Dysregulation of mitochondrial biogenesis in vascular endothelial and smooth muscle cells of aged rats

• Published in: American journal of physiology. Heart and circulatory physiology 2008-05, Vol.294 (5), p.H2121-H2128
• Main Authors: Ungvari, Zoltan, Labinskyy, Nazar, Gupte, Sachin, Chander, Praveen N, Edwards, John G, Csiszar, Anna
• Format: Article
• Language: English
• Subjects: Age Factors; Aging - metabolism; Aging - pathology; Animals; Blood vessels; Cell culture; Cells, Cultured; Cellular Senescence; Down-Regulation; Electron Transport Chain Complex Proteins - metabolism; Electron Transport Complex IV - metabolism; Endothelial Cells - enzymology; Endothelial Cells - metabolism; Endothelial Cells - pathology; Endothelium, Vascular - metabolism; Endothelium, Vascular - pathology; Endothelium, Vascular - physiopathology; Enzyme Inhibitors - pharmacology; Gene expression; Hydrogen Peroxide - metabolism; Male; Metabolism; Microscopy, Confocal; Microscopy, Electron, Transmission; Mitochondria - enzymology; Mitochondria - metabolism; Mitochondria - pathology; Mitochondria, Muscle - metabolism; Mitochondrial Proteins - antagonists & inhibitors; Mitochondrial Proteins - genetics; Mitochondrial Proteins - metabolism; Muscle, Smooth, Vascular - metabolism; Muscle, Smooth, Vascular - pathology; Muscle, Smooth, Vascular - physiopathology; Myocytes, Smooth Muscle - enzymology; Myocytes, Smooth Muscle - metabolism; Myocytes, Smooth Muscle - pathology; Oxidation; Oxidative Stress; Potassium Cyanide - pharmacology; Rats; Rats, Inbred F344; RNA Interference; RNA, Small Interfering - metabolism; Rodents; Signal transduction; Superoxides - metabolism
• ISSN: 0363-6135; 1522-1539
• DOI: 10.1152/ajpheart.00012.2008

Departments of 1 Physiology and 2 Pathology, New York Medical College, Valhalla, New York Submitted 4 January 2008 ; accepted in final form 26 February 2008 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- 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. vascular senescence Address for reprint requests and other correspondence: A. Csiszar or Z. Ungvari, Dept. of Physiology, New York Medical College, Valhalla, NY 10595 (e-mail: anna_csiszar{at}nymc.edu )