Abstract 161: Differential Effects of Short- and Long-Term Increase in Endothelial ROS on Coronary Vascular Function

Abstract

Introduction: Increase in reactive oxygen species (ROS) is often associated with vascular pathophysiological conditions. Our recent findings demonstrated that transient increase in ROS improved coronary endothelial function. However, long-term effects of endothelium-specific increase in ROS on endothelial function are not known.

Hypothesis: The short-term (four to eight weeks) versus the long-term (16 to 20 weeks) increase in NADPH oxidase-derived ROS will have differential effects on vascular endothelium.

Methods: Our binary (Tet-ON/OFF) conditional transgenic mouse (Tet-Nox2:VE-Cad-tTA) induces 1.8±0.42-fold increase in NADPH oxidase-derived ROS in endothelium. Using these animals, we have examined the effects of short-term vs. the long-term effects of ROS on endothelial cell (EC) signaling and coronary endothelial function.

Results: We demonstrate that whereas EC-dependent coronary vasodilation was significantly increased after short-term increase in ROS, coronary vasodilation was drastically reduced after long-term increase in EC-ROS in Tet-OFF Nox2 mice compared to their Tet-ON (control) littermates. Using EC isolated from mouse heart, we demonstrate that, whereas Nox2-derived both short-term and long-term increase in ROS increased activation of AMPK and eNOS, and nitric oxide (NO) synthesis, long-term increase in ROS abrogated these positive effects due to increased peroxynitrite and nitrotyrosylation of MnSOD. We also show that long-term ROS increase resulted in abrogation of EC proliferation and reduction in EC mitochondrial content compared to short-term ROS exposure.

Conclusion: This study demonstrates that whereas short-term increase in ROS is beneficial for EC function, long-term increase in ROS results in loss of EC mitochondria and inhibition of endothelial function.