Diclofenac induces proteasome and mitochondrial dysfunction in murine cardiomyocytes and hearts

Rajeshwary Ghosh, Sumanta K. Goswami, Luis Felipe B B Feitoza, Bruce Hammock, Aldrin V Gomes

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Background One of the most common nonsteroidal anti-inflammatory drugs (NSAIDs) used worldwide, diclofenac (DIC), has been linked to increased risk of cardiovascular disease (CVD). The molecular mechanism(s) by which DIC causes CVD is unknown. Methods Proteasome activities were studied in hearts, livers, and kidneys from male Swiss Webster mice treated with either 100 mg/kg DIC for 18 h (acute treatment) or 10 mg/kg DIC for 28 days (chronic treatment). Cultured H9c2 cells and neonatal cardiomyocytes were also treated with different concentrations of DIC and proteasome function, cell death and ROS generation studied. Isolated mouse heart mitochondria were utilized to determine the effect of DIC on various electron transport chain complex activities. Results DIC significantly inhibited the chymotrypsin-like proteasome activity in rat cardiac H9c2 cells, murine neonatal cardiomyocytes, and mouse hearts, but did not affect proteasome subunit expression levels. Proteasome activity was also affected in liver and kidney tissues from DIC treated animals. The levels of polyubiquitinated proteins increased in hearts from DIC treated mice. Importantly, the levels of oxidized proteins increased while the β5i immunoproteasome activity decreased in hearts from DIC treated mice. DIC increased ROS production and cell death in H9c2 cells and neonatal cardiomyocytes while the cardioprotective NSAID, aspirin, had no effect on ROS levels or cell viability. DIC inhibited mitochondrial Complex III, a major source of ROS, and impaired mitochondrial membrane potential suggesting that mitochondria are the major sites of ROS generation. Conclusion These results suggest that DIC induces cardiotoxicity by a ROS dependent mechanism involving mitochondrial and proteasome dysfunction.

Original languageEnglish (US)
Pages (from-to)923-935
Number of pages13
JournalInternational Journal of Cardiology
Volume223
DOIs
StatePublished - Nov 15 2016

Fingerprint

Diclofenac
Proteasome Endopeptidase Complex
Cardiac Myocytes
Cell Death
Anti-Inflammatory Agents
Cardiovascular Diseases
Kidney
Heart Mitochondria
Mitochondrial Membrane Potential
Electron Transport Complex III
Liver
Chymotrypsin
Electron Transport
Pharmaceutical Preparations
Aspirin
Cultured Cells
Cell Survival
Mitochondria
Proteins

Keywords

  • Cardiac cells
  • Cell death
  • Diclofenac
  • Mitochondria
  • Proteasome
  • Reactive oxygen species

ASJC Scopus subject areas

  • Medicine(all)
  • Cardiology and Cardiovascular Medicine

Cite this

Diclofenac induces proteasome and mitochondrial dysfunction in murine cardiomyocytes and hearts. / Ghosh, Rajeshwary; Goswami, Sumanta K.; Feitoza, Luis Felipe B B; Hammock, Bruce; Gomes, Aldrin V.

In: International Journal of Cardiology, Vol. 223, 15.11.2016, p. 923-935.

Research output: Contribution to journalArticle

Ghosh, Rajeshwary ; Goswami, Sumanta K. ; Feitoza, Luis Felipe B B ; Hammock, Bruce ; Gomes, Aldrin V. / Diclofenac induces proteasome and mitochondrial dysfunction in murine cardiomyocytes and hearts. In: International Journal of Cardiology. 2016 ; Vol. 223. pp. 923-935.
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