Short‐term Ibuprofen Treatment cause Gender‐Specific Differences in Proteasomal and Mitochondrial functions in Mice Heart

Abstract

Ibuprofen is the most common pain‐killer widely used for the management of dental pain, headache, migraine and rheumatoid arthritis. Concern has been raised due to adverse cardiovascular side effects associated with the chronic use of ibuprofen. Thus, understanding the short‐term effects of ibuprofen on cardiac function is crucial to the safe use of the drug among individuals with established cardiovascular disorders. The objective of this study was to evaluate whether ibuprofen caused gender‐specific differences in mitochondrial and proteasomal functions in mice cardiac tissue and to gain insights into the molecular mechanisms underlying these differences. To determine whether there is a sex difference on protein homeostasis with respect to ibuprofen treatment 8‐week‐old aged matched male and female C57BL/6J mice were treated with ibuprofen (100 mg/kg/day) dissolved in drinking water for seven days and were randomly assigned to control group and group treated with ibuprofen. Ibuprofen significantly reduced caspase‐like (β1), and trypsin‐like (β2) 26S proteasome activities in both male and female heart. However, ibuprofen reduced chymotrypsin‐like (β5 proteasome activity) in the female heart but not male hearts. Notably, immunoproteasome β1i (expression) and β5i (expression and activity) significantly increased in females relative to males. In contrast, a trend towards the decrease in expression of β2i and β5i immunoproteasome was observed in ibuprofen‐treated male mice. To determine mitochondrial function, measurement of mitochondrial respiratory chain complexes revealed that ibuprofen treatment significantly decreased complex I activity in female heart compared with males. Short‐term ibuprofen treatment also decreased heart weight in male mice but not in female mice. Western blots and oxyblots analysis showed no differences in the expression levels of polyubiquitinated proteins, free ubiquitins and oxidized proteins in both males and females. Our in vitro study with rat cardiac H9c2 cells showed that ibuprofen‐induced reactive oxygen species (ROS) generation, decreased mitochondrial complex II activity, reduced mitochondrial membrane potential and had variable effects on cell viability. In conclusion, our findings suggest that short‐term ibuprofen treatment results in gender‐specific adverse changes in cardiac mitochondrial function and protein homeostasis.Support or Funding InformationAmerican Heart Association (AHA) 16GRNT31350040 grant (A.V.G.)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.