4-Hydroxy tempol-induced impairment of mitochondrial function and augmentation of glucose transport in vascular endothelial and smooth muscle cells

Alpert, Evgenia; Altman, Hamutal; Totary, Hanan; Gruzman, Arie; Barnea, Dana; Barash, V.; Sasson, Shlomo

doi:10.1016/j.bcp.2004.02.005

Cited by 25 publications

(22 citation statements)

References 54 publications

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“…Next we determined whether there is was any difference in glucose transporters in these cells. It has been previously established that Glut-1 and Glut-2 are the major glucose transporters found in BAECs (14,17,18,23). The Western blots of Glut-1 and Glut-2 showed that the Glut-1 is very much reduced in heat-shocked cells, whereas there was no change in Glut-2 (Fig.…”

Section: Increased Hsp90⅐enos Interactions In Heat-shocked Cells and mentioning

confidence: 72%

“…7). ROS and oxidative stress are known to regulate Glut-1 (17,18), and NO is known to have anti-oxidant properties (40). Thus, by decreasing ROS the observed increase in NO produced by heat shock would lead to the observed decrease Glut-1 and glucose uptake (Fig.…”

Section: Discussionmentioning

confidence: 97%

“…Expression, stability, and function of Glut-1 are influenced by many factors, including glucose metabolites such as advanced glycation end product-induced oxidative stress and the ROS that is generated by enzymatic reactions such as NADPH oxidase and NOS (17)(18)(19). Indeed, ROS has been proven to affect the regulation of glucose transport through Glut-1 and favor increased uptake of glucose by endothelial cells.…”

mentioning

confidence: 99%

“…Indeed, ROS has been proven to affect the regulation of glucose transport through Glut-1 and favor increased uptake of glucose by endothelial cells. Thus, alteration of oxidative stress in hyperglycemic endothelial cells was found to directly affect glucose homeostasis (17,18). Recently we demonstrated that non-lethal heat shock (hyperthermia) reduced superoxide generation (13).…”

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confidence: 99%

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Hyperthermia-induced Hsp90·eNOS Preserves Mitochondrial Respiration in Hyperglycemic Endothelial Cells by Down-regulating Glut-1 and Up-regulating G6PD Activity

Presley

Vedam

Druhan

et al. 2010

Journal of Biological Chemistry

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Uncoupling of NO production from NADPH oxidation by endothelial nitric-oxide synthase (eNOS) is enhanced in hyperglycemic endothelium, potentially due to dissociation of heat shock proteins 90 (Hsp90), and cellular glucose homeostasis is enhanced by a ROS-induced positive feed back mechanism. In this study we investigated how such an uncoupling impacts oxygen metabolism and how the oxidative phosphorylation can be preserved by heat shock (42°C for 2 h, hyperthermia) in bovine aortic endothelial cells. Normal and heat-shocked bovine aortic endothelial cells were exposed to normoglycemia (NG, 5.0 mM) or hyperglycemia (30 mM). With hyperglycemia treatment, O 2 consumption rate was reduced (from V O 2 max ‫؍‬ 7.51 ؎ 0.54 to 2.35 ؎ 0.27 mm Hg/min/10 6 cells), whereas in heat-shocked cells, O 2 consumption rate remained unaltered (8.19 ؎ 1.01 mm Hg/min/10 ؋ 10 6 cells). Heat shock was found to enhance Hsp90/endothelial NOS interactions and produce higher NO. Moreover, ROS generation in the hyperglycemic condition was also reduced in heat-shocked cells. Interestingly, glucose uptake was reduced in heat-shocked cells as a result of decrease in Glut-1 protein level. Glucose phosphate dehydrogenase activity that gives rise to NADPH generation was increased by hyperthermia, and mitochondrial oxidative metabolism was preserved. In conclusion, the present study provides a novel mechanism wherein the reduced oxidative stress in heat-shocked hyperglycemic cells down-regulates Glut-1 and glucose uptake, and fine-tuning of this pathway may be a potential approach to use for therapeutic benefit of diabetes mellitus. Heat shock proteins (Hsps)2 play critical roles in endothelial function in the hyperglycemic state, although their exact function is not clearly established. Along with hyperglycemia, the production of superoxide, insulin resistance, and a decline in vascular bioavailability of nitric oxide (NO) contribute to extreme rates of morbidity and mortality (1-4). Various factors regulate endothelial nitric-oxide synthase (eNOS) signaling in endothelial cells by modulating its phosphorylation/de-phosphorylation dynamics and the coupling/uncoupling of its redox reactions. Protein kinase B (Akt) phosphorylates eNOS on serine 1177 and increases the production of NO (5), and it is found to be very critical in overall glucose metabolism and cell survival (6). Hsp90 binding to eNOS was found to be a prerequisite for successive Akt-mediated stimulation of eNOS, and indeed, Hsp90 can be considered as a scaffold between eNOS and Akt (5,7,8). Vascular endothelial growth factor enhances the recruitment of Hsp90 and facilitates Akt-dependent phosphorylation of eNOS, which results in increased NO production. NO generation is reduced under diabetic conditions due to NOS uncoupling (i.e. incomplete redox transformation of NADPH, arginine, and O 2 to NO, citrulline, and H 2 O, leading instead to the generation of reactive oxygen species) resulting in the generation of more superoxide, and Hsp levels, especially Hsp90, are reduced in hypergly...

