Key Therapeutic Targets to Treat Hyperglycemia-Induced Atherosclerosis Analyzed Using a Petri Net-Based Model

Area of Science:

• Cardiovascular Research
• Metabolic Disorders
• Computational Biology

Background:

• Diabetes mellitus (DM) is characterized by chronic hyperglycemia, damaging cells and accelerating atherosclerosis.
• Atherosclerosis in diabetic patients poses significant complications, necessitating strategies to slow its progression.
• Identifying specific molecular targets for inhibition within complex biological networks is challenging.

Purpose of the Study:

• To identify critical network targets for inhibiting atherosclerosis in the context of hyperglycemia using in silico methods.
• To evaluate potential therapeutic strategies for mitigating hyperglycemia-induced atherosclerosis.

Main Methods:

• Development of a computational model using Petri net theory to analyze molecular interactions.
• In silico analysis to identify key inhibitory targets within the atherosclerosis network in DM.
• Evaluation of the effects of inhibiting specific pathways, including protein kinase C (PKC), aldose reductase, AGE-RAGE axis, and NADPH oxidase.

Main Results:

• Blocking protein kinase C beta (PKCβ) and gamma (PKCγ) isoforms may inhibit atherosclerosis progression in diabetic patients.
• Aldose reductase inhibition slows atherosclerosis and reduces PKC (β and γ) expression in DM.
• Inhibition of the AGE-RAGE axis shows potential for treating hyperglycemia-induced atherosclerosis.
• NADPH oxidase blockade moderately slowed atherosclerosis but effectively halted mitochondrial reactive oxygen species (ROS) production.

Conclusions:

• Targeting PKCβ/γ and aldose reductase are promising strategies for slowing diabetic atherosclerosis.
• The AGE-RAGE axis represents a potential therapeutic target for hyperglycemia-related atherosclerosis.
• NADPH oxidase inhibition's impact on mitochondrial ROS offers a unique therapeutic angle.