Objective: 

Cyclosporine (CsA) reduces myocardial infarction through cyclophylin D (CypD) blockade. Preliminary data show that CsA partially decreases gastrocnemius (GC) mitochondrial dysfunction after aortic clamping (1). To further determine the implication of CypD, we determined CypD levels in normal heart and GC and in GC after ischemia-reperfusion (IR).

Methods: 

Anaesthetized Wistar rats were randomized to control (n = 8), IR (n = 10, clamping of the infra-renal aorta for 3 h followed by 2 h of reperfusion), or IR+CsA groups (n = 7, 10mg/kg CsA administered intraperitoneally 90 and 30 min prior to reperfusion). Maximal oxidative capacitiy (Vmax) and coupling of phosphorylation to oxidation (ACR) were determined in GC permeabilized fibers. Tissue superoxide anion was assessed with dihydroethidium (DHE) staining. CypD expression was assessed by Western-blot.

Results: 

CypD levels were increased in normal heart as compared to GC (5.52±0.86 vs 2.18±0.38 arbitrary units (A.U.), p<0.05). Compared to Sham, IR significantly decreased GC Vmax (5.98±0.56 vs 4.08±0.38 mMO2/min/g; p < 0.05), ACR (1.98±0.20 vs 1.38±0.06; p<0.05) and increased GC superoxide anion (3992±706 vs. 1812±322 A.U.; p< 0.05). IR tended to decrease GC CypD expression (-21%, NS)

CsA normalized ACR and superoxide anion, partially restored Vmax (5.02±0.39 mMO2/min/g; NS), and unmodified CypD (1.28±0.14 A.U.).

Conclusions: 

Aortic cross clamping induced GC mitochondrial dysfunction and ROS overproduction. CsA decreased oxidative stress and partially restored GC mitochondrial function. A lower level of CypD in GC, as compared to the heart might participate in these results.

Reference: 1) Pottecher J et al (2010) Intensive Care Med 32: S143.