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2008 ; 86
(4
): 1286-92
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Cyclosporine preserves mitochondrial morphology after myocardial
ischemia/reperfusion independent of calcineurin inhibition
#MMPMID18805178
Leshnower BG
; Kanemoto S
; Matsubara M
; Sakamoto H
; Hinmon R
; Gorman JH 3rd
; Gorman RC
Ann Thorac Surg
2008[Oct]; 86
(4
): 1286-92
PMID18805178
show ga
BACKGROUND: Opening of the mitochondrial permeability transition pore (MPTP) has
been shown to contribute to myocardial ischemia/reperfusion injury. We sought to
demonstrate that the myocardial protective effect of inhibiting MPTP opening with
cyclosporine A (CsA) results in stabilization of mitochondrial morphology and is
independent of CsA-induced calcineurin inhibition. METHODS: Thirty-seven rabbits
were divided into three groups: control (n = 15), CsA (MPTP and calcineurin
inhibitor, n = 12), or FK506 (calcineurin inhibitor, n = 10). Each group received
a 1-hour infusion of either a saline vehicle, 25 mg/kg CsA or 1 mg/kg FK506. All
animals underwent 30 minutes of regional ischemia and 3 hours of reperfusion.
Myocardial infarct size was determined using Evans blue dye and
triphenyltetrazolium chloride. In situ oligo ligation was used to assess
apoptotic cell death. Transmission electron microscopy was used to quantitatively
evaluate morphologic differences in the mitochondria between groups. RESULTS:
Infarct size in the CsA group (39% +/- 3%) was significantly reduced compared
with the control group (60% +/- 2%, p < 0.001) and FK506 group (55% +/- 3%, p =
0.001). Apoptotic cell death was also attenuated in the CsA group (1.2% +/- 0.5%)
compared with the control group (4.3% +/- 0.8%, p = 0.01) and FK506 group (4.1%
+/- 0.9%, p = 0.05). Transmission electron microscopy revealed a preservation of
normal mitochondrial morphology and a reduction in the percentage of disrupted
mitochondria in the CsA group (20% +/- 7%) compared with the control group (53%
+/- 12%) and FK506 group (47% +/- 9%). CONCLUSIONS: Cyclosporine A-induced MPTP
inhibition preserves mitochondrial morphology after myocardial
ischemia/reperfusion and limits myocyte necrosis and apoptosis. These effects are
independent of calcineurin inhibition.