NSAIDs-dependent adaption of the mitochondria-proteasome system in immortalized human cardiomyocytes

Laura Brandolini,Michele D’Angelo,Elisabetta Benedetti,Cristina Giorgio,Vanessa Castelli,Annamaria Cimini,Michela Bagnasco,Andrea Antonosante,Marcello Allegretti

doi:10.1038/s41598-020-75394-x

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.

Highlights

The progressive consumption growth of non-steroidal anti-inflammatory drugs (NSAIDs) has progressively raised the attention toward the gastrointestinal, renal, and cardiovascular toxicity
Myoblast determination protein 1 (MyoD), a skeletal muscle-specific bHLH transcription factor, which is early activated during myogenesis, and normally down-regulated in differentiated human cardiomyocytes[41,42], was significantly reduced in 7DIV cardiomyocytes compared to 2DIV condition, as shown by western blotting analysis (Fig. 1C)
Several placebo-controlled trials focused on COX-2 inhibitors showing an increased risk of atherothrombotic vascular events associated with the use of these drugs[60,61]

Summary

Introduction

The progressive consumption growth of non-steroidal anti-inflammatory drugs (NSAIDs) has progressively raised the attention toward the gastrointestinal, renal, and cardiovascular toxicity. 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. Whereas the use of NSAIDs is commonly associated with minor side effects, the progressive consumption growth has progressively raised the attention toward the gastrointestinal, renal, and cardiovascular toxicity[2] profile of the class and numerous studies investigated the specific characteristics of each NSAID to better assess its risk/benefit p rofile[3]

Methods

Results

Conclusion