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Section: Increased Hsp90⅐enos Interactions In Heat-shocked Cells and mentioning

confidence: 72%

Section: Discussionmentioning

confidence: 97%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Hyperthermia-induced Hsp90·eNOS Preserves Mitochondrial Respiration in Hyperglycemic Endothelial Cells by Down-regulating Glut-1 and Up-regulating G6PD Activity

Presley

Vedam

Druhan

et al. 2010

Journal of Biological Chemistry

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“…Previously it has also been known that SOD mimetics are known to function as either antioxidants or prooxidants depending on the experimental conditions (33). Tempol treatment induced oxidative stress and impaired mitochondrial function in vascular endothelial and smooth muscle cells (34), while treatment with tempol in drinking water reduces oxidative stress in obese Zucker rats (35). The exact mechanism of this prooxidant effect of tempol in our study is not known, but we speculate that increased accumulation of H 2 O 2 may cause oxidative stress.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Lipid Infusion–Induced Skeletal Muscle Insulin Resistance by Cotreatment With Tempol and Glutathione in Mice

et al. 2009

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Abstract. In the present study, we examined whether lipid infusion-induced insulin resistance in skeletal muscle could be reversed by the antioxidants tempol, glutathione (GSH), or tempol with GSH in male C57BL/6J mice via hyperinsulinemic-euglycemic clamp. Lipid infusion increased the mRNA level of mitochondrial type superoxide dismutase (Mn-SOD), glutathione peroxidase 1, tumor necrosis factor-α, and interleukin-6. Lipid infusion decreased GSH and GSH /glutathione disulfide (GSSG) ratio and increased the activities of JNK and p38 in skeletal muscle. Lipid infusion induced insulin resistance in whole body and skeletal muscle. Treatment with the SOD mimetic tempol did not prevent oxidative stress, the inflammatory response, and insulin resistance induced by lipid infusion. Tempol alone increased oxidative stress and aggravated the lipid-induced inflammatory response. GSH at 100 and 200 μmol ⋅ kg −1 ⋅ h −1 did not prevent insulin resistance and the inflammatory response by lipid infusion. On the contrary, GSH at 100 μmol ⋅ kg −1 ⋅ h −1 with tempol prevented insulin resistance in the whole body and skeletal muscle, and it completely reversed oxidative stress and the inflammatory response. These results suggest that lipid infusion-induced insulin resistance in skeletal muscle is produced by oxidative stress and cotreatment with tempol and GSH inhibits lipid-induced insulin resistance.

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Stress‐induced autonomic dysregulation of mitochondrial function in the rat urothelium

Kullmann

McDonnell

Wolf‐Johnston

et al. 2018

Neurourology and Urodynamics

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Aim Chronic stress exacerbates the symptoms of most pain disorders including interstitial cystitis/bladder pain syndrome (IC/BPS). Abnormalities in urothelial cells (UTC) occur in this debilitating bladder condition. The sequence of events that might link stress (presumably through increased sympathetic nervous system‐SNS activity) to urothelial dysfunction are unknown. Since autonomic dysregulation, mitochondrial dysfunction, and oxidative stress all occur in chronic pain, we investigated whether chronic psychological stress initiated a cascade linking these three dysfunctions. Methods Adult female Wistar Kyoto rats were exposed to 10 days of water avoidance stress (WAS). Bladders were then harvested for Western blot and single cell imaging in UTC cultures. Results UTC from WAS rats exhibited depolarized mitochondria membrane potential (Ψm ∼30% more depolarized compared to control), activated AMPK and altered UT mitochondria bioenergetics. Expression of the fusion protein mitofusion‐2 (MFN‐2) was upregulated in the mucosa, suggesting mitochondrial structural changes consistent with altered cellular metabolism. Intracellular calcium levels were elevated in cultured WAS UTC, consistent with impaired cellular function. Stimulation of cultured UTC with alpha‐adrenergic (α‐AR) receptor agonists increased reactive oxidative species (ROS) production, suggesting a direct action of SNS activity on UTC. Treatment of rats with guanethidine to block SNS activity prevented most of WAS‐induced changes. Conclusions Chronic stress results in persistent sympathetically mediated effects that alter UTC mitochondrial function. This may impact the urothelial barrier and signaling, which contributes to bladder dysfunction and pain. This is the first demonstration, to our knowledge, of a potential autonomic mechanism directly linking stress to mitochondrial dysfunction.

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4-Hydroxy tempol-induced impairment of mitochondrial function and augmentation of glucose transport in vascular endothelial and smooth muscle cells

Cited by 25 publications

References 54 publications

Hyperthermia-induced Hsp90·eNOS Preserves Mitochondrial Respiration in Hyperglycemic Endothelial Cells by Down-regulating Glut-1 and Up-regulating G6PD Activity

Hyperthermia-induced Hsp90·eNOS Preserves Mitochondrial Respiration in Hyperglycemic Endothelial Cells by Down-regulating Glut-1 and Up-regulating G6PD Activity

Inhibition of Lipid Infusion–Induced Skeletal Muscle Insulin Resistance by Cotreatment With Tempol and Glutathione in Mice

Stress‐induced autonomic dysregulation of mitochondrial function in the rat urothelium

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