Donate Help Contact The AHA Sign In Home
American Heart Association
Circulation Research
Search: search_blue_button Advanced Search
Circulation Research. 2007;100:1512-1521
Published online before print April 19, 2007, doi: 10.1161/01.RES.0000267723.65696.4a
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Data Supplement
Right arrow All Versions of this Article:
100/10/1512    most recent
01.RES.0000267723.65696.4av1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowRequest Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Alcendor, R. R.
Right arrow Articles by Sadoshima, J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Alcendor, R. R.
Right arrow Articles by Sadoshima, J.
Related Collections
Right arrow Congestive
Right arrow Apoptosis
Right arrow Heart failure - basic studies
Right arrow Hypertrophy
Right arrow Oxidant stress
Right arrowRelated Article
(Circulation Research. 2007;100:1512.)
© 2007 American Heart Association, Inc.


Integrative Physiology

Sirt1 Regulates Aging and Resistance to Oxidative Stress in the Heart

Ralph R. Alcendor, Shumin Gao, Peiyong Zhai, Daniela Zablocki, Eric Holle, Xianzhong Yu, Bin Tian, Thomas Wagner, Stephen F. Vatner, Junichi Sadoshima

From the Cardiovascular Research Institute (R.R.A., S.G., P.Z., D.Z., S.F.V., J.S.), Department of Cell Biology and Molecular Medicine; Department of Biochemistry and Molecular Biology (B.T.), University of Medicine & Dentistry of New Jersey, New Jersey Medical School, Newark; and Oncology Research Institute (E.H., X.Y., T.W.), Greenville, SC.

Correspondence to Junichi Sadoshima, MD PhD, Cardiovascular Research Institute, UMDNJ, 185 S Orange Ave, MSB G609, Newark, NJ 07103. E-mail sadoshju{at}umdnj.edu

Silent information regulator (Sir)2, a class III histone deacetylase, mediates lifespan extension in model organisms and prevents apoptosis in mammalian cells. However, beneficial functions of Sir2 remain to be shown in mammals in vivo at the organ level, such as in the heart. We addressed this issue by using transgenic mice with heart-specific overexpression of Sirt1, a mammalian homolog of Sir2. Sirt1 was significantly upregulated (4- to 8-fold) in response to pressure overload and oxidative stress in nontransgenic adult mouse hearts. Low (2.5-fold) to moderate (7.5-fold) overexpression of Sirt1 in transgenic mouse hearts attenuated age-dependent increases in cardiac hypertrophy, apoptosis/fibrosis, cardiac dysfunction, and expression of senescence markers. In contrast, a high level (12.5-fold) of Sirt1 increased apoptosis and hypertrophy and decreased cardiac function, thereby stimulating the development of cardiomyopathy. Moderate overexpression of Sirt1 protected the heart from oxidative stress induced by paraquat, with increased expression of antioxidants, such as catalase, through forkhead box O (FoxO)-dependent mechanisms, whereas high levels of Sirt1 increased oxidative stress in the heart at baseline. Thus, mild to moderate expression of Sirt1 retards aging of the heart, whereas a high dose of Sirt1 induces cardiomyopathy. Furthermore, although high levels of Sirt1 increase oxidative stress, moderate expression of Sirt1 induces resistance to oxidative stress and apoptosis. These results suggest that Sirt1 could retard aging and confer stress resistance to the heart in vivo, but these beneficial effects can be observed only at low to moderate doses (up to 7.5-fold) of Sirt1.


Key Words: Sirt1 • aging • longevity factor • oxidative stress


Related Article:

Do We Age on Sirt1 Expression?
Daniel Sedding and Judith Haendeler
Circ. Res. 2007 100: 1396-1398. [Extract] [Full Text] [PDF]



This article has been cited by other articles:


Home page
Am. J. Physiol. Heart Circ. Physiol.Home page
N. Makino, T. Maeda, J.-i. Oyama, Y. Higuchi, and K. Mimori
Improving insulin sensitivity via activation of PPAR-{gamma} increases telomerase activity in the heart of OLETF rats
Am J Physiol Heart Circ Physiol, December 1, 2009; 297(6): H2188 - H2195.
[Abstract] [Full Text] [PDF]


Home page
Circ. Res.Home page
Z. Lu, I. Scott, B. R. Webster, and M. N. Sack
The Emerging Characterization of Lysine Residue Deacetylation on the Modulation of Mitochondrial Function and Cardiovascular Biology
Circ. Res., October 23, 2009; 105(9): 830 - 841.
[Abstract] [Full Text] [PDF]


Home page
DiabetesHome page
X.-N. Li, J. Song, L. Zhang, S. A. LeMaire, X. Hou, C. Zhang, J. S. Coselli, L. Chen, X. L. Wang, Y. Zhang, et al.
Activation of the AMPK-FOXO3 Pathway Reduces Fatty Acid-Induced Increase in Intracellular Reactive Oxygen Species by Upregulating Thioredoxin
Diabetes, October 1, 2009; 58(10): 2246 - 2257.
[Abstract] [Full Text] [PDF]


Home page
Circ. Res.Home page
C.-P. Hsu, S. Oka, D. Shao, N. Hariharan, and J. Sadoshima
Nicotinamide Phosphoribosyltransferase Regulates Cell Survival Through NAD+ Synthesis in Cardiac Myocytes
Circ. Res., August 28, 2009; 105(5): 481 - 491.
[Abstract] [Full Text] [PDF]


