Mitochondria-targeted ROS scavenger improves post-ischemic recovery of cardiac function and attenuates mitochondrial abnormalities in aged rats

Abstract

Mitochondria-generated reactive oxygen species (ROS) play a crucial role in the pathogenesis of aging and age-associated diseases. In this study, we evaluated the effects of XJB-5-131 (XJB), a mitochondria-targeted ROS and electron scavenger, on cardiac resistance to ischemia-reperfusion (IR)-induced oxidative stress in aged rats. Male adult (5-month old, n=17) and aged (29-month old, n=19) Fischer Brown Norway (F344/BN) rats were randomly assigned to the following groups: adult (A), adult+XJB (AX), aged (O), and aged+XJB (OX). XJB was administered 3 times per week (3 mg/kg body weight, IP) for four weeks. At the end of the treatment period, cardiac function was continuously monitored in excised hearts using the Langendorff technique for 30 min, followed by 20-min of global ischemia, and 60-min reperfusion. XJB improved post-ischemic recovery of aged hearts, as evidenced by greater left ventricular developed-pressures and rate-pressure products than the untreated, aged-matched group. The state 3 respiration rates at complexes I, II and IV of mitochondria isolated from XJB-treated aged hearts were 57% (P<0.05), 25% (P<0.05) and 28% (P<0.05), respectively, higher than controls. Ca2+-induced swelling, an indicator of permeability transition pore opening, was reduced in mitochondria of XJB-treated aged rats. In addition, XJB significantly attenuated the H2O2-induced depolarization of the mitochondrial inner membrane as well as total and mitochondrial ROS levels in cultured cardiomyocytes. This study underlines the importance of mitochondrial ROS in aging-induced cardiac dysfunction and suggests that targeting mitochondrial ROS may be an effective therapeutic approach to protect the aged heart against IR injury.

Mitochondria and aging: A role for the mitochondrial transition pore?

“…This may be the consequence of the oxidative stress due to the increase in ROS production coupled with a decline in antioxidant defenses (Ferrara et al., 2008; Judge, Jang, Smith, & Hagen, 2005; Meng, Wong, Chen, & Ruan, 2007) prevailing in the aging heart. The observations that a mitochondria‐targeted ROS scavenger improved postischemic recovery of cardiac function (Escobales et al., 2014) and that the ROS scavenger Tempol restored pharmacological conditioning in aged rats (Zhu, Rebecchi, Glass, et al., 2013; Zhu, Rebecchi, Wang, et al., 2013) while preventing mPTP opening support this hypothesis.…”

Resveratrol Improves Survival and Prolongs Life Following Hemorrhagic Shock

“…Mitochondria is likely to be a major focal point for the generation of reactive oxygen species (16)(17)(18)(19). In addition, oxygen insufficiency results in decreased mitochondrial function resulting in altered cellular energetics.…”

Nitrite Confers Preconditioning and Cytoprotection After Ischemia/Reperfusion Injury Through the Modulation of Mitochondrial Function

“…show decreased mitochondrial damage as well as attenuated cell and tissue death after I/R (1,37,63,124). Finally, genetic strategies to inhibit PTP opening prevent apoptosis and decrease infarct size in animal models of myocardial I/R (5,53).…”