Published online before print January 29, 2007, doi: 10.1161/CIRCULATIONAHA.106.662296
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Circulation. 2007;115:909-917.)
© 2007 American Heart Association, Inc.
Molecular Cardiology |
Insulin-Resistant Heart Exhibits a Mitochondrial Biogenic Response Driven by the Peroxisome Proliferator-Activated Receptor-
/PGC-1 Gene Regulatory Pathway
From the Center for Cardiovascular Research (J.G.D., J.L.F., B.N.F., D.P.K.), Departments of Medicine (J.L.F., B.N.F., D.P.K.), Pediatrics (J.G.D., D.P.K.), and Molecular Biology and Pharmacology (D.P.K.), Washington University School of Medicine, St. Louis, Mo; and Department of Human Nutrition (D.M.M.), Kansas State University, Manhattan.
Correspondence to Daniel P. Kelly, MD, Center for Cardiovascular Research, Washington University School of Medicine, 660 S Euclid Ave, Campus Box 8086, St. Louis, MO 63110. E-mail dkelly{at}im.wustl.edu
Received August 31, 2006; accepted December 7, 2006.
Background— Obesity and diabetes mellitus are complex metabolic problems of pandemic proportion, contributing to significant cardiovascular mortality. Recent studies have shown altered mitochondrial function in the hearts of diabetic animals. We hypothesized that regulatory events involved in the control of mitochondrial function are activated in the prediabetic, insulin-resistant stage.
Methods and Results— Morphometric analyses demonstrated that cardiac myocyte mitochondrial volume density was increased in insulin-resistant uncoupling protein-diptheria toxin A (UCP-DTA) transgenic mice, a murine model of metabolic syndrome, compared with littermate controls. Mitochondrial DNA content and expression of genes involved in multiple mitochondrial pathways were also increased in insulin-resistant UCP-DTA hearts. The nuclear receptor, peroxisome proliferator-activated receptor-
(PPAR), is known to activate metabolic genes in the diabetic heart. Therefore, we evaluated the role of PPAR in the observed mitochondrial biogenesis response in the insulin-resistant heart. Insulin-resistant UCP-DTA mice crossed into a PPAR-null background did not exhibit evidence of mitochondrial biogenesis or induction of mitochondrial gene expression. Conversely, transgenic mice with cardiac-specific overexpression of PPAR exhibited signatures of cardiac mitochondrial biogenesis. A screen for candidate mediators of the PPAR-driven mitochondrial biogenic response revealed that expression of PPAR
coactivator-1 (PGC-1), a known regulator of mitochondrial biogenesis, was activated in wild-type UCP-DTA mice but not in PPAR-deficient UCP-DTA mice.
Conclusions— These results demonstrate that mitochondrial biogenesis occurs early in the development of diabetic cardiac dysfunction through a transcriptional regulatory circuit that involves activation of PGC-1 gene expression by the fatty acid–activated nuclear receptor PPAR.
CLINICAL PERSPECTIVE
This article has been cited by other articles:
 |
|
 |
|
  R. Ventura-Clapier, A. Garnier, and V. Veksler Transcriptional control of mitochondrial biogenesis: the central role of PGC-1{alpha} Cardiovasc Res, July 15, 2008; 79(2): 208 - 217. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. Ungvari, N. Labinskyy, S. Gupte, P. N. Chander, J. G. Edwards, and A. Csiszar Dysregulation of mitochondrial biogenesis in vascular endothelial and smooth muscle cells of aged rats Am J Physiol Heart Circ Physiol, May 1, 2008; 294(5): H2121 - H2128. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. D. Abel, S. E. Litwin, and G. Sweeney Cardiac Remodeling in Obesity Physiol Rev, April 1, 2008; 88(2): 389 - 419. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J.-a Kim, Y. Wei, and J. R. Sowers Role of Mitochondrial Dysfunction in Insulin Resistance Circ. Res., February 29, 2008; 102(4): 401 - 414. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. M. Grundy Thyroid mimetic as an option for lowering low-density lipoprotein PNAS, January 15, 2008; 105(2): 409 - 410. [Full Text] [PDF]
|
|
|
|
|
|
M. K. Duda, K. M. O'Shea, B. Lei, B. R. Barrows, A. M. Azimzadeh, T. E. McElfresh, B. D. Hoit, W. J. Kop, and W. C. Stanley Dietary supplementation with {omega}-3 PUFA increases adiponectin and attenuates ventricular remodeling and dysfunction with pressure overload Cardiovasc Res, November 1, 2007; 76(2): 303 - 310. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Boudina, S. Sena, H. Theobald, X. Sheng, J. J. Wright, X. X. Hu, S. Aziz, J. I. Johnson, H. Bugger, V. G. Zaha, et al. Mitochondrial Energetics in the Heart in Obesity-Related Diabetes: Direct Evidence for Increased Uncoupled Respiration and Activation of Uncoupling Proteins Diabetes, October 1, 2007; 56(10): 2457 - 2466. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. J. Chess, B. Lei, B. D. Hoit, A. M. Azimzadeh, and W. C. Stanley Deleterious effects of sugar and protective effects of starch on cardiac remodeling, contractile dysfunction, and mortality in response to pressure overload Am J Physiol Heart Circ Physiol, September 1, 2007; 293(3): H1853 - H1860. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. D. Lopaschuk, C. D.L. Folmes, and W. C. Stanley Cardiac Energy Metabolism in Obesity Circ. Res., August 17, 2007; 101(4): 335 - 347. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Boudina and E. D. Abel Diabetic Cardiomyopathy Revisited Circulation, June 26, 2007; 115(25): 3213 - 3223. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. N. Finck and D. P. Kelly Peroxisome Proliferator-Activated Receptor {gamma} Coactivator-1 (PGC-1) Regulatory Cascade in Cardiac Physiology and Disease Circulation, May 15, 2007; 115(19): 2540 - 2548. [Full Text] [PDF]
|
|