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Nrf2-related gene expression is impaired during a glucose challenge in type II diabetic rat hearts
Max A Thorwald1, Jose A Godoy-Lugo2, Gema J Rodriguez2
1School of Natural Sciences, University of California, Merced, United States; Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, United States.
Abstract:
Diabetic hearts are susceptible to damage from inappropriate activation of the renin angiotensin system (RAS) and hyperglycemic events both of which contribute to increased oxidant production. Prolonged elevation of oxidants impairs mitochondrial enzyme function, further contributing to metabolic derangement. Nuclear factor erythriod-2-related factor 2 (Nrf2) induces antioxidant genes including those for glutathione (GSH) synthesis following translocation to the nucleus. We hypothesized that an acute elevation in glucose impairs Nrf2-related gene expression in diabetic hearts, while AT1 antagonism would aid in Nrf2-mediated antioxidant production and energy replenishment. We used four groups (n = 6-8/group) of 25-week-old rats: 1) LETO (lean strain-control), 2) type II diabetic OLETF, 3) OLETF + angiotensin receptor blocker (ARB; 10 mg olmesartan/kg/d × 8 wks), and 4) ARBM (4 weeks on ARB, 4 weeks off) to study the effects of acutely elevated glucose on cardiac mitochondrial function and Nrf2 signaling in the diabetic heart. Animals were gavaged with a glucose bolus (2 g/kg) and groups were dissected at T0, T180, and T360 minutes. Nrf2 mRNA was 32% lower in OLETF rats compared to LETO and remained suppressed in response to glucose. LETO Nrf2 mRNA increased 25% at T360 in response to glucose while no changes were observed in diabetic hearts. GCLC and GCLM mRNA decreased in diabetic hearts 33% and 44% respectively and remained suppressed in response to glucose while ARB treatment increased GCLM transcripts 90% at T180. These data illustrate that during T2DM and in response to glucose, cardiac Nrf2's adaptive response to environmental stressors such as glucose is impaired in diabetic hearts and that ARB treatment may aid Nrf2's impaired dynamic response.
Insights
Diabetic hearts show impaired antioxidant gene expression in response to high glucose. Angiotensin receptor blocker treatment may help restore this crucial Nrf2-mediated defense mechanism.
Area of Science:
- Cardiovascular Biology
- Metabolic Disease Research
- Molecular Medicine
Background:
- Diabetic hearts are vulnerable to damage from activated renin-angiotensin system (RAS) and hyperglycemia, leading to increased oxidative stress.
- Oxidative stress impairs mitochondrial function and exacerbates metabolic dysfunction in diabetic conditions.
- Nuclear factor erythriod-2-related factor 2 (Nrf2) is a key regulator of antioxidant genes, including those for glutathione (GSH) synthesis.
Purpose of the Study:
- To investigate the hypothesis that acute glucose elevation impairs Nrf2-related gene expression in diabetic hearts.
- To determine if AT1 antagonism can enhance Nrf2-mediated antioxidant production and energy replenishment in diabetic hearts.
- To examine the effects of glucose on cardiac mitochondrial function and Nrf2 signaling in type 2 diabetic rats.
Main Methods:
- Utilized four groups of rats: LETO (control), OLETF (type II diabetic), OLETF + ARB (olmesartan), and ARBM (ARB withdrawal).
- Administered a glucose bolus (2 g/kg) and collected tissue samples at 0, 180, and 360 minutes post-gavage.
- Quantified Nrf2, GCLC, and GCLM mRNA levels to assess gene expression and signaling pathway activation.
Main Results:
- Nrf2 mRNA was significantly lower in diabetic OLETF rats compared to controls and remained suppressed following glucose challenge.
- LETO rats showed a 25% increase in Nrf2 mRNA post-glucose, while diabetic hearts exhibited no change.
- GCLC and GCLM mRNA levels were reduced in diabetic hearts; ARB treatment increased GCLM transcripts by 90% at 180 minutes.
Conclusions:
- Cardiac Nrf2's adaptive response to glucose-induced stress is impaired in type 2 diabetes.
- Angiotensin receptor blocker (ARB) treatment shows potential in aiding the impaired dynamic response of Nrf2 signaling.
- These findings suggest ARB therapy may be beneficial in mitigating oxidative stress and metabolic derangements in diabetic hearts.
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