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. 2022 Aug 22;11(16):2614.
doi: 10.3390/cells11162614.

Targeting on Nrf2/Sesn2 Signaling to Rescue Cardiac Dysfunction during High-Fat Diet-Induced Obesity

Meredith Krause-Hauch  1   2 , Julia Fedorova  1 , Linda Ines Zoungrana  1 , Hao Wang  1 , Mohammad Kasim Fatmi  1 , Zehui Li  3 , Migdalia Iglesias  1 , Lily Slotabec  1 , Ji Li  1   2
Affiliations

Targeting on Nrf2/Sesn2 Signaling to Rescue Cardiac Dysfunction during High-Fat Diet-Induced Obesity

Meredith Krause-Hauch et al. Cells. .

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 (Sesn2flox/flox 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.

Keywords: Nrf2; Sesn2; high-fat diet; obesity.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Experimental design and timeline. cSesn2−/−, tTa-tet-Sesn2, and their wildtype littermates (Sesn2flox/flox and tet-Sesn2, respectively) were randomly assigned to a normal chow (NC) diet or a high-fat (HF) diet at 4 weeks of age. After 16 weeks of dietary intervention, echocardiogram data and tissue samples were collected for bioanalysis.
Figure 2
Figure 2
Body weight over time. Body weights were measured weekly until mice reached 16 weeks of dietary intervention. (A) Comparison of body weights over 16 weeks for Sesn2flox/flox and cSesn2−/− mice on NC and HF diets. * p < 0.05 vs. Sesn2flox/flox NC; # p < 0.05 vs. cSesn2−/− HF. (B) Comparison of body weights over 16 weeks for tet-Sesn2 and tTa-tet-Sesn2 mice on NC and HF diets. * p < 0.05 vs. tet-Sesn2 NC; # p < 0.05 vs. tTa-tet-Sesn2 HF. Data are means ± SE.
Figure 3
Figure 3
Western blotting results and representative images. Sesn2 and Nrf2 expression in (A) Sesn2flox/flox and cSesn2−/− and (B) tet-Sesn2 and tTa-tet-Sesn2 mice under NC and HF diets. Analysis is means ± SE. n = 6 per group.
Figure 3
Figure 3
Western blotting results and representative images. Sesn2 and Nrf2 expression in (A) Sesn2flox/flox and cSesn2−/− and (B) tet-Sesn2 and tTa-tet-Sesn2 mice under NC and HF diets. Analysis is means ± SE. n = 6 per group.
Figure 4
Figure 4
Effect of Sesn2 on cardiac function after 16 weeks of dietary intervention. (A) Systolic function of the heart (LVFS and LVEF). (B) Diastolic function of the heart (E/A and E/e′). n = 6–8 per group. Means ± SE.
Figure 5
Figure 5
Effect of Sesn2 on the accumulation of cardiac fibrosis and inflammatory damage. (A) Representative Masson’s trichrome staining. (B) Collagen volume fraction (CVF). Means ± SE. (C) Representative hematoxylin and eosin staining; n = 8 per group.
Figure 6
Figure 6
ROS staining results and representative images for mouse LV tissue. (A) Sesn2flox/flox and cSesn2−/− and (B) tet-Sesn2 and tTa-tet-Sesn2. Means ± SE. n = 6 per group.
Figure 7
Figure 7
Effect of obesity on human hearts. (A) Western blot analysis of Sesn2 and Nrf2 in human LV tissue. (B) Representative Masson’s trichrome and hematoxylin and eosin staining; CVF = collagen volume fraction. (C) Representative images of mitochondrial superoxide production (MitoSox). Normal BMI (control) n = 3; obese BMI (obese) n = 9. Means ± SE.
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