Title : Use of mitochondrial ROS inhibitor to protect coronary microvascular/endothelial function
Abstract:
Cardioplegic ischemia/reperfusion (I/R), hypoxia/re-oxygenation (H/R) and diabetes mellitus (DM) are associated with increased oxidative stress which contribute to coronary microvascular/endothelial dysfunction. Mitochondrial reactive oxidative species (mROS), a major source of ROS in the endothelium following I/R and DM plays an important role in vascular endothelial dysfunction. Thus, we hypothesized that inhibition of mROS may protect against coronary microvascular endothelial dysfunction/relaxation. Using cell and vessel models of cardioplegic I/R in the setting of mouse T2DM, we found that acute inhibition of mROS with Mito-Tempo reduced cardioplegic H/R-induced endothelial mROS and Ca2+ overload in both the nondiabetic and diabetes mellitus groups, respectively (P<.05). Inhibition of significantly increased vasodilatory responses of coronary arterioles to the endothelium-dependent vasodilator ADP and the SK channel activator NS309 along with enhancement of endothelial SK channel activity (P<.05). In-vivo study indicate chronic inhibition of mROS with Mito-Tempo for 4 weeks remarkedly improved the relaxation responses of mouse coronary microvessels to ADP and SNP at dose-dependent manner. Furthermore, chronic inhibition of mROS also increased endothelial SK channel current density along with reduced mROS levels. Treatment with mito-TEMPO significantly reduced pro-apoptosis protein/gene expression, and increased anti-apoptosis protein/gene expression in endothelial cells in the setting of H/R. Thus, mROS inhibition may be a novel therapeutic approach for coronary endothelial protection against cardioplegic-I/R injury in patients with and without DM.
