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Anesthesiology:
doi: 10.1097/ALN.0000000000000295
Perioperative Medicine: Basic Science

Cardioprotective Trafficking of Caveolin to Mitochondria Is Gi-protein Dependent

Wang, Jiawan M.D.; Schilling, Jan M. M.D.; Niesman, Ingrid R. Ph.D.; Headrick, John P. Ph.D.; Finley, J. Cameron B.S.; Kwan, Evan B.S.; Patel, Piyush M. M.D.; Head, Brian P. Ph.D.; Roth, David M. M.D., Ph.D.; Yue, Yun M.D.; Patel, Hemal H. Ph.D.

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Abstract

Background: Caveolae are a nexus for protective signaling. Trafficking of caveolin to mitochondria is essential for adaptation to cellular stress though the trafficking mechanisms remain unknown. The authors hypothesized that G protein–coupled receptor/inhibitory G protein (Gi) activation leads to caveolin trafficking to mitochondria.
Methods: Mice were exposed to isoflurane or oxygen vehicle (30 min, ±36 h pertussis toxin pretreatment, an irreversible Gi inhibitor). Caveolin trafficking, cardioprotective “survival kinase” signaling, mitochondrial function, and ultrastructure were assessed.
Results: Isoflurane increased cardiac caveolae (n = 8 per group; data presented as mean ± SD for Ctrl versus isoflurane; [caveolin-1: 1.78 ± 0.12 vs. 3.53 ± 0.77; P < 0.05]; [caveolin-3: 1.68 ± 0.29 vs. 2.67 ± 0.46; P < 0.05]) and mitochondrial caveolin levels (n = 16 per group; [caveolin-1: 0.87 ± 0.18 vs. 1.89 ± .19; P < 0.05]; [caveolin-3: 1.10 ± 0.29 vs. 2.26 ± 0.28; P < 0.05]), and caveolin-enriched mitochondria exhibited improved respiratory function (n = 4 per group; [state 3/complex I: 10.67 ± 1.54 vs. 37.6 ± 7.34; P < 0.05]; [state 3/complex II: 37.19 ± 4.61 vs. 71.48 ± 15.28; P < 0.05]). Isoflurane increased phosphorylation of survival kinases (n = 8 per group; [protein kinase B: 0.63 ± 0.20 vs. 1.47 ± 0.18; P < 0.05]; [glycogen synthase kinase 3β: 1.23 ± 0.20 vs. 2.35 ± 0.20; P < 0.05]). The beneficial effects were blocked by pertussis toxin.
Conclusions: Gi proteins are involved in trafficking caveolin to mitochondria to enhance stress resistance. Agents that target Gi activation and caveolin trafficking may be viable cardioprotective agents.

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