Different effects of the nonsteroidal anti-inflammatory drugs meclofenamate sodium and naproxen sodium on proteasome activity in cardiac cells

J Mol Cell Cardiol. 2016 May;94:131-144. doi: 10.1016/j.yjmcc.2016.03.016. Epub 2016 Apr 3.


The use of nonsteroidal anti-inflammatory drugs (NSAIDs) like meclofenamate sodium (MS), used to reduce pain, has been associated with an increased risk of cardiovascular disease (CVD). Naproxen (NAP), another NSAID, is not associated with increased risk of CVD. The molecular mechanism(s) by which NSAIDs induce CVD is unknown. We investigated the effects of MS and NAP on protein homeostasis and cardiotoxicity in rat cardiac H9c2 cells and murine neonatal cardiomyocytes. MS, but not NAP, significantly inhibited proteasome activity and reduced cardiac cell viability at pharmacological levels found in humans. Although proteasome subunit gene and protein expression were unaffected by NSAIDs, MS treated cell lysates showed higher 20S proteasome content, while purified proteasomes from MS treated cells had lower proteasome activity and higher levels of oxidized subunits than proteasomes from control cells. Addition of exogenous proteasome to MS treated cells improved cell viability. Both MS and NAP increased ROS production, but the rate of ROS production was greater in MS than in NAP treated cells. The ROS production is likely from mitochondria, as MS inhibited mitochondrial Complexes I and III, major sources of ROS, while NAP inhibited Complex I. MS also impaired mitochondrial membrane potential while NAP did not. Antioxidants were able to prevent the reduced cell viability caused by MS treatment. These results suggest that NSAIDs induce cardiotoxicity by a ROS dependent mechanism involving mitochondrial and proteasome dysfunction and may explain why some NSAIDs should not be given to patients for long periods.

Keywords: Cardiac cells; Cell death; Mitochondria; Nonsteroidal anti-inflammatory drugs; Proteasome; Reactive oxygen species.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • Cell Survival / drug effects
  • Electron Transport Complex II / metabolism
  • Meclofenamic Acid / pharmacology*
  • Membrane Potential, Mitochondrial / drug effects
  • Mice
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Myocytes, Cardiac / drug effects*
  • Myocytes, Cardiac / metabolism*
  • Naproxen / pharmacology*
  • Oxidation-Reduction
  • Prostaglandin-Endoperoxide Synthases / metabolism
  • Proteasome Endopeptidase Complex / metabolism*
  • Reactive Oxygen Species / metabolism
  • Ubiquitinated Proteins / metabolism


  • Anti-Inflammatory Agents, Non-Steroidal
  • Reactive Oxygen Species
  • Ubiquitinated Proteins
  • Meclofenamic Acid
  • Naproxen
  • Prostaglandin-Endoperoxide Synthases
  • Electron Transport Complex II
  • Proteasome Endopeptidase Complex