Effects of Mitochondrial-Targeted Antioxidants on Real-Time Blood Nitric Oxide and Hydrogen Peroxide Release in Acute Hyperglycemic Rats

摘要

Diabetes and prediabetes are major public health concerns worldwide due to the high risk of developing micro-and macro-vascular complications. Hyperglycemia, the major criteria for diabetes diagnosis, is causally related to the pathogenesis of vascular complications in diabetic patients. An early event during hyperglycemia is vascular endothelial dysfunction. Normally, the vascular endothelium facilitates blood flow principally by releasing endothelial-derived nitric oxide (NO) via vascular endothelial NO synthase (eNOS) in the presence of an essential co-factor, tetrahydrobiopterin (BH4). By contrast, acute and chronic hyperglycemia increase oxidative stress and reduce NO bioavailability [1,2]. The reduced endothelial-derived NO bioavailability promotes vasoconstrictive, pro-inflammatory, and pro-thrombotic events, initiating inflammation, thereby recruiting leukocytes, resulting in tissue/organ damage (Figure 1). Therefore, reduction of oxidative stress during hyperglycemia will mitigate vascular endothelial dysfunction and organ damage. Crabtree, et al. [1] found that mitochondria-derived superoxide (SO) contributes to hyperglycemia-induced oxidative stress in cultured vascular endothelial cells. Subsequently, the overproduction of SO promotes the oxidation of BH4 to dihydrobiopterin (BH2). The reduced BH4/BH2 ratio leads to BH2, not BH4, binding to oxygenase domain of eNOS, which causes eNOS to shift its product profile from NO to SO [1] (Figure 1). However, the role of mitochondria in acute hyperglycemia-induced oxidative stress and blood NO reduction has not been evaluated in vivo. Recently, our lab showed that mitoquinone (MitoQ) and SS31 (Szeto-Schiller, D-Arg-Dmt-Lys-Phe-Amide) peptide (Figure 2), mitochondria-targeted antioxidants, significantly reduced blood H2O2 (an index of oxidative stress) and increased blood NO levels in a hind limb ischemia/reperfusion (I/R) animal model [3]. Oxidative stress is also an important cause of reperfusion injury during I/R. Thus, we hypothesize that MitoQ and SS-31 will reduce blood oxidative stress and increase blood NO levels under acute hyperglycemic conditions.