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Targeting on Nrf2/Sesn2 Signaling to Rescue Cardiac Dysfunction during High-Fat Diet-Induced Obesity
Meredith Krause-Hauch1,2, Julia Fedorova1, Linda Ines Zoungrana1
1Department of Surgery, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA.
Abstract:
Obesity is of concern to the population because it is known to cause inflammation and oxidative stress throughout the body, leading to patient predisposition for health conditions such as diabetes, hypertension, and some cancers. However, some proteins that are activated in times of oxidative stress may provide cytoprotective properties. In this study, we aim to gain further understanding of the interconnection between Nrf2 and Sesn2 during obesity-related stress and how this relationship can play a role in cardio-protection. Cardiomyocyte-specific Sesn2 knockout (cSesn2-/-) and Sesn2 overexpressed (tTa-tet-Sesn2) mice and their wildtype littermates (Sesn2 and tet-Sesn2, respectively) were assigned to either a normal chow (NC) or a high-fat (HF) diet to induce obesity. After 16 weeks of dietary intervention, heart function was evaluated via echocardiography and cardiac tissue was collected for analysis. Immunoblotting, histology, and ROS staining were completed. Human heart samples were obtained via the LifeLink Foundation and were also subjected to analysis. Overall, these results indicated that the overexpression of Sesn2 appears to have cardio-protective effects on the obese heart through the reduction of ROS and fibrosis present in the tissues and in cardiac function. These results were consistent for both mouse and human heart samples. In human samples, there was an increase in Sesn2 and Nrf2 expression in the obese patients' LV tissue. However, there was no observable pattern of Sesn2/Nrf2 expression in mouse LV tissue samples. Further investigation into the link between the Sesn2/Nrf2 pathway and obesity-related oxidative stress is needed.
Insights
Obesity causes inflammation and oxidative stress. Sesn2 overexpression protects the heart by reducing reactive oxygen species (ROS) and fibrosis in obese mice and humans.
Area of Science:
- Cardiovascular Biology
- Metabolic Disease Research
- Oxidative Stress Mechanisms
Background:
- Obesity is linked to inflammation and oxidative stress, increasing susceptibility to chronic diseases.
- Certain proteins activated during oxidative stress may offer cytoprotective benefits.
- The interplay between Nrf2 and Sesn2 in obesity-related stress and cardiac protection requires further elucidation.
Purpose of the Study:
- To investigate the relationship between Nrf2 and Sesn2 in obesity-induced cardiac stress.
- To determine the role of this relationship in cardio-protection.
- To assess the impact of Sesn2 modulation on cardiac function and pathology in obesity.
Main Methods:
- Utilized cardiomyocyte-specific Sesn2 knockout and overexpressed mouse models.
- Administered normal chow or high-fat diets for 16 weeks to induce obesity.
- Evaluated cardiac function using echocardiography and analyzed cardiac tissues via immunoblotting, histology, and ROS staining. Human heart samples were also analyzed.
Main Results:
- Overexpression of Sesn2 demonstrated cardio-protective effects in obese mouse models.
- Sesn2 overexpression reduced reactive oxygen species (ROS) and fibrosis in cardiac tissues.
- Findings were consistent in both mouse and human heart samples, with increased Sesn2 and Nrf2 expression observed in obese human cardiac tissue.
Conclusions:
- Sesn2 overexpression confers cardio-protection against obesity-related stress.
- The reduction of ROS and fibrosis by Sesn2 contributes to improved cardiac function.
- Further research is necessary to fully understand the Sesn2/Nrf2 pathway's role in obesity and oxidative stress.
