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Cyclosporine A normalizes mitochondrial coupling, reactive oxygen species production, and inflammation and partially restores skeletal muscle maximal oxidative capacity in experimental aortic cross-clamping.
J Vasc Surg. 2013 Apr; 57(4):1100-1108.e2.JV

Abstract

OBJECTIVE

By binding to cyclophilin D, cyclosporine A (CsA) inhibits mitochondrial permeability transition pore (mPTP) opening and prevents mitochondrial dysfunction and ultimately cell death after ischemia-reperfusion (IR) injury in cardiac muscle. This study tested whether CsA would decrease skeletal muscle oxidative stress and mitochondrial dysfunctions after aortic cross-clamping related IR.

METHODS

Forty-five Wistar rats were investigated. The sham group (n = 8) had aortic exposure but no ischemia, the IR group (n = 10) had aortic cross-clamping for 3 hours followed by 2 hours of reperfusion, and the IR+CsA group (n = 9) had two intraperitoneal injections of 10 mg of CsA at 90 and 150 minutes of ischemia before reperfusion. Mitochondrial coupling (acceptor control ratio) and mitochondrial respiratory chain complexes' activities were measured. Reactive oxygen species (ROS) production, cyclophilin D expression, and muscle inflammation were determined using dihydroethidium staining, Western blot, and immunohistochemistry, respectively. An additional 18 sham rats were investigated to determine CsA blood levels and the effects of CsA on mitochondrial respiration and calcium retention capacity, a marker of mPTP opening, both in myocardium and gastrocnemius with and without CsA.

RESULTS

Compared with sham, IR decreased mitochondrial coupling (1.38 ± 0.06 vs 1.98 ± 0.20; P = .0092), increased ROS production (3992 ± 706 arbitrary units [AU] vs 1812 ± 322 AU; P = .033), was associated with macrophage infiltration, and decreased maximal oxidative capacity (V(max): 4.08 ± 0.38 μmol O(2)/min/g vs 5.98 ± 0.56 μmol O(2)/min/g; P = .015). Despite IR, CsA treatment totally restored mitochondrial coupling (1.93 ± 0.12; P = .023 vs IR), normalized ROS (1569 ± 348 AU; P = .0098 vs IR), and decreased inflammation. The V(max) was slightly enhanced (5.02 ± 0.39 μmol O(2)/min/g; P = .33 vs IR; P = .35 vs sham). Compared with myocardium, gastrocnemius muscle was characterized by a decreased cyclophilin D content (-50%) associated with an earlier opening of mPTP (calcium retention capacity increased from 10.85 ± 1.35 μM/mg dry weight [DW] to 12.11 ± 2.77 μM/mg DW; P = .65; and from 11.07 ± 1.67 to 37.65 ± 11.41 μM/mg DW; P = .0098 in gastrocnemius and heart, respectively).

CONCLUSIONS

Cyclosporine A normalized ROS production, decreased inflammation, and restored mitochondrial coupling during aortic cross-clamping. Incomplete Vmax protection might be due to low cyclophilin D expression in gastrocnemius, preventing CsA from blocking mPTP opening.

Authors+Show Affiliations

Pôle Anesthésie Réanimation Chirurgicale, SAMU, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

