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Cited by 180Cardiac Fibrosis and RemodelingCardiovascular Function and Risk FactorsCell death mechanisms and regulation

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

Barouch, Lili A., Gao, Daqing, Chen, Lei, Miller, Karen L., Xu, Wenhong, Phan, Alexander C., Kittleson, Michelle M., Minhas, Khalid M. +3 more·2006·Circulation Research
DOI 10.1161/01.res.0000199348.10580.1d
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Abstract

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.

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  • Cardiac hypertrophy has been reported in old but not in young db/db mice.

    “Similarly, cardiac hypertrophy has been reported in old but not in young db/db mice (23, 24).”

    From Cardiac remodeling in obesity (2008) · cites this paper as [24]

  • Some groups have reported cardiac hypertrophy in hearts of young ob/ob mice, while others have only observed this phenotype in older animals.

    “For example, while some groups have reported cardiac hypertrophy in hearts of young ob/ob mice (30, 34, 227), others have only observed this phenotype in older animals (23, 24).”

    From Cardiac remodeling in obesity (2008) · cites this paper as [24]

  • Leptin-deficient ob/ob mice exhibit a higher degree of cardiomyocyte apoptosis that can be restored to normal levels by leptin administration.

    “For example, leptin-deficient ob/ob mice exhibit a higher degree of cardiomyocyte apoptosis that can be restored to normal levels by leptin administration (24).”

    From Cardiac remodeling in obesity (2008) · cites this paper as [24]

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Research works printed but not linked: 1

  1. Breslow MJ, Min-Lee K, Brown DR, Chacko VP, Palmer D, Berkowitz DE. Effect of leptin deficiency on metabolic rate in ob/ob mice. Am J Physiol. 1999;276:E443-E449.

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Authors
Barouch, L. A., Gao, D., Chen, L., Miller, K. L., Xu, W., Phan, A. C., Kittleson, M. M., Minhas, K. M., Berkowitz, D. E., Wei, C., & Hare, J. M.
Affiliations
Johns Hopkins University (US)
ORCID
Venue
Circulation Research
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2006-01-06
Volume
98
Issue
1
Pages
119-124
ISSN
  • 0009-7330 (ISSN-L)
  • 1524-4571
DOI
10.1161/01.res.0000199348.10580.1d
OpenAlex
W2165747324
Cited by
180
References
37
Citations by year
2026: 3 · 2025: 3 · 2024: 4 · 2023: 3 · 2022: 13 · 2021: 7 · 2020: 6 · 2019: 6 · 2018: 12 · 2017: 14 · 2016: 8 · 2015: 8 · 2014: 12 · 2013: 12 · 2012: 13
FWCI
4.33
Type
journal article
Language
en
Open access
closed
Locations
  • Circulation Research (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Donald W. Reynolds Foundation
  • Amgen
  • National Institutes of Health
  • National Institute on Aging (R01AG025017)
  • National Heart, Lung, and Blood Institute (R01 HL65455, K08HL076220, R01HL065455, R01HL061299, R01 HL-61299)
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Function and Risk Factors
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
Keywords
cardiomyocyte apoptosis, leptin signaling, leptin resistance, obesity, DNA damage, 8-oxoguanine, DNA repair, left ventricular hypertrophy, aging, caspase-3, cardiac dysfunction, mortality, ob/ob mice, db/db mice, triglycerides
MeSH terms
Animals, DNA Damage, DNA Repair, Cardiomegaly, Mice, Inbred C57BL, Mice, Obese, Obesity, Triglycerides, Signal Transduction, Apoptosis, Oxidative Stress, In Situ Nick-End Labeling, Leptin, Myocytes, Cardiac, Mice

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