Abstract
Aging is a major factor in the decline of limb blood flow with ischemia. However, the underlying mechanism remains unclear. We investigated the role of mitochondrial reactive oxygen species (ROS) with regard to limb perfusion recovery in aging during ischemia. We performed femoral artery ligation in young and old mice with or without treatment with a scavenger of mitochondrial superoxide, MitoTEMPO (180 μg/kg/day, from pre-operative day 7 to post-operative day (POD) 21) infusion using an implanted mini-pump. The recoveries of cutaneous blood flow in the ischemic hind limb were lower in old mice than in young mice but were improved in MitoTEMPO-treated old mice. Mitochondrial DNA damage appeared in ischemic aged muscles but was eliminated by MitoTEMPO treatment. For POD 2, MitoTEMPO treatment suppressed the expression of p53 and the ratio of Bax/Bcl2 and upregulated the expression of hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) in ischemic aged skeletal muscles. For POD 21, MitoTEMPO treatment preserved the expression of PGC-1α in ischemic aged skeletal muscle. The ischemic soleus of old mice showed a lower mitochondrial respiratory control ratio in POD 21 compared to young mice, which was recovered in MitoTEMPO-treated old mice. Scavenging of mitochondrial superoxide attenuated mitochondrial DNA damage and preserved the mitochondrial respiration, in addition to suppression of the expression of p53 and preservation of the expression of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) in ischemic skeletal muscles with aging. Resolution of excessive mitochondrial superoxide could be an effective therapy to recover blood flow of skeletal muscle during ischemia in senescence.
Highlights
Senescence is an irreversible risk factor for most forms of cardiovascular and peripheral artery disease (PAD) [1,2,3]
In PAD patients, mitochondrial dysfunction and increased oxidative stress-induced damage have been reported [12,13]. It seems that the resolution of mitochondrial reactive oxygen species (ROS) in aged mammals is attributed to collateral growth under ischemia through the recovery of mitochondria or other signaling pathways
Transient or low levels of ROS act as mediators of angiogenesis through the hypoxia-inducible factor (HIF)-vascular endothelial growth factor (VEGF)/VEGF receptor-2 signaling pathway and the VEGF-independent pathway, the latter of which involves the generation of lipid oxidation products [14]
Summary
Senescence is an irreversible risk factor for most forms of cardiovascular and peripheral artery disease (PAD) [1,2,3]. Previous reports demonstrated aging-dependent impairment of blood flow with critical limb ischemia [4,5]. Age-dependent increases in oxidative stress occur through multiple mechanisms, including mitochondrial dysfunction. In PAD patients, mitochondrial dysfunction and increased oxidative stress-induced damage have been reported [12,13]. Taken together, it seems that the resolution of mitochondrial ROS in aged mammals is attributed to collateral growth under ischemia through the recovery of mitochondria or other signaling pathways. We elucidated the effect of mitochondrial ROS in aging with respect to mitochondrial DNA (mtDNA) and apoptosis
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