Published online before print June 8, 2006, doi: 10.1161/01.RES.0000231289.63468.08
© 2006 American Heart Association, Inc.
Cellular Biology |
Diabetes Promotes Cardiac Stem Cell Aging and Heart Failure, Which Are Prevented by Deletion of the p66shc Gene
From the Cardiovascular Research Institute (M.R., N.L., T.H., A.B., A.D.A., M.E.P.I., G.E., S.V., K.U., C.C., P.A., A.L., J.K.), Department of Medicine, New York Medical College, Valhalla, NY; Department of Experimental Oncology (M.G., P.G.P.), European Institute of Oncology, Milan, Italy; and Cardiovascular Center (T.F.L.), University Zürich-Irchel, Switzerland.
Correspondence to Jan Kajstura, PhD, Cardiovascular Research Institute, Vosburgh Pavilion, Rm 302, New York Medical College, Valhalla, NY 10595. E-mail jan_kajstura{at}nymc.edu
Diabetes leads to a decompensated myopathy, but the etiology of the cardiac disease is poorly understood. Oxidative stress is enhanced with diabetes and oxygen toxicity may alter cardiac progenitor cell (CPC) function resulting in defects in CPC growth and myocyte formation, which may favor premature myocardial aging and heart failure. We report that in a model of insulin-dependent diabetes mellitus, the generation of reactive oxygen species (ROS) leads to telomeric shortening, expression of the senescent associated proteins p53 and p16INK4a, and apoptosis of CPCs, impairing the growth reserve of the heart. However, ablation of the p66shc gene prevents these negative adaptations of the CPC compartment, interfering with the acquisition of the heart senescent phenotype and the development of heart failure with diabetes. ROS elicit 3 cellular reactions: low levels activate cell growth, intermediate quantities trigger cell apoptosis, and high amounts initiate cell necrosis. CPC replication predominates in diabetic p66shc–/–, whereas CPC apoptosis and myocyte apoptosis and necrosis prevail in diabetic wild type. Expansion of CPCs and developing myocytes preserves cardiac function in diabetic p66shc–/–, suggesting that intact CPCs can effectively counteract the impact of uncontrolled diabetes on the heart. The recognition that p66shc conditions the destiny of CPCs raises the possibility that diabetic cardiomyopathy is a stem cell disease in which abnormalities in CPCs define the life and death of the heart. Together, these data point to a genetic link between diabetes and ROS, on the one hand, and CPC survival and growth, on the other.
Key Words: cardiac stem cells • myocyte regeneration • replicative senescence • telomeric shortening
This article has been cited by other articles:
 |
|
 |
|
  P. Spallarossa, P. Altieri, C. Aloi, S. Garibaldi, C. Barisione, G. Ghigliotti, G. Fugazza, A. Barsotti, and C. Brunelli Doxorubicin induces senescence or apoptosis in rat neonatal cardiomyocytes by regulating the expression levels of the telomere binding factors 1 and 2 Am J Physiol Heart Circ Physiol, December 1, 2009; 297(6): H2169 - H2181. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Di Stefano, C. Cencioni, G. Zaccagnini, A. Magenta, M. C. Capogrossi, and F. Martelli p66ShcA modulates oxidative stress and survival of endothelial progenitor cells in response to high glucose Cardiovasc Res, June 1, 2009; 82(3): 421 - 429. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Sainz and M. Sata When p66ShcA is away, mice EPCs sweetly play Cardiovasc Res, June 1, 2009; 82(3): 388 - 389. [Full Text] [PDF]
|
|
|
|
 |
|
 C.-H. Chen, R. A.F. Dixon, L.-Y. Ke, and J. T. Willerson Vascular Progenitor Cells in Diabetes Mellitus: Roles of Wnt Signaling and Negatively Charged Low-Density Lipoprotein Circ. Res., May 8, 2009; 104(9): 1038 - 1040. [Full Text] [PDF]
|
|
|
|
 |
|
