This Article Full Text Full Text (PDF) All Versions of this Article: 98/1/119    most recent 01.RES.0000199348.10580.1dv1 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 Barouch, L. A. Articles by Hare, J. M. Search for Related Content PubMed PubMed Citation Articles by Barouch, L. A. Articles by Hare, J. M. Related Collections Obesity Animal models of human disease Apoptosis Heart failure - basic studies Hypertrophy

(Circulation Research. 2006;98:119.)
© 2006 American Heart Association, Inc.

Integrative Physiology

Cardiac Myocyte Apoptosis Is Associated With Increased DNA Damage and Decreased Survival in Murine Models of Obesity

Lili A. Barouch, Daqing Gao, Lei Chen, Karen L. Miller, Wenhong Xu, Alexander C. Phan, Michelle M. Kittleson, Khalid M. Minhas, Dan E. Berkowitz, Chiming Wei, Joshua M. Hare

From the Departments of Medicine (L.A.B., K.L.M., W.X., A.C.P., M.M.K., K.M.M., J.M.H.), Surgery (D.G., L.C., C.W.), and Anesthesia and Critical Care Medicine (D.E.B.) and the Institute for Cell Engineering (J.M.H.), Johns Hopkins University School of Medicine, Baltimore, Md.

Correspondence to Lili A. Barouch, MD, Johns Hopkins University, Division of Cardiology, 720 Rutland Ave, Ross 1050, Baltimore, MD 21205. E-mail barouch{at}jhmi.edu

Disruption of leptin signaling is associated with obesity, heart failure, and cardiac hypertrophy, but the role of leptin in cardiac myocyte apoptosis is unknown. We tested the hypothesis that apoptosis increases in leptin-deficient ob/ob and leptin-resistant db/db mice and is associated with aging and left ventricular hypertrophy, increased DNA damage, and decreased survival. We studied young (2- to 3-month-old) and old (12- to 14-month-old) ob/ob and db/db mice and wild-type (WT) controls (n=2 to 4 per group). As expected, ventricular wall thickness and heart weights were similar among young ob/ob, db/db, and WT mice, but higher in old ob/ob and db/db versus old WT. Young ob/ob and db/db showed markedly elevated apoptosis by TUNEL staining and caspase 3 levels compared with WT. Differences in apoptosis were further accentuated with age. Leptin treatment significantly reduced apoptosis in ob/ob mice both in intact hearts and isolated myocytes. Tissue triglycerides were increased in ob/ob hearts, returning to WT levels after leptin repletion. Furthermore, the DNA damage marker, 8oxoG (8-oxo-7,8-dihydroguanidine), was increased, whereas the DNA repair marker, MYH glycosylase, was decreased in old ob/ob and db/db compared with old WT mice. Both ob/ob and db/db mice had decreased survival compared with WT mice. We conclude that leptin-deficient and leptin-resistant mice demonstrate increased apoptosis, DNA damage, and mortality compared with WT mice, suggesting that normal leptin signaling is necessary to prevent excess age-associated DNA damage and premature mortality. These data offer novel insights into potential mechanisms of myocardial dysfunction and early mortality in obesity.

Key Words: obesity • apoptosis • DNA damage • mortality

This article has been cited by other articles:

				O. H.I. Majane, L. Vengethasamy, E. F. du Toit, S. Makaula, A. J. Woodiwiss, and G. R. Norton Dietary-Induced Obesity Hastens the Progression From Concentric Cardiac Hypertrophy to Pump Dysfunction in Spontaneously Hypertensive Rats Hypertension, December 1, 2009; 54(6): 1376 - 1383. [Abstract] [Full Text] [PDF]

				K. R. McGaffin, C. S. Moravec, and C. F. McTiernan Leptin Signaling in the Failing and Mechanically Unloaded Human Heart Circ Heart Fail, November 1, 2009; 2(6): 676 - 683. [Abstract] [Full Text] [PDF]

