Advanced glycation end products receptor RAGE controls myocardial dysfunction and oxidative stress in high-fat fed mice by sustaining mitochondrial dynamics and autophagy-lysosome pathway

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. [Display omitted] •High fat diet HFD induces mitochondrial dysfunction and autophagy inhibition.•Deficiency of RAGE upheld antioxidant capacity and reactivated autophagic flux.•Myocardial and mitochondrial dysfunction were reversed in HFD RAGE deficient mice.•Healthier mitochondria population supported cardiac function in those mice.