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P66Shc (Shc1) Zebrafish Mutant Line as a Platform for Testing Decreased Reactive Oxygen Species in Pathology
Landon Haslem1, Jennifer M Hays1, Xin A Zhang2,3
1Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
Abstract:
Reactive oxygen species (ROS) dysregulation exacerbates many pathologies but must remain within normal ranges to maintain cell function. Since ROS-mediated pathology and routine cell function are coupled, in vivo models evaluating low-ROS background effects on pathology are limited. Some models alter enzymatic antioxidant expression/activity, while others involve small molecule antioxidant administration. These models cause non-specific ROS neutralization, decreasing both beneficial and detrimental ROS. This is detrimental in cardiovascular pathology, despite the negative effects excessive ROS has on these pathologies. Thus, current trends in ROS-mediated pathology have shifted toward selective inhibition of ROS producers that are dysregulated during pathological insults, such as p66Shc. In this study, we evaluated a zebrafish heterozygote p66Shc hypomorphic mutant line as a low-ROS myocardial infarction (MI) pathology model that mimics mammalian MI. Our findings suggest this zebrafish line does not have an associated negative phenotype, but has decreased body mass and tissue ROS levels that confer protection against ROS-mediated pathology. Therefore, this line may provide a low-ROS background leading to new insights into disease.
Insights
A novel zebrafish model with reduced reactive oxygen species (ROS) offers a unique low-ROS background for studying cardiovascular pathology, particularly myocardial infarction (MI). This model shows promise for understanding disease mechanisms without negative side effects.
Area of Science:
- Cardiovascular Research
- Zebrafish Models
- Reactive Oxygen Species Biology
Background:
- Reactive oxygen species (ROS) dysregulation is implicated in numerous pathologies.
- Existing in vivo models for studying ROS-related diseases often neutralize ROS non-specifically, impacting both beneficial and detrimental ROS levels.
- Targeting specific ROS-producing enzymes, like p66Shc, is a newer strategy for studying ROS-mediated pathologies.
Purpose of the Study:
- To evaluate a zebrafish heterozygote p66Shc hypomorphic mutant line as a model for low-ROS myocardial infarction (MI).
- To assess if this zebrafish line can mimic mammalian MI while maintaining a low-ROS background.
- To investigate the potential of this model for studying ROS-mediated cardiovascular pathology.
Main Methods:
- Development and characterization of a zebrafish heterozygote p66Shc hypomorphic mutant line.
- Evaluation of the mutant line for associated phenotypes, including body mass and tissue ROS levels.
- Assessment of the mutant line's utility as a model for myocardial infarction (MI) pathology.
Main Results:
- The p66Shc hypomorphic zebrafish line exhibits no significant negative phenotype.
- This zebrafish line demonstrates decreased body mass and lower tissue ROS levels.
- The reduced ROS levels in this model confer protection against ROS-mediated pathology.
Conclusions:
- The p66Shc hypomorphic zebrafish line serves as a viable low-ROS model for studying myocardial infarction (MI).
- This model offers a unique platform to investigate ROS-mediated diseases without the confounding effects of broad ROS neutralization.
- The findings suggest this zebrafish line can provide novel insights into cardiovascular pathology and related diseases.
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