				J. Gutkowska, T. L. Broderick, D. Bogdan, D. Wang, J.-M. Lavoie, and M. Jankowski Downregulation of oxytocin and natriuretic peptides in diabetes: possible implications in cardiomyopathy J. Physiol., October 1, 2009; 587(19): 4725 - 4736. [Abstract] [Full Text] [PDF]

				H. Bugger and E. D. Abel Rodent models of diabetic cardiomyopathy Dis. Model. Mech., September 1, 2009; 2(9-10): 454 - 466. [Abstract] [Full Text] [PDF]

				K. R. McGaffin, B. Zou, C. F. McTiernan, and C. P. O'Donnell Leptin attenuates cardiac apoptosis after chronic ischaemic injury Cardiovasc Res, July 15, 2009; 83(2): 313 - 324. [Abstract] [Full Text] [PDF]

				D. J. Chess and W. C. Stanley Role of diet and fuel overabundance in the development and progression of heart failure Cardiovasc Res, July 15, 2008; 79(2): 269 - 278. [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]

				S.-D. Lee, W.-W. Kuo, D.-T. Bau, F.-Y. Ko, F.-L. Wu, C.-H. Kuo, F.-J. Tsai, P. S. Wang, M.-C. Lu, and C.-Y. Huang The coexistence of nocturnal sustained hypoxia and obesity additively increases cardiac apoptosis J Appl Physiol, April 1, 2008; 104(4): 1144 - 1153. [Abstract] [Full Text] [PDF]

				A. Van den Bergh, A. Vanderper, P. Vangheluwe, F. Desjardins, I. Nevelsteen, W. Verreth, F. Wuytack, P. Holvoet, W. Flameng, J.-L. Balligand, et al. Dyslipidaemia in type II diabetic mice does not aggravate contractile impairment but increases ventricular stiffness Cardiovasc Res, January 15, 2008; 77(2): 371 - 379. [Abstract] [Full Text] [PDF]

				R. Yang and L. A. Barouch Leptin Signaling and Obesity: Cardiovascular Consequences Circ. Res., September 14, 2007; 101(6): 545 - 559. [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]

				P. Yue, T. Arai, M. Terashima, A. Y. Sheikh, F. Cao, D. Charo, G. Hoyt, R. C. Robbins, E. A. Ashley, J. Wu, et al. Magnetic resonance imaging of progressive cardiomyopathic changes in the db/db mouse Am J Physiol Heart Circ Physiol, May 1, 2007; 292(5): H2106 - H2118. [Abstract] [Full Text] [PDF]

				L. L. Zhang, D. Yan Liu, L. Q. Ma, Z. D. Luo, T. B. Cao, J. Zhong, Z. C. Yan, L. J. Wang, Z. G. Zhao, S. J. Zhu, et al. Activation of Transient Receptor Potential Vanilloid Type-1 Channel Prevents Adipogenesis and Obesity Circ. Res., April 13, 2007; 100(7): 1063 - 1070. [Abstract] [Full Text] [PDF]

				D. Qi and B. Rodrigues Glucocorticoids produce whole body insulin resistance with changes in cardiac metabolism Am J Physiol Endocrinol Metab, March 1, 2007; 292(3): E654 - E667. [Abstract] [Full Text] [PDF]

				N. Sharma, I. C. Okere, M. K. Duda, D. J. Chess, K. M. O'Shea, and W. C. Stanley Potential impact of carbohydrate and fat intake on pathological left ventricular hypertrophy Cardiovasc Res, January 15, 2007; 73(2): 257 - 268. [Abstract] [Full Text] [PDF]

				D. An and B. Rodrigues Role of changes in cardiac metabolism in development of diabetic cardiomyopathy Am J Physiol Heart Circ Physiol, October 1, 2006; 291(4): H1489 - H1506. [Abstract] [Full Text] [PDF]