4-Hydroxy tempol-induced impairment of mitochondrial function and augmentation of glucose transport in vascular endothelial and smooth muscle cells.
The water-soluble and cell permeable nitroxide derivative 4-hydroxy tempol (TPL) has been shown to reduce or ameliorate oxidative stress-induced dysfunction and damage in vascular endothelial cells. We studied the effects of TPL on glucose transport and metabolism in bovine aortic endothelial (VEC) and smooth muscle cells (VSMC) under normal and high glucose conditions. Normally, these cells operate an autoregulatory protective mechanism that limits the rate of glucose transport under hyperglycemic conditions by decreasing the cell content of their typical glucose transporter GLUT-1 mRNA and protein as well as its plasma membrane abundance. TPL augmented the rate of glucose transport both under normo- and hyperglycemic conditions by increasing GLUT-1 mRNA and protein content and its plasma membrane abundance in both types of cells, leading to an increased flux of glucose into the cells. These effects were found related to ROS-generating and oxidant activities of TPL and to a decreased rate of mitochondrial ATP production under both normo- and hyperglycemic conditions. Since impaired mitochondrial functions, and in particular decreased rate of ATP production, augment the expression of GLUT-1 protein and glucose transport and metabolism, we suggest that the stimulatory effects of TPL in vascular cells results from its unfavorable interactions in the mitochondrion. It is therefore suggested that effects of TPL in cells of cardiovascular system be evaluated in parallel to its adverse effects on glucose and energy metabolism.
Alpert
Evgenia
E
Department of Pharmacology, School of Pharmacy, The Hebrew University-Hadassah Faculty of Medicine, P.O. Box 12272, Jerusalem 91120, Israel.
Altman
Hamutal
H
Totary
Hanan
H
Gruzman
Arie
A
Barnea
Dana
D
Barash
Varda
V
Sasson
Shlomo
S
D000111:Acetylcysteine / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001205:Ascorbic Acid / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects; D002417:Cattle; D002462:Cell Membrane / Q000187:drug effects; D002839:Chromans / Q000494:pharmacology; D003497:Cyclic N-Oxides / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D051272:Glucose Transporter Type 1; D006146:Guanidines / Q000494:pharmacology; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology; D009004:Monosaccharide Transport Proteins / Q000235:genetics / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D013113:Spin Labels
D000975:Antioxidants; D002839:Chromans; D003497:Cyclic N-Oxides; D051272:Glucose Transporter Type 1; D006146:Guanidines; D009004:Monosaccharide Transport Proteins; D012333:RNA, Messenger; D013113:Spin Labels; D000255:Adenosine Triphosphate; D005947:Glucose; D001205:Ascorbic Acid; C010643:6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid; C004479:pimagedine; C001803:tempol; D000111:Acetylcysteine