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NSAIDs-dependent adaption of the mitochondria-proteasome system in immortalized human cardiomyocytes
Laura Brandolini1, Andrea Antonosante2, Cristina Giorgio1
1Dompé Farmaceutici SpA, Via Campo di Pile, L'Aquila, Italy.
Abstract:
The progressive consumption growth of non-steroidal anti-inflammatory drugs (NSAIDs) has progressively raised the attention toward the gastrointestinal, renal, and cardiovascular toxicity. Increased risk of cardiovascular diseases was strictly associated with the usage of COX-2 selective NSAIDs. Other studies allowed to clarify that the cardiovascular risk is not limited to COX-2 selective but also extended to non-selective NSAIDs, such as Diclofenac and Ketoprofen. To date, although a less favorable cardiovascular risk profile for Diclofenac as compared to Ketoprofen is reported, the mechanisms through which NSAIDs cause adverse cardiovascular events are not entirely understood. The present study aimed to evaluate the effects of Ketoprofen in comparison with Diclofenac in immortalized human cardiomyocytes. The results obtained highlight the dose-dependent cardiotoxicity of Diclofenac compared to Ketoprofen. Despite both drugs induce the increase in ROS production, decrease of mitochondrial membrane potential, and proteasome activity modulation, only Diclofenac exposure shows a marked alteration of these intracellular parameters, leading to cell death. Noteworthy, Diclofenac decreases the proteasome 26S DC and this scenario may be dependent on the intracellular overload of oxidized proteins. The data support the hypothesis that immortalized human cardiomyocytes exposed to Ketoprofen are subjected to tolerable stress events, conversely Diclofenac exposition triggers cell death.
Insights
Diclofenac causes dose-dependent cardiotoxicity in human heart cells, unlike Ketoprofen. Diclofenac induces cell death by increasing oxidative stress and impairing proteasome function, highlighting significant cardiovascular risks.
Area of Science:
- Cardiology
- Pharmacology
- Toxicology
Background:
- Non-steroidal anti-inflammatory drugs (NSAIDs) consumption is rising, prompting concerns about their toxicity.
- Cardiovascular risks are linked to both COX-2 selective and non-selective NSAIDs, including Diclofenac and Ketoprofen.
- Mechanisms underlying NSAID-induced cardiovascular adverse events remain unclear.
Purpose of the Study:
- To compare the effects of Ketoprofen and Diclofenac on immortalized human cardiomyocytes.
- To elucidate the differential cardiotoxic mechanisms of these two NSAIDs.
Main Methods:
- Exposure of immortalized human cardiomyocytes to varying doses of Ketoprofen and Diclofenac.
- Assessment of reactive oxygen species (ROS) production.
- Measurement of mitochondrial membrane potential.
- Evaluation of proteasome activity.
- Analysis of cell viability.
Main Results:
- Diclofenac demonstrated dose-dependent cardiotoxicity, whereas Ketoprofen showed tolerable stress.
- Both NSAIDs increased ROS production and decreased mitochondrial membrane potential.
- Diclofenac significantly altered these parameters and led to cell death.
- Diclofenac exposure decreased proteasome 26S activity, potentially due to oxidized protein overload.
Conclusions:
- Diclofenac exhibits greater cardiotoxicity than Ketoprofen in human cardiomyocytes.
- Diclofenac's toxicity involves significant oxidative stress, mitochondrial dysfunction, and proteasome impairment, leading to cell death.
- These findings underscore the differential cardiovascular risks associated with NSAID usage.
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