Abstract
Endothelial dysfunction is common in acute and chronic organ injury. Isoflurane is a widely used halogenated volatile anesthetic during the perioperative period and protects against endothelial cell death and inflammation. In this study, we tested whether isoflurane induces endothelial ecto-5′-nucleotidase (CD73) and cytoprotective adenosine generation to protect against endothelial cell injury. Clinically relevant concentrations of isoflurane induced CD73 activity and increased adenosine generation in cultured human umbilical vein or mouse glomerular endothelial cells. Surprisingly, isoflurane-mediated induction of endothelial CD73 activity occurred within 1 hr and without synthesizing new CD73. We determined that isoflurane rapidly increased CD73 containing endothelial microparticles into the cell culture media. Indeed, microparticles isolated from isoflurane-treated endothelial cells had significantly higher CD73 activity as well as increased CD73 protein. In vivo, plasma from mice anesthetized with isoflurane had significantly higher endothelial cell-derived CD144+ CD73+ microparticles and had increased microparticle CD73 activity compared to plasma from pentobarbital-anesthetized mice. Supporting a critical role of CD73 in isoflurane-mediated endothelial protection, a selective CD73 inhibitor (APCP) prevented isoflurane-induced protection against human endothelial cell inflammation and apoptosis. In addition, isoflurane activated endothelial cells Rho kinase evidenced by myosin phosphatase target subunit-1 and myosin light chain phosphorylation. Furthermore, isoflurane-induced release of CD73 containing microparticles was significantly attenuated by a selective Rho kinase inhibitor (Y27632). Taken together, we conclude that the volatile anesthetic isoflurane causes Rho kinase-mediated release of endothelial microparticles containing preformed CD73 and increase adenosine generation to protect against endothelial apoptosis and inflammation.
Highlights
More than 1 trillion endothelial cells in human body cover the entire circulatory system and play an integral role in maintaining homeostasis of all organs [1]
We determined that isoflurane treatment significantly increased adenosine levels in human and mouse endothelial cell culture media when compared with carrier gas-treated cells (Figure 1A)
Endothelial Cells The set of experiments determined whether isoflurane stimulates CD73 activity to increase adenosine generation in cultured endothelial cells
Summary
More than 1 trillion endothelial cells in human body cover the entire circulatory system and play an integral role in maintaining homeostasis of all organs [1]. Endothelial cells regulate vascular tone, angiogenesis, coagulation and release several critically important autocrine and paracrine compounds including sphingosine 1-phosphate, adenosine, nitric oxide, and prostaglandins [2,3]. Endothelial cell death occurs frequently after ischemia and reperfusion injury, diabetes, coronary artery disease and sepsis [3,5,6]. Volatile anesthetics have non-anesthetic effects on the heart, vasculature and respiratory system by regulating blood pressure, heart rate, airway tone and systemic vascular resistance [8,9]. Volatile anesthetics have anti-necrotic and anti-inflammatory effects and protect against ischemia reperfusion injury of the heart, kidney and intestine [9,10,11]. Volatile anesthetics attenuate the hyperactive systemic inflammatory response during sepsis [12]
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