People with diabetes are 2-4-times more likely to develop an accelerated and aggressive form of heart disease than people without diabetes. The standard treatment for people with diabetes that are at increased risk of developing heart disease, and those that already have heart disease, is to reduce plasma LDL, or 'bad' cholesterol (LDL-C) levels with a statin. However, target LDL-C levels are often not achieved in these patients, and many of them remain at increased risk of having a heart attack, even when the recommended LDL-C level is reached.
This project asks whether heart disease can be reduced in these patients by targeting alternative pathways that are unrelated to LDL-C lowering, such as inhibiting inflammation and oxidation. We and others have reported that high density lipoproteins (HDLs), or 'good cholesterol', inhibit inflammation and oxidation. These cardioprotective effects have been attributed to apoA-I, the main HDL protein constituent. However, oxidative modification of apoA-I by the pro-oxidant enzyme myeloperoxidase (MPO) impairs the cardioprotective functions of HDLs.
MPO also increases heart disease by oxidizing LDLs and preventing blood vessels from functioning properly. HDL dysfunction and MPO-mediated oxidative stress can additionally increase the likelihood of a patient experiencing a potentially fatal heart attack due to generation of blood clots that block arteries. This project asks for the first time whether C-II-a, a novel, small peptide that mimics the cardioprotective functions of apoA-I, and a new class of potent MPO inhibitors called 2-thioxanthines, can prevent heart disease from developing, and reverse established heart disease in mouse models of diabetes. The optimal timing for C-II-a and MPO inhibitor treatment in patients with diabetes that have had a heart attack will also be identified.
Last updated12 July 2021