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Inhibition of Mitochondrial Permeability Transition Prevents Sepsis-Induced Myocardial Dysfunction and Mortality

Jérome Larche, MD^_*,, Steve Lancel, PhD^_*,, Sidi Mohamed Hassoun^_*,, Raphael Favory, MD^_*,, Brigitte Decoster, PhD^_*,, Philippe Marchetti, MD, PhD, Claude Chopin, MD^_* and Remi Neviere, MD, PhD^_*,,_*

^_* EA 2689, Université de Lille 2
Département de Physiologie
INSERM U459, Faculté de Médecine 1, Lille, France

View larger version (9K): [in a new window]   Figure 1 Survival rate of different groups of mice: survival rate of mice undergoing cecal ligation and puncture without treatment (CLP) was compared with that of animals treated with 2, 10, and 100 mg/kg cyclosporine A (A) or N-methyl-4-isoleucine cyclosporine (NIM811) (B). Mice overexpressing B cell leukemia (Bcl)-2 had a survival rate of 80% (C). Sample size is 12 in each group. Survival studies were conducted twice. *p < 0.05, sham versus treatment or transgenic CLP mice; p < 0.05, CLP versus treatment or transgenic CLP mice, by Kaplan-Meier, log-rank.

View larger version (14K): [in a new window]   Figure 2 Cardiac function of sham and cecal ligation and puncture (CLP) wild-type mice and transgenic mice overexpressing B-cell leukemia (Bcl). (A) Left ventricular (LV) tension and (B) maximal increases in pressure (dF/dt max) values were recorded after a 30-min equilibration period. Sample size is 12 in each group. Results are expressed as means ± SEM and analyzed by means of one-way analysis of variance and Bonferroni's multiple comparison post hoc adjustment. *p = 0.005 versus sham mice (Bonferroni adjusted; ten comparisons). p = 0.005 versus CLP mice (Bonferroni adjusted; ten comparisons). NIM811 = N-methyl-4-isoleucine cyclosporine.

View larger version (16K): [in a new window]   Figure 3 Representative example of mitochondrial permeability transition induced by calcium overload in preparation of isolated mitochondria. Recordings are displayed in one sham (a), one cecal ligation and puncture (CLP) (b), one cyclosporine-A–treated CLP (c), one N-methyl-4-isoleucine cyclosporine (NIM811)-treated CLP (d), and one CLP transgenic mouse (e). In sham mice (a), a Ca2+ load of 260 µmol/l (26 pulses of 10 µmol/l Ca2+) was required to induce mitochondrial permeability transition versus 80 µmol/l Ca2+ (8 pulses of 10 µmol/l Ca2+) in wild-type CLP mice.

View larger version (12K): [in a new window]   Figure 4 The Ca2+ load required for mitochondrial permeability transition in sham and CLP wild-type mice and mice overexpressing Bcl-2. Sample size is 12 in each group. Results are expressed as means ± SEM and analyzed by means of one-way analysis of variance and Bonferroni's multiple comparison post hoc adjustment. *p = 0.005 versus sham mice (Bonferroni adjusted; ten comparisons). p = 0.005 versus CLP mice (Bonferroni adjusted; ten comparisons). Abbreviations as in Figure 2.

View larger version (32K): [in a new window]   Figure 5 (A) Representative caspase-9–like (LEHDase) and (B) caspase-3–like (DEVDase) activities in heart left ventricle of sham and CLP wild-type mice and mice overexpressing Bcl-2. Inset panel presents LEHDase maximal fluorescence intensity (counts per second [cps]) measured (em = 437 nm) as means ± SEM of in each group (sample size is 12 in each group). Results are analyzed by means of one-way analysis of variance and Bonferroni's multiple comparison post hoc adjustment. *p = 0.005 versus sham mice (Bonferroni adjusted; 10 comparisons). p = 0.005 versus CLP mice (Bonferroni adjusted; 10 comparisons). Abbreviations as in Figure 2.