injected with CyA (5mg/Kg), hydrocortisone (Hcrt: 20mg/kg), CyA+Hcrt, or saline (Con) IP daily for 2-weeks. Thoracic aortic (TAo) segments were assessed for endothelial-dependent (Edep) and independent (Eind) relaxation following exposure to acetylcholine and sodium nitroprusside by deriving the %maximum relaxation (Emax). Vessel sensitivity to vasoconstriction was also assessed in each group using ET. Protein expression of eNOS, ETA and ETB receptors (Rc) in the TAo were determined. Free radical production (ROS) was also measured. Oxidative injury (OI) was assessed by changes in 8-isoprostane levels.
Results: Exposure to CyA resulted in impaired Edep vasorelaxation compared to control and Hcrt (Emax: CyA: 23±7%, CyA+Hcrt: 30±7%, Hcrt: 60±2%, Con: 52±8%, p=0.001). No significant differences in Eind vasorelaxation were seen. Compared to Con, all treatment groups demonstrated increased sensitivity to ET; however, Hcrt synergistically increased CyA induced vasospasm (%maximum contraction: CyA+Hcrt: 348±10%, CyA: 266±3%, Hcrt: 248±1%, Con: 209±2%, p<0.01). CyA and Hcrt downregulated eNOS expression compared to Con (p<0.01) while concomitant treatment synergistically reduced eNOS protein expression. ETA Rc expression was significantly upregulated in all treatment groups compared to Con with no significant changes in ETB Rc expression. CyA and CyA+Hcrt treatment significantly increased ROS production compared to Con and Hcrt (p<0.01). CyA exposure with or without Hcrt resulted in TAo oxidative injury as observed by increased 8-isoprostane levels compared to Hcrt and Con (p<0.001).
Conclusion: CyA and Hcrt results in vascular dysfunction characterized by impaired NO and ET homeostasis. Corticosteroid therapy enhances CyA induced vascular injury by altering eNOS and ETA Rc expression. Our findings suggest that corticosteroid treatment aggravates CyA induced vasomotor dysfunction. Novel therapies to preserve the endothelium must, therefore, target BOTH the NO and ET signaling pathways.
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