Oxidative stress signaling in the pathogenesis of diabetic cardiomyopathy and the potential therapeutic role of antioxidant naringenin

Figure 1.. The pathophysiological mechanism of diabetic cardiomyopathy. The occurrence and development of diabetic cardiomyopathy involve multiple mechanisms. These include mitochondrial dysfunction, oxidative stress, inflammation, calcium processing disorders, endoplasmic reticulum stress, microvascular dysfunction, renin-angiotensin-aldosterone system (RAAS) activation, and multiple cardiometabolic abnormalities. Both are involved in structural remodeling and functional defects of diabetic myocardium.

Figure 2.. The role of different signaling pathways in DCM. Diabetes induces the formation of AGEs, which can simultaneously induce the activation of NOXs, RAGE and NF-κB to induce the excessive production of ROS, followed by the enhancement of oxidative stress. The activation of NOXs, RAGE and NF-κB can also cause and inflammation and oxidative damage. Oxidative stress can cause cardiomyocyte injury, apoptosis, extracellular matrix accumulation, myocardial fibrosis, remodeling, and dysfunction, all of which are characteristic of DCM. Nrf2 signaling pathway to produce antioxidant factors such as SOD and NQO1 to reduce oxidative damage. AGEs: advanced glycosylation end products; RAGE: receptor for AGEs; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells; NOX: NADPH oxidase; Nrf2: nuclear factor erythroid 2-related factor 2; ROS: reactive oxygen species; DCM: diabetic cardiomyopathy.

Figure 3.. The role of naringenin in DCM. Naringenin can inhibit the activation of ARG/RAGE, NOXs and NF-κB signaling pathways, and promote the activation of Nrf2 signaling. Naringenin, by altering the expression of these signaling pathways, can reduce the structural changes of cardiac muscle cells in many ways and alleviate heart failure.