 Y. H. Noh, J. Y. Baek, W. Jeong, S. G. Rhee, and T.-S. Chang Sulfiredoxin Translocation into Mitochondria Plays a Crucial Role in Reducing Hyperoxidized Peroxiredoxin III J. Biol. Chem., March 27, 2009; 284(13): 8470 - 8477. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Guo, Z. Gertsberg, N. Ozgen, and S. F. Steinberg p66Shc Links {alpha}1-Adrenergic Receptors to a Reactive Oxygen Species-Dependent AKT-FOXO3A Phosphorylation Pathway in Cardiomyocytes Circ. Res., March 13, 2009; 104(5): 660 - 669. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Malhotra, H. Vashistha, V. S. Yadav, M. G. Dube, S. P. Kalra, M. Abdellatif, and L. G. Meggs Inhibition of p66ShcA redox activity in cardiac muscle cells attenuates hyperglycemia-induced oxidative stress and apoptosis Am J Physiol Heart Circ Physiol, February 1, 2009; 296(2): H380 - H388. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Chen, H. Li, F. Addabbo, F. Zhang, E. Pelger, D. Patschan, H.-C. Park, M.-C. Kuo, J. Ni, G. Gobe, et al. Adoptive Transfer of Syngeneic Bone Marrow-Derived Cells in Mice with Obesity-Induced Diabetes: Selenoorganic Antioxidant Ebselen Restores Stem Cell Competence Am. J. Pathol., February 1, 2009; 174(2): 701 - 711. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Liu, T. Ramjiganesh, Y.-H. Chen, S. W. Chung, S. R. Hall, S. L. Schissel, R. F. Padera Jr, R. Liao, K. G. Ackerman, J. Kajstura, et al. Disruption of Striated Preferentially Expressed Gene Locus Leads to Dilated Cardiomyopathy in Mice Circulation, January 20, 2009; 119(2): 261 - 268. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Dimmeler and A. Leri Aging and Disease as Modifiers of Efficacy of Cell Therapy Circ. Res., June 6, 2008; 102(11): 1319 - 1330. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. Pfister and R. Liao Pump to Survive: Novel Cytoprotective Strategies for Cardiac Progenitor Cells Circ. Res., May 9, 2008; 102(9): 998 - 1001. [Full Text] [PDF]
|
|
|
|
 |
|
 F. Cosentino, P. Francia, G. G. Camici, P. G. Pelicci, M. Volpe, and T. F. Luscher Final Common Molecular Pathways of Aging and Cardiovascular Disease: Role of the p66Shc Protein Arterioscler Thromb Vasc Biol, April 1, 2008; 28(4): 622 - 628. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. J. Crespo, J. Zalacain, D. C. Dunbar, N. Cruz, and L. Arocho Cardiac Oxidative Stress Is Elevated at the Onset of Dilated Cardiomyopathy in Streptozotocin-Diabetic Rats Journal of Cardiovascular Pharmacology and Therapeutics, March 1, 2008; 13(1): 64 - 71. [Abstract] [PDF]
|
|
|
|
|
|
G. Zaccagnini, F. Martelli, A. Magenta, C. Cencioni, P. Fasanaro, C. Nicoletti, P. Biglioli, P. G. Pelicci, and M. C. Capogrossi p66ShcA and Oxidative Stress Modulate Myogenic Differentiation and Skeletal Muscle Regeneration after Hind Limb Ischemia J. Biol. Chem., October 26, 2007; 282(43): 31453 - 31459. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Tateishi, E. Ashihara, N. Takehara, T. Nomura, S. Honsho, T. Nakagami, S. Morikawa, T. Takahashi, T. Ueyama, H. Matsubara, et al. Clonally amplified cardiac stem cells are regulated by Sca-1 signaling for efficient cardiovascular regeneration J. Cell Sci., May 15, 2007; 120(10): 1791 - 1800. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. P. Fadini, S. Sartore, C. Agostini, and A. Avogaro Significance of Endothelial Progenitor Cells in Subjects With Diabetes Diabetes Care, May 1, 2007; 30(5): 1305 - 1313. [Full Text] [PDF]
|
|
|
|
 |
|
 Y. L. Tang and M. I. Phillips Invited commentary Ann. Thorac. Surg., April 1, 2007; 83(4): 1499 - 1500. [Full Text] [PDF]
|
|
|
|
 |
|
 C. L. Navarro, P. Cau, and N. Levy Molecular bases of progeroid syndromes Hum. Mol. Genet., October 15, 2006; 15(suppl_2): R151 - R161. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Messina and A. Giacomello Diabetic Cardiomyopathy: A "Cardiac Stem Cell Disease" Involving p66Shc, an Attractive Novel Molecular Target for Heart Failure Therapy Circ. Res., July 7, 2006; 99(1): 1 - 2. [Full Text] [PDF]
|
|