This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 116/8/901    most recent CIRCULATIONAHA.107.691253v1 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 Luptak, I. Articles by Tian, R. Search for Related Content PubMed PubMed Citation Articles by Luptak, I. Articles by Tian, R. Related Collections Nutrition Contractile function Biochemistry and metabolism Animal models of human disease Energy metabolism Genetically altered mice Ischemic biology - basic studies

(Circulation. 2007;116:901-909.)
© 2007 American Heart Association, Inc.

Heart Failure

Long-Term Effects of Increased Glucose Entry on Mouse Hearts During Normal Aging and Ischemic Stress

Ivan Luptak, MD, PhD^*; Jie Yan, MD, PhD^*; Lei Cui, MD; Mohit Jain, MD, PhD; Ronglih Liao, PhD; Rong Tian, MD, PhD

From the Division of Cardiovascular Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Mass.

Correspondence to Dr Rong Tian, Nuclear Magnetic Resonance Laboratory for Physiological Chemistry, Brigham and Women’s Hospital, 221 Longwood Ave, Room 252, Boston, MA 02115. E-mail rtian{at}rics.bwh.harvard.edu

Received January 19, 2007; accepted June 18, 2007.

Background— A shift of substrate preference toward glucose in the heart is considered a reversion to fetal metabolic profile, but its role in the pathogenesis of cardiac diseases is incompletely understood.

Methods and Results— We performed a 2-year follow-up study in transgenic mice with sustained high glucose uptake and utilization in the heart by cardiac-specific overexpression of the insulin-independent glucose transporter GLUT1 (GLUT1-TG). Compared with wild-type litter mates, the GLUT1-TG mice showed a normal survival rate and unaltered contractile function of the heart monitored by serial echocardiography and by pressure–volume studies in isolated perfused hearts in the 2-year period. Furthermore, when hearts were subjected to ischemia-reperfusion, cardiac function of young and old GLUT1-TG recovered to the same level (86% and 83%, respectively) and exceeded that of both young and old wild-type hearts (52% and 35%, respectively; P<0.05). Nuclear magnetic resonance spectroscopic measurements with ³¹P showed delayed ATP depletion, reduced acidosis during ischemia, and improved recovery of high-energy phosphate content in old GLUT1-TG hearts (P<0.05 versus old wild-type). During reperfusion, glucose oxidation was 3-fold higher and fatty acid oxidation was 45% lower in old GLUT1-TG hearts compared with old wild-type (P<0.05), which suggests that the deleterious effects of excessive fatty acid oxidation during reperfusion was prevented in old GLUT1-TG hearts.

Conclusions— We have demonstrated that a normal heart is able to adapt to long-term increases in basal glucose entry into cardiomyocytes without development of glucotoxicity. Furthermore, life-long increases in glucose uptake result in a favorable metabolic phenotype that affords protections against aging-associated increase of susceptibility to ischemic injury.

---

 

CLINICAL PERSPECTIVE

This article has been cited by other articles:

				J. Yan, M. E. Young, L. Cui, G. D. Lopaschuk, R. Liao, and R. Tian Increased Glucose Uptake and Oxidation in Mouse Hearts Prevent High Fatty Acid Oxidation but Cause Cardiac Dysfunction in Diet-Induced Obesity Circulation, June 2, 2009; 119(21): 2818 - 2828. [Abstract] [Full Text] [PDF]

				G. Y. Oudit, Z. Kassiri, J. Zhou, Q. C. Liu, P. P. Liu, P. H. Backx, F. Dawood, M. A. Crackower, J. W. Scholey, and J. M. Penninger Loss of PTEN attenuates the development of pathological hypertrophy and heart failure in response to biomechanical stress Cardiovasc Res, June 1, 2008; 78(3): 505 - 514. [Abstract] [Full Text] [PDF]

				E. D. Abel Glucose for the Aging Heart? Circulation, August 21, 2007; 116(8): 884 - 887. [Full Text] [PDF]