Targeted expression of cyclin D2 ameliorates late stage anthracycline cardiotoxicity

Wuqiang Zhu, Sean Reuter, Loren Field

Research output: Contribution to journalArticle

Abstract

AIMS: Doxorubicin (DOX) is a widely used and effective anti-cancer therapeutic. DOX treatment is associated with both acute and late onset cardiotoxicity, limiting its overall efficacy. Here, the impact of cardiomyocyte cell cycle activation was examined in a juvenile model featuring aspects of acute and late onset DOX cardiotoxicity. METHODS AND RESULTS: Two-week old MHC-cycD2 transgenic mice (which express cyclin D2 in postnatal cardiomyocytes and exhibit sustained cardiomyocyte cell cycle activity; D2 mice) and their wild type (WT) littermates received weekly DOX injections for 5 weeks (25 mg/kg cumulative dose). One week after the last DOX treatment (acute stage), cardiac function was suppressed in both groups. Acute DOX cardiotoxicity in D2 and WT mice was associated with similar increases in the levels of cardiomyocyte apoptosis and Ku70/Ku80 expression (markers of DNA damage and oxidative stress), as well as similar reductions in hypertrophic cardiomyocyte growth. Cardiac dysfunction persisted in WT mice for 13 weeks following the last DOX treatment (late stage) and was accompanied by increased levels of cardiomyocyte apoptosis, Ku expression, and myocardial fibrosis. In contrast, D2 mice exhibited a progressive recovery in cardiac function, which was indistinguishable from saline-treated animals by 9 weeks following the last DOX treatment. Improved cardiac function was accompanied by reductions in the levels of late stage cardiomyocyte apoptosis, Ku expression, and myocardial fibrosis. CONCLUSION: These data suggest that cardiomyocyte cell cycle activity can promote recovery of cardiac function and preserve cardiac structure following DOX treatment.

Original languageEnglish (US)
Pages (from-to)960-965
Number of pages6
JournalCardiovascular research
Volume115
Issue number5
DOIs
StatePublished - Apr 15 2019

Fingerprint

Cyclin D2
Anthracyclines
Doxorubicin
Cardiac Myocytes
Cell Cycle
Apoptosis
Fibrosis
Therapeutics
Cardiotoxicity
Recovery of Function
Transgenic Mice
DNA Damage
Oxidative Stress

Keywords

  • Cardiac regeneration
  • Cardiomyocyte apoptosis
  • Heart failure

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Targeted expression of cyclin D2 ameliorates late stage anthracycline cardiotoxicity. / Zhu, Wuqiang; Reuter, Sean; Field, Loren.

In: Cardiovascular research, Vol. 115, No. 5, 15.04.2019, p. 960-965.

Research output: Contribution to journalArticle

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