Home page
Cardiovasc ResHome page
K. Boengler, R. Schulz, and G. Heusch
Loss of cardioprotection with ageing
Cardiovasc Res, July 15, 2009; 83(2): 247 - 261.
[Abstract] [Full Text] [PDF]


Home page
J ANIM SCIHome page
T. Shan, Y. Wang, T. Wu, C. Liu, J. Guo, Y. Zhang, J. Liu, and Z. Xu
Porcine sirtuin 1 gene clone, expression pattern, and regulation by resveratrol
J Anim Sci, March 1, 2009; 87(3): 895 - 904.
[Abstract] [Full Text] [PDF]


Home page
Cardiovasc ResHome page
H. Tsutsui, S. Kinugawa, and S. Matsushima
Mitochondrial oxidative stress and dysfunction in myocardial remodelling
Cardiovasc Res, February 15, 2009; 81(3): 449 - 456.
[Abstract] [Full Text] [PDF]


Home page
Endocr Relat CancerHome page
C. Weidinger, K. Krause, A. Klagge, S. Karger, and D. Fuhrer
Forkhead box-O transcription factor: critical conductors of cancer's fate
Endocr. Relat. Cancer, December 1, 2008; 15(4): 917 - 929.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Heart Circ. Physiol.Home page
K. Shinmura, K. Tamaki, and R. Bolli
Impact of 6-mo caloric restriction on myocardial ischemic tolerance: possible involvement of nitric oxide-dependent increase in nuclear Sirt1
Am J Physiol Heart Circ Physiol, December 1, 2008; 295(6): H2348 - H2355.
[Abstract] [Full Text] [PDF]


Home page
J. Biol. Chem.Home page
W.-Q. Tan, K. Wang, D.-Y. Lv, and P.-F. Li
Foxo3a Inhibits Cardiomyocyte Hypertrophy through Transactivating Catalase
J. Biol. Chem., October 31, 2008; 283(44): 29730 - 29739.
[Abstract] [Full Text] [PDF]


Home page
Mol. Cell. Biol.Home page
N. R. Sundaresan, S. A. Samant, V. B. Pillai, S. B. Rajamohan, and M. P. Gupta
SIRT3 Is a Stress-Responsive Deacetylase in Cardiomyocytes That Protects Cells from Stress-Mediated Cell Death by Deacetylation of Ku70
Mol. Cell. Biol., October 15, 2008; 28(20): 6384 - 6401.
[Abstract] [Full Text] [PDF]


Home page
Proc. Natl. Acad. Sci. USAHome page
P. T. Pfluger, D. Herranz, S. Velasco-Miguel, M. Serrano, and M. H. Tschop
Sirt1 protects against high-fat diet-induced metabolic damage
PNAS, July 15, 2008; 105(28): 9793 - 9798.
[Abstract] [Full Text] [PDF]


Home page
Cardiovasc ResHome page
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]


Home page
Proc. Natl. Acad. Sci. USAHome page
A. J. Griswold, K. T. Chang, A. P. Runko, M. A. Knight, and K.-T. Min
Sir2 mediates apoptosis through JNK-dependent pathways in Drosophila
PNAS, June 24, 2008; 105(25): 8673 - 8678.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Heart Circ. Physiol.Home page
A. Csiszar, N. Labinskyy, A. Podlutsky, P. M. Kaminski, M. S. Wolin, C. Zhang, P. Mukhopadhyay, P. Pacher, F. Hu, R. de Cabo, et al.
Vasoprotective effects of resveratrol and SIRT1: attenuation of cigarette smoke-induced oxidative stress and proinflammatory phenotypic alterations
Am J Physiol Heart Circ Physiol, June 1, 2008; 294(6): H2721 - H2735.
[Abstract] [Full Text] [PDF]


Home page
Circ. Res.Home page
O. Vakhrusheva, C. Smolka, P. Gajawada, S. Kostin, T. Boettger, T. Kubin, T. Braun, and E. Bober
Sirt7 Increases Stress Resistance of Cardiomyocytes and Prevents Apoptosis and Inflammatory Cardiomyopathy in Mice
Circ. Res., March 28, 2008; 102(6): 703 - 710.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Heart Circ. Physiol.Home page
J. B. Pillai, M. Chen, S. B. Rajamohan, S. Samant, V. B. Pillai, M. Gupta, and M. P. Gupta
Activation of SIRT1, a class III histone deacetylase, contributes to fructose feeding-mediated induction of the {alpha}-myosin heavy chain expression
Am J Physiol Heart Circ Physiol, March 1, 2008; 294(3): H1388 - H1397.
[Abstract] [Full Text] [PDF]


Home page
Circ. Res.Home page
K. N. Papanicolaou, Y. Izumiya, and K. Walsh
Forkhead Transcription Factors and Cardiovascular Biology
Circ. Res., January 4, 2008; 102(1): 16 - 31.
[Abstract] [Full Text] [PDF]


Home page
Circ. Res.Home page
D. Sedding and J. Haendeler
Do We Age on Sirt1 Expression?
Circ. Res., May 25, 2007; 100(10): 1396 - 1398.
[Full Text] [PDF]


Home page
Cold Spring Harb Symp Quant BiolHome page
L. Guarente
Sirtuins in Aging and Disease
Cold Spring Harb Symp Quant Biol, January 1, 2007; 72(0): 483 - 488.
[Abstract] [PDF]