Other

Massachusetts Institute of Technology

Helena E Miettinen

Monty Krieger

Anne Braun

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&#x2212;/&#x2212; SR-BI+/&#x2212;) were fed PROBUCOL beginning at the time of mating. Offspring are weaned at three weeks and fed PROBUCOL. In contrast to animals (Apo E&#x2212;/&#x2212; SR-BI&#x2212;/&#x2212;) not fed PROBUCOL, 50% of whom are dead at six weeks, all animals (Apo E&#x2212;/&#x2212; SR-BI&#x2212;/&#x2212;) 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.

Screening of compounds for treatment of atherosclerosis and heart attack

SR-BI is present at relatively high levels on the membranes of hepatocytes and steroidogenic tissues, including the adrenal gland, testes, and ovaries, where it mediates the uptake and transport of cholesteryl ester from high density lipoproteins. It has been demonstrated that transgenic animals which do not produce SR-BI are healthy, with the exception that the females are infertile. SR-BI KO females have abnormal HDLs, ovulate dysfunctional oocytes and are infertile. Surgical, genetic and pharmacologic methods were used to show that the fertility of SR-BI KