Related Experiment Video
Updated: Feb 24, 2026
Mouse Electroacupuncture Fixation Device Fabrication for Electroacupuncture Pretreatment in Diabetic Cardiomyopathy Mouse Model
Published on: April 18, 2025
Advanced glycation end products receptor RAGE controls myocardial dysfunction and oxidative stress in high-fat fed
Yichi Yu1, Lei Wang1, Florian Delguste2
1INSERM U995, LIRIC /Team "Glycation: from inflammation to aging", Lille University, France; School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Abstract:
Oxidative stress and mitochondrial dysfunction are recognized as major contributors of cardiovascular damage in diabetes and high fat diet (HFD) fed mice. Blockade of receptor for advanced glycation end products (RAGE) attenuates vascular oxidative stress and development of atherosclerosis. We tested whether HFD-induced myocardial dysfunction would be reversed in RAGE deficiency mice, in association with changes in oxidative stress damage, mitochondrial respiration, mitochondrial fission and autophagy-lysosomal pathway. Cardiac antioxidant capacity was upregulated in RAGE-/- mice under normal diet as evidenced by increased superoxide dismutase and sirtuin mRNA expressions. Mitochondrial fragmentation and mitochondrial fission protein Drp1 and Fis1 expressions were increased in RAGE-/- mice. Autophagy-related protein expressions and cathepsin-L activity were increased in RAGE-/- mice suggesting sustained autophagy-lysosomal flux. HFD induced mitochondrial respiration defects, cardiac contractile dysfunction, disrupted mitochondrial dynamics and autophagy inhibition, which were partially prevented in RAGE-/- mice. Our results suggest that cardioprotection against HFD in RAGE-/- mice include reactivation of autophagy, as inhibition of autophagic flux by chloroquine fully abrogated beneficial myocardial effects and its stimulation by rapamycin improved myocardial function in HFD wild type mice. As mitochondrial fission is necessary to mitophagy, increased fragmentation of mitochondrial network in HFD RAGE-/- mice may have facilitated removal of damaged mitochondria leading to better mitochondrial quality control. In conclusion, modulation of RAGE pathway may improve mitochondrial damage and myocardial dysfunction in HFD mice. Attenuation of cardiac oxidative stress and maintenance of healthy mitochondria population ensuring adequate energy supply may be involved in myocardial protection against HFD.
Insights
Mice lacking the receptor for advanced glycation end products (RAGE) show improved heart function despite a high-fat diet. This protection involves enhanced antioxidant capacity and better mitochondrial quality control through autophagy.
Area of Science:
- Cardiovascular biology
- Mitochondrial medicine
- Metabolic disease research
Background:
- Oxidative stress and mitochondrial dysfunction contribute to cardiovascular damage in diabetes and high-fat diets (HFD).
- Blockade of the receptor for advanced glycation end products (RAGE) reduces vascular oxidative stress and atherosclerosis.
Purpose of the Study:
- To investigate if RAGE deficiency reverses HFD-induced myocardial dysfunction.
- To examine changes in oxidative stress, mitochondrial respiration, fission, and autophagy-lysosomal pathways in RAGE-deficient mice on an HFD.
Main Methods:
- Comparison of wild-type and RAGE-deficient mice on normal and high-fat diets.
- Assessment of cardiac antioxidant capacity, mitochondrial dynamics (fission proteins), and autophagy-lysosomal pathway markers.
- Evaluation of mitochondrial respiration and cardiac contractile function.
Main Results:
- RAGE-deficient mice exhibited upregulated cardiac antioxidant capacity and increased mitochondrial fragmentation with enhanced autophagy markers.
- HFD induced mitochondrial dysfunction, contractile deficits, and autophagy inhibition in wild-type mice, effects partially prevented in RAGE-deficient mice.
- Inhibition of autophagy worsened HFD effects, while stimulation improved function in wild-type mice, indicating autophagy's crucial role.
Conclusions:
- RAGE deficiency confers cardioprotection against HFD, involving autophagy reactivation and improved mitochondrial quality control via enhanced fission-mediated mitophagy.
- Modulating the RAGE pathway may offer a therapeutic strategy for mitigating mitochondrial damage and myocardial dysfunction in HFD-induced conditions.
