Abstract
ObjectiveGas microembolism remains a serious risk associated with surgical procedures and decompression. Despite this, the signaling consequences of air bubbles in the vasculature are poorly understood and there is a lack of pharmacological therapies available. Here, we investigate the mitochondrial consequences of air bubble contact with endothelial cells.Methods and ResultsHuman umbilical vein endothelial cells were loaded with an intracellular calcium indicator (Fluo-4) and either a mitochondrial calcium indicator (X-Rhod-1) or mitochondrial membrane potential indicator (TMRM). Contact with 50–150 µm air bubbles induced concurrent rises in intracellular and mitochondrial calcium, followed by a loss of mitochondrial membrane potential. Pre-treating cells with 1 µmol/L ruthenium red, a TRPV family calcium channel blocker, did not protect cells from the mitochondrial depolarization, despite blocking the intracellular calcium response. Mitigating the interactions between the air-liquid interface and the endothelial surface layer with 5% BSA or 0.1% Pluronic F-127 prevented the loss of mitochondrial membrane potential. Finally, inhibiting protein kinase C-α (PKCα), with 5 µmol/L Gö6976, protected cells from mitochondrial depolarization, but did not affect the intracellular calcium response.ConclusionsOur results indicate that air bubble contact with endothelial cells activates a novel, calcium-independent, PKCα-dependent signaling pathway, which results in mitochondrial depolarization. As a result, mitochondrial dysfunction is likely to be a key contributor to the pathophysiology of gas embolism injury. Further, this connection between the endothelial surface layer and endothelial mitochondria may also play an important role in vascular homeostasis and disease.
Highlights
Gas embolism occurs when a gas, typically air, enters the vasculature
Our results indicate that air bubble contact with endothelial cells activates a novel, calcium-independent, protein kinase C-a (PKCa)-dependent signaling pathway, which results in mitochondrial depolarization
Mitochondrial dysfunction is likely to be a key contributor to the pathophysiology of gas embolism injury
Summary
Gas embolism occurs when a gas, typically air, enters the vasculature. This can occur during a surgical procedure or as a result of a decompression event [1]. Bubbles can cause damage in the microcirculation of any organ, obstruct blood vessels, or even air-lock the heart [2]. Despite greater awareness and improved practice, gas microembolism continues to be a serious risk associated with surgical procedures, those involving cardiopulmonary bypass (CPB), and likely contributes to the incidence of cognitive deficit following such surgeries [3]. Despite the dangers associated with gas embolism, there is a lack of pharmacological therapies. The ‘‘gold standard’’ therapy, hyperbaric oxygen, is both limited in effectiveness and potentially difficult and dangerous to administer [2]
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