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(Circulation. 2007;115:2055-2064.)
© 2007 American Heart Association, Inc.

Vascular Medicine

Paraoxonase-2 Reduces Oxidative Stress in Vascular Cells and Decreases Endoplasmic Reticulum Stress–Induced Caspase Activation

Sven Horke, PhD; Ines Witte, PhD; Petra Wilgenbus, MS; Maximilian Krüger, BS; Dennis Strand, PhD; Ulrich Förstermann, MD, PhD

From the Department of Pharmacology (S.H., I.W., P.W., M.K., U.F.) and First Department of Internal Medicine (D.S.), Johannes Gutenberg University, Mainz, Germany.

Correspondence to Sven Horke, PhD, Department of Pharmacology, Johannes Gutenberg University, Obere Zahlbacher Strasse 67, 55131 Mainz, Germany. E-mail horke{at}uni-mainz.de

Received August 8, 2006; accepted January 19, 2007.

Background— In the vascular system, elevated levels of reactive oxygen species (ROS) produce oxidative stress and predispose to the development of atherosclerosis. Therefore, it is important to understand the systems producing and those scavenging vascular ROS. Here, we analyzed the ROS-reducing capability of paraoxonase-2 (PON2) in different vascular cells and its involvement in the endoplasmic reticulum stress pathway known as the unfolded protein response.

Methods and Results— Quantitative real-time polymerase chain reaction and Western blotting revealed that PON2 is equally expressed in vascular cells and appears in 2 distinct glycosylated isoforms. By determining intracellular ROS, we show that overexpression of PON2 markedly reduced ROS, whereas its knockdown increased ROS levels significantly. Using microscopic and biochemical methods, we found PON2 mainly in the nuclear membrane and endoplasmic reticulum. Furthermore, PON2 expression was induced at both the promoter and protein levels by endoplasmic reticulum stress pathway unfolded protein response. This pathway may promote both apoptotic and survival mechanisms. Functionally, PON2 reduced unfolded protein response–accompanying oxidative stress and unfolded protein response–derived caspase activation.

Conclusion— We suggest that PON2 represents an endogenous defense mechanism against vascular oxidative stress and unfolded protein response–induced cell death, thereby contributing to the prevention of atherosclerosis.

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