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- Title
Enhanced cell-volume regulation in cyclosporin A cardioprotection.
- Authors
Diaz, Roberto J.; Fernandes, Kelly; Lytvyn, Yuliya; Hawrylyshyn, Krista; Harvey, Kordan; Hossain, Taneya; Hinek, Alina; Wilson, Gregory J.
- Abstract
Aims Cyclosporin A (CsA) has been shown to protect against ischaemia/reperfusion injury presumably by its inhibition of mitochondrial permeability transition pore opening through cyclophilin D inhibition. We examine if CsA cardioprotection involves a cell-volume regulatory mechanism. Methods and results To address this issue, cultured rabbit cardiomyocytes were subjected to the following protocols: (i) cardiomyocytes were treated with 200 nM CsA either given for 10 min followed by 10 min of washout prior to 30 min hypo-osmotic stress (200 mOsm) or administered throughout 75 min simulated ischaemia/60 min simulated reperfusion. Cell necrosis and cell swelling were determined by trypan blue staining and cell-volume measurements, respectively; (ii) SPQ(6-methoxy-N-(3-sulfopropyl)quinolinium) dye loaded cardiomyocytes were treated with 200 nM CsA for 10 min followed by 10 min washout and intracellular Cl− concentration measured (Cl− efflux); (iii) 5,5′,6,6′-tetrachloro-1,1′,3,3′- tetraethylbenzimi-dazolylcarbocyanine iodide(JC-1) loaded cardiomyocytes were treated with 200 nM CsA to inhibit mitochondrial membrane potential (ΔΨm) dissipation (an index of mitochondria permeability transition pore opening) by either valinomycin (2 μM) or ischaemia/reperfusion injury. Cl− channels were blocked by indanyloxyacetic acid 94 (IAA-94, 50 μM). CsA not only significantly (P < 0.001) reduced the % of dead cells following simulated ischaemia/reperfusion but it also triggered an efflux of Cl−, hence enhancing cardiomyocyte cell-volume regulatory response. CsA protection against cell necrosis and its effect on Cl− transport/volume regulation were all blocked by IAA-94. IAA-94 had no effect on ΔΨm. Conclusion These data indicate that CsA protects against cell necrosis at least in part by enhancing cardiomyocyte volume regulation, and not simply by inhibiting MPTP opening.
- Subjects
CELLULAR control mechanisms; CYCLOSPORINE; CELL size; CARDIOVASCULAR disease prevention; ISCHEMIA; CYCLOPHILINS; HEART cells; CELL culture
- Publication
Cardiovascular Research, 2013, Vol 98, Issue 3, p411
- ISSN
0008-6363
- Publication type
Article
- DOI
10.1093/cvr/cvt056