This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 100/10/1512    most recent 01.RES.0000267723.65696.4av1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Alcendor, R. R. Articles by Sadoshima, J. Search for Related Content PubMed PubMed Citation Articles by Alcendor, R. R. Articles by Sadoshima, J. Related Collections Congestive Hypertrophy Oxidant stress Apoptosis Heart failure - basic studies Related 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. [Full Text] [PDF]

This article has been cited by other articles:

				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]

				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]

				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]

				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]

				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]

				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]

				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]