What does oxidative stress do to the heart? Examining proteomic changes

Heart Proteomics Research

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June 1, 2020, 8:56 p.m.


The heart is an organ that is very sensitive to oxidative stress. In many heart diseases including cardiomyopathy and heart failure, research has found telltale signs of oxidative damage. Reactive oxygen species can create free radicals that react with and modify the molecular components that make up the heart. Because of this many efforts have been given to explore whether antioxidants can be used to delay or reverse the progression of heart disease, but so far the outcome has not been very satisfactory. This is partially because we still do not completely understand how the heart responds to oxidative stress and what are the specific components inside the heart that are changed.

To address this question, we used quantitative mass spectrometry in a recent project to monitor how the proteome of the heart responds to an acute dose of oxidative stressor. We used paraquat as a model of exposure to oxidative stressors in the mouse. Paraquat is an herbicide that has been associated with toxic side effects including causing Parkinson's disease, and in laboratory medicine has been used widely as a model of oxidative stress to the heart. Paraquat accumulates in the mitochondria of the heart creates free radicals. Mice that are exposed to toxic doses of paraquats have been shown to have reduced cardiac output.

Oxidative stress changes protein abundance and localization

In our experiments, we exposed mice to paraquats for 24 hours and examined what are the protein damages that the compound induced in the hearts of the animals. Using tandem mass tag based quantitative mass spectrometry, we monitored the abundance of over 4,000 protein species. We found that exposure to paraquat led to widespread changes in protein abundance in multiple pathways that suggest that in response to oxidative damage, the heart is attempting to reduce metabolism and oxygen usage as well as protein synthesis, whereas antioxidant proteins and protein homeostasis pathways are up-regulated.

We also found evidence that in addition to protein abundance changes, some proteins may change in their subcellular localization in response to stress. Hexokinase 2 is one such example and is a glycolytic protein that is known to shuttle between the cytosol and the mitochondria in response to different stimuli. Overall, this dataset revealed a large number of complex proteomic alterations in response to acute oxidative stress that may be useful for identifying future therapeutic targets to offset the damage of oxidative stressors.

The full details and methods can be found in our manuscript coauthored by Vishantie, Silas, Cody and Erin, which has been posted as a preprint on bioRxiv.