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

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.

Sestrin2 Mediates Metformin Rescued the Age-Related Cardiac Dysfunctions of Cardiorenal Syndrome Type 3

“…Therefore, an additional investigation into the Sesn2-AMPK pathway could lead to better comprehension of the mechanism via which Sesn2 offers its cardioprotective effects during CRS3. Furthermore, under OS, Sesn2 is upregulated causing nuclear factor erythroid 2-related factor 2 (Nrf2) to travel from the cytoplasm to the nucleus, where it can offer protection against OS through the expression of Sesn2 [ 6 , 8 , 32 ]. Given this positive feedback loop, future studies into the connection between Nrf2 and Sesn2 during CRS3 could be beneficial.…”

“…LV total protein underwent SDS-PAGE and electrotransfer to polyvinylidene difluoride membranes (Millipore, Bedford, MA, USA) [ 6 , 9 ]. Rabbit Sesn2 antibody (Cat #10795-1-AP, Cat #21346-1-AP) from Proteintech ® (Chicago, IL, USA) and Ab178518 from Abcam (Waltham, MA), were used following the manufacturer’s protocol.…”

“…Oxidative stress (OS) is the imbalance between the amount of reactive oxygen species (ROS) and antioxidants. OS can damage DNA, lipids, and proteins, leading to conditions such as cancer, and neurodegenerative and cardiovascular diseases [ 5 , 6 ]. Renal ischemia-reperfusion injury (IRI) is a common way via which AKI is induced, and is a risk factor for the development of CRS3 [ 5 ].…”

chi‐miR‐130b‐3p regulates the ZEA‐induced oxidative stress damage through the KEAP1/NRF2 signaling pathway by targeting SESN2 in goat GCs

“…Quantities of studies have verified that SESN2 plays an active role in maintaining intracellular homeostasis when cells are invaded by multiple stimuli. Kim et al illustrated that SESN2 suppressed sepsis by inducing mitophagy and inhibiting NLRP3 activation in macrophages, 29 the overexpression of SESN2 appeared to have cardio‐protective effects on the obese heart through the reduction of ROS and fibrosis present in the tissues and in cardiac function according to Krause‐Hauch et al 30 , and SESN2 has been proved to attenuate the damage of endothelial progenitor cells induced by angiotensin II through regulating the KEAP1/NRF2 signal pathway 31 . Based on these existing findings, we set out to explore the role played by SESN2 when GCs are exposed to the ZEA, which to date remains unknown.…”

Muscular Sestrins: Roles in Exercise Physiology and Stress Resistance

“…Sestrins are also thought to mediate the cardioprotective activities of several therapeutic compounds, such as empagliflozin [66] and pentamethylquercetin [67,68]. Even without direct cardiac injury, loss of Sestrin2 by itself can provoke cardiac fibrosis and inflammatory damage during obesity, which is relatively mild in its Sestrin-proficient WT counterpart [69]. Likewise, in Drosophila, loss of Sestrin also provoked early onset development of cardiac arrhythmia and decreased cardiac output [17].…”