Therapeutic Approach of Flavonoid in Ameliorating Diabetic Cardiomyopathy by Targeting Mitochondrial-Induced Oxidative Stress

Figures

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  Figure 1. Prolonged hyperglycemia can produce reactive oxygen species (ROS) via activation of protein kinase C (PKC) pathways and advanced glycation end products (AGEs) production, leading to altered metabolism regulation, altered mitochondrial biogenesis, impaired mitochondrial calcium handling, and impaired electron transport chain. These actions will cause mitochondrial to deteriorate and generate more ROS. The ROS produced results in oxidative stress, which can initiate inflammation, fibrosis, and apoptosis, causing diabetic cardiomyopathy (DCM).

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  Figure 2. In diabetic condition, hyperglycemia causes impairment of electron transport chain (ETC). Due to incomplete reduction of oxygen, electron (ē) will escape from the ETC and lead to superoxide (O2*) production. Furthermore, glucose-depletion in the mitochondria boost respiration and enhance ETC capacity which then enhances production of superoxide that leads to increased consumption of SOD. Reduction in SOD activity results in the accumulation of superoxides and reduced their conversion to hydrogen peroxide (H2O2). Moreover, elevated O-GlcNAc was found in hyperglycemic condition which then reduces the activity of complex IV. The activity of ATP synthase also declines as high glucose triggers NOX expression and further enhances expression of calpain-1, leading to ATP synthase cleavage and thus reduces the production of ATP. Red arrow indicates increase/decrease of level/activity; black arrow indicates flow of mechanisms in ETC; ‘x’ symbol indicates inhibition of H2O2 production.

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  Figure 3. In hyperglycemic condition, reduction of glucose uptake will suppress glucose oxidation. Hence, the energy metabolism will shift from glucose to fatty acid utilization. AMPK, regulator of energy homeostasis, will be downregulated hence suppressing PGC1α expression. PGC1α suppression downregulates PPARα and enhances free fatty acid uptake, acyl CoA as well as escalating β-oxidation. In parallel with that, the TCA cycle is also deprived. The increase of DAG resulting from persistent hyperglycemia enhances PKC activation and AGEs formation which then promote ROS generation. In addition, the surge of β-oxidation produce byproduct, NADH and FADH2 as well as enhanced UCP3 expression further cause reduction in electron transport chain activity. Furthermore, PGC1α suppression also leads to mitochondrial biogenesis impairment via reduction of mitochondrial transcription. PGC1α suppression will also cause poor calcium handling which then enhance mitochondrial permeability transition pore (mPTP) opening and diminishes mitochondrial membrane polarization. Enhanced β-oxidation, impaired of mitochondrial biogenesis and poor calcium handling will then cause reduction of ETC hence cause…

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  Figure 4. Chemical structures and example of sources where they are found abundant in for each flavonoid subclasses.

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  Figure 5. Role of flavonoids in targeting mitochondrial induce oxidative stress in DCM. Flavonoids have been proven to alleviate mitochondrial dysfunction by targeting mechanisms involving oxidative stress in mitochondria including activation of AMPK which then activate PGC1α. PGC1α enhances mitochondrial biogenesis as well as PPARα expression and cause reduction of β-oxidation in mitochondria which then downregulate UCP3. Flavonoids also reduce the formation of Ca2+ induced mPTP which preserve mitochondrial number and prevent apoptosis. Furthermore, flavonoids were proven to enhance GLUT4 activity which then led to increase glucose uptake as well as enhance MMP that cause increase in ETC activities which further elevate ATP production. Moreover, flavonoids can act as antioxidant and scavenge ROS as well as increase SOD and Prx3 enzyme which later attenuate oxidative stress. This figure is illustrated based on the review of the previous research. Black arrow indicates flow of mechanisms; red arrow indicates increase/decrease of level/activity.