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Diabetes Promotes Cardiac Stem Cell Aging and Heart Failure, Which Are Prevented by Deletion of the p66 shc Gene
Open accessAbstract
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 p16 INK4a , and apoptosis of CPCs, impairing the growth reserve of the heart. However, ablation of the p66 shc 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 p66 shc−/− , whereas CPC apoptosis and myocyte apoptosis and necrosis prevail in diabetic wild type. Expansion of CPCs and developing myocytes preserves cardiac function in diabetic p66 shc−/− , suggesting that intact CPCs can effectively counteract the impact of uncontrolled diabetes on the heart. The recognition that p66 shc 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.
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“Cardiac progenitor aging is accelerated in diabetes, and heart disease is a major complication of diabetes (74).”
From Cellular Senescence in Type 2 Diabetes: A Therapeutic Opportunity (2015) · cites this paper as [74]
In the citing paper
“Remarkably, p66Shc-deficient mice have been found to be resistant to many complications of experimental diabetes, including diabetic nephropathy, diabetic cardiomyopathy, cardiac stem cell death, hyperglycemia-induced endothelial dysfunction and enhanced lipid peroxidation, and impaired wound healing (61, 128, 291, 357).”
From Redox regulation of mitochondrial function (2012) · cites this paper as [357]
In the citing paper
“Consequently, work has shown that p66Shc−/− mice are protected against streptozotocin-induced diabetic cardiomyopathy191, diabetes mellitus-induced vascular endothelial dysfunction and oxidative stress187.”
From Mitochondrial and metabolic dysfunction in ageing and age-related diseases (2022) · cites this paper as [191]
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Metadata
- Authors
- Rota, M., LeCapitaine, N., Hosoda, T., Boni, A., De Angelis, A., Padin-Iruegas, M. E., Esposito, G., Vitale, S., Urbanek, K., Casarsa, C., Giorgio, M., Lüscher, T. F., Pelicci, P. G., Anversa, P., Leri, A., & Kajstura, J.
- Affiliations
- New York Medical College (US)
- 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.
- ORCID
- Venue
- Circulation Research
- Published
- 2006-07-07
- Volume
- 99
- Issue
- 1
- Pages
- 42-52
- ISSN
- 0009-7330 (ISSN-L)
- 1524-4571
- OpenAlex
- W2153859777
- Cited by
- 330
- References
- 48
- Citations by year
- 2026: 4 · 2025: 2 · 2024: 7 · 2023: 7 · 2022: 12 · 2021: 12 · 2020: 12 · 2019: 7 · 2018: 12 · 2017: 18 · 2016: 18 · 2015: 20 · 2014: 19 · 2013: 29 · 2012: 26
- FWCI
- 9.10
- Type
- journal article
- Language
- en
- Open access
- Licence
- other-oa
- Locations
- Circulation Research (publishedVersion)
- PubMed (publishedVersion)
- Archivio Istituzionale della Ricerca - Università degli Studi della Campania "Luigi Vanvitelli" (submittedVersion)
- Padua Research Archive (University of Padova) (submittedVersion)
- INFM-OAR (INFN Catania) (submittedVersion, other-oa)
- Funders
- National Institutes of Health (5r01ag026107-05)
- National Institute on Aging (AG 23071, R01AG017042, P01AG023071, AG-26107, AG17042)
- National Heart, Lung, and Blood Institute (R37HL081737, HL65573, HL65577, HL-81737, P01HL078825, HL 38132, R01HL065573, HL 78825, HL 75480, R01HL065577, R01HL075480, R01HL038132)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Congenital heart defects research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Mesenchymal stem cell research
- Keywords
- diabetes mellitus, cardiac stem cells, heart failure, p66Shc, reactive oxygen species, oxidative stress, cellular senescence, telomere shortening, p53, p16INK4a, apoptosis, cardiomyocyte differentiation, diabetic cardiomyopathy, type 1 diabetes, gene deletion
- MeSH terms
- Src Homology 2 Domain-Containing, Transforming Protein 1, Animals, Cardiac Output, Low, Cell Division, Diabetes Mellitus, Experimental, Heart, Myocardium, Stem Cells, Cellular Senescence, Cell Death, Gene Deletion, Reactive Oxygen Species, Mice, Knockout, Oxidative Stress, Myocytes, Cardiac, Adaptor Proteins, Signal Transducing, Mice, Shc Signaling Adaptor Proteins
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