Screening of compounds for treatment of atherosclerosis and heart attack

Abstract

Transgenic animals that do not express functional SR-BI and ApoE develop severe atherosclerosis, by age four weeks in transgenic mice. Moreover, these animals exhibit progressive heart dysfunction by as early as age four weeks, and die by age nine weeks. This animal model has now been demonstrated to be useful as a screen for compounds which alleviate the symptoms of atherosclerosis and heart disease. Animals (Apo E−/− SR-BI+/−) were fed PROBUCOL beginning at the time of mating. Offspring are weaned at three weeks and fed PROBUCOL. In contrast to animals (Apo E−/− SR-BI−/−) not fed PROBUCOL, 50% of whom are dead at six weeks, all animals (Apo E−/− SR-BI−/−) on PROBUCOL have a normal phenotype (MRI of heart function, ECG, echocardiogram, histology) at six weeks. At seven to eight months, there is evidence of atherosclerosis and some myocardial infarction. This demonstrates that the compound has a preventative action. Animals who are taken off of the PROBUCOL all die within ten to twelve weeks. In another study, the majority of animals whose parents were not fed PROBUCOL, but who received the PROBUCOL beginning at about five weeks of age, survived for a few months, demonstrating that the compound also has a therapeutic benefit.