23332985

Citation

Pottecher, Julien, et al. "Cyclosporine a Normalizes Mitochondrial Coupling, Reactive Oxygen Species Production, and Inflammation and Partially Restores Skeletal Muscle Maximal Oxidative Capacity in Experimental Aortic Cross-clamping." Journal of Vascular Surgery, vol. 57, no. 4, 2013, pp. 1100-1108.e2.
Pottecher J, Guillot M, Belaidi E, et al. Cyclosporine A normalizes mitochondrial coupling, reactive oxygen species production, and inflammation and partially restores skeletal muscle maximal oxidative capacity in experimental aortic cross-clamping. J Vasc Surg. 2013;57(4):1100-1108.e2.
Pottecher, J., Guillot, M., Belaidi, E., Charles, A. L., Lejay, A., Gharib, A., Diemunsch, P., & Geny, B. (2013). Cyclosporine A normalizes mitochondrial coupling, reactive oxygen species production, and inflammation and partially restores skeletal muscle maximal oxidative capacity in experimental aortic cross-clamping. Journal of Vascular Surgery, 57(4), 1100-e2. https://doi.org/10.1016/j.jvs.2012.09.020
Pottecher J, et al. Cyclosporine a Normalizes Mitochondrial Coupling, Reactive Oxygen Species Production, and Inflammation and Partially Restores Skeletal Muscle Maximal Oxidative Capacity in Experimental Aortic Cross-clamping. J Vasc Surg. 2013;57(4):1100-1108.e2. PubMed PMID: 23332985.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Cyclosporine A normalizes mitochondrial coupling, reactive oxygen species production, and inflammation and partially restores skeletal muscle maximal oxidative capacity in experimental aortic cross-clamping. AU - Pottecher,Julien, AU - Guillot,Max, AU - Belaidi,Elise, AU - Charles,Anne-Laure, AU - Lejay,Anne, AU - Gharib,Abdallah, AU - Diemunsch,Pierre, AU - Geny,Bernard, Y1 - 2013/01/18/ PY - 2012/07/23/received PY - 2012/09/07/revised PY - 2012/09/15/accepted PY - 2013/1/22/entrez PY - 2013/1/22/pubmed PY - 2013/5/23/medline SP - 1100 EP - 1108.e2 JF - Journal of vascular surgery JO - J Vasc Surg VL - 57 IS - 4 N2 - OBJECTIVE: By binding to cyclophilin D, cyclosporine A (CsA) inhibits mitochondrial permeability transition pore (mPTP) opening and prevents mitochondrial dysfunction and ultimately cell death after ischemia-reperfusion (IR) injury in cardiac muscle. This study tested whether CsA would decrease skeletal muscle oxidative stress and mitochondrial dysfunctions after aortic cross-clamping related IR. METHODS: Forty-five Wistar rats were investigated. The sham group (n = 8) had aortic exposure but no ischemia, the IR group (n = 10) had aortic cross-clamping for 3 hours followed by 2 hours of reperfusion, and the IR+CsA group (n = 9) had two intraperitoneal injections of 10 mg of CsA at 90 and 150 minutes of ischemia before reperfusion. Mitochondrial coupling (acceptor control ratio) and mitochondrial respiratory chain complexes' activities were measured. Reactive oxygen species (ROS) production, cyclophilin D expression, and muscle inflammation were determined using dihydroethidium staining, Western blot, and immunohistochemistry, respectively. An additional 18 sham rats were investigated to determine CsA blood levels and the effects of CsA on mitochondrial respiration and calcium retention capacity, a marker of mPTP opening, both in myocardium and gastrocnemius with and without CsA. RESULTS: Compared with sham, IR decreased mitochondrial coupling (1.38 ± 0.06 vs 1.98 ± 0.20; P = .0092), increased ROS production (3992 ± 706 arbitrary units [AU] vs 1812 ± 322 AU; P = .033), was associated with macrophage infiltration, and decreased maximal oxidative capacity (V(max): 4.08 ± 0.38 μmol O(2)/min/g vs 5.98 ± 0.56 μmol O(2)/min/g; P = .015). Despite IR, CsA treatment totally restored mitochondrial coupling (1.93 ± 0.12; P = .023 vs IR), normalized ROS (1569 ± 348 AU; P = .0098 vs IR), and decreased inflammation. The V(max) was slightly enhanced (5.02 ± 0.39 μmol O(2)/min/g; P = .33 vs IR; P = .35 vs sham). Compared with myocardium, gastrocnemius muscle was characterized by a decreased cyclophilin D content (-50%) associated with an earlier opening of mPTP (calcium retention capacity increased from 10.85 ± 1.35 μM/mg dry weight [DW] to 12.11 ± 2.77 μM/mg DW; P = .65; and from 11.07 ± 1.67 to 37.65 ± 11.41 μM/mg DW; P = .0098 in gastrocnemius and heart, respectively). CONCLUSIONS: Cyclosporine A normalized ROS production, decreased inflammation, and restored mitochondrial coupling during aortic cross-clamping. Incomplete Vmax protection might be due to low cyclophilin D expression in gastrocnemius, preventing CsA from blocking mPTP opening. SN - 1097-6809 UR - https://www.unboundmedicine.com/medline/citation/23332985/Cyclosporine_A_normalizes_mitochondrial_coupling_reactive_oxygen_species_production_and_inflammation_and_partially_restores_skeletal_muscle_maximal_oxidative_capacity_in_experimental_aortic_cross_clamping_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0741-5214(12)02007-1 DB - PRIME DP - Unbound Medicine ER -