Isoflurane, but not sevoflurane, increases transendothelial albumin permeability in the isolated rat lung: role for enhanced phosphorylation of caveolin-1.
ABSTRACT Caveolae mediated transendothelial transport of albumin has recently been shown to be the primary mechanism regulating microvascular endothelial albumin permeability. The authors investigated the effects of isoflurane and sevoflurane on pulmonary endothelial albumin permeability and assessed the potential role of the caveolae scaffold protein, caveolin-1, in these effects.
Isolated rat lungs and cultured rat lung microvessel endothelial cells (RLMVECs) were exposed to 1.0 or 2.0 minimum alveolar concentration (MAC) isoflurane or sevoflurane for 30 min. I-albumin permeability-surface area product and capillary filtration coefficient were determined in the isolated lungs. In RLMVECs, uptake and transendothelial transport of I-albumin were measured in the absence and presence of pretreatment with 2 mm methyl-beta-cyclodextrin, a caveolae-disrupting agent. Uptake of fluorescent-labeled albumin, as well as phosphorylation of Src kinase and caveolin-1, was also determined. In Y14F-caveolin-1 mutant (nonphosphorylatable) expressing RLMVECs, uptake of I-albumin and phosphorylation of caveolin-1 were evaluated.
In the isolated lungs, 2.0 MAC isoflurane increased I-albumin permeability-surface area product by 48% without affecting capillary filtration coefficient. In RLMVECs, isoflurane more than doubled the uptake of I-albumin and caused a 54% increase in the transendothelial transport of I-albumin. These effects were blocked by pretreatment with methyl-beta-cyclodextrin. The isoflurane-induced increase in uptake of I-albumin in wild-type RLMVECs was abolished in the Y14F-caveolin-1 mutant expressing cells. Isoflurane also caused a twofold increase in Src and caveolin-1 phosphorylation. Neither 1.0 MAC isoflurane nor 1.0 or 2.0 MAC sevoflurane affected any index of albumin transport or phosphorylation of caveolin-1.
Isoflurane, but not sevoflurane, increased lung transendothelial albumin permeability through enhancement of caveolae-mediated albumin uptake and transport in the isolated lung. This effect may involve an enhanced phosphorylation of caveolin-1.
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ABSTRACT: Caveolae are flask-like invaginations of the cell surface that have been identified as signaling epicenters. Within these microdomains, caveolins are structural proteins of caveolae, which are able to interact with numerous signaling molecules affecting temporal and spatial dimensions required in cardiac protection. This complex moiety is essential to the mechanisms involved in volatile anesthetics. In this review we will outline a general overview of caveolae and caveolins and their role in protective signaling with a focus on the effects of volatile anesthetics. These recent developments have allowed us to better understand the mechanistic effect of volatile anesthestics and their potential in cardiac protection.Current pharmaceutical design 02/2014; · 4.41 Impact Factor
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ABSTRACT: 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. 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. 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. 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.Anesthesiology 05/2014; · 6.17 Impact Factor