Dysregulation of mitochondrial biogenesis in vascular endothelial and smooth muscle cells of aged rats.
Mitochondrial biogenesis is involved in the control of cell metabolism, signal transduction, and regulation of mitochondrial reactive oxygen species (ROS) production. Despite the central role of mitochondria in cellular aging and endothelial physiology, there are no studies extant investigating age-related alterations in mitochondrial biogenesis in blood vessels. Electronmicroscopy and confocal microscopy (en face Mitotracker staining) revealed that in aortas of F344 rats, a decline in mitochondrial biogenesis occurs with aging. In aged vessels, the expression of the mitochondrial biogenesis factors (including mitochondrial transcription factor A and peroxisome proliferator-activated receptor-gamma coactivator-1) was decreased. The vascular expression of complex I, III, and IV significantly declined with age, whereas aging did not alter the expression of complex II and V. Cytochrome c oxidase (COX) expression/activity exhibited the greatest age-related decline, which was associated with increased mitochondrial ROS production in the aged vessels. In cultured coronary arterial endothelial cells, a partial knockdown of COX significantly increased mitochondrial ROS production. In conclusion, vascular aging is characterized by a decline in mitochondrial mass in the endothelial cells and an altered expression of components of the mitochondrial electron transport chain likely due to a dysregulation of mitochondrial biogenesis factors. We posit that impaired mitochondrial biogenesis and downregulation of COX may contribute to the increased mitochondrial oxidative stress in aged endothelial cells.
Ungvari
Zoltan
Z
Department of Physiology, New York Medical College, Valhalla, NY 10595, USA. zoltan_ungvari@nymc.edu
Labinskyy
Nazar
N
Gupte
Sachin
S
Chander
Praveen N
PN
Edwards
John G
JG
Csiszar
Anna
A
D000367:Age Factors; D000375:Aging / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D002478:Cells, Cultured; D016922:Cellular Senescence; D015536:Down-Regulation; D045222:Electron Transport Chain Complex Proteins / Q000378:metabolism; D003576:Electron Transport Complex IV / Q000378:metabolism; D042783:Endothelial Cells / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000378:metabolism; D008297:Male; D018613:Microscopy, Confocal; D046529:Microscopy, Electron, Transmission; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D008931:Mitochondria, Muscle / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D032389:Myocytes, Smooth Muscle / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress; D011190:Potassium Cyanide / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D013481:Superoxides / Q000378:metabolism
D045222:Electron Transport Chain Complex Proteins; D004791:Enzyme Inhibitors; D024101:Mitochondrial Proteins; D034741:RNA, Small Interfering; D013481:Superoxides; D006861:Hydrogen Peroxide; D003576:Electron Transport Complex IV; D011190:Potassium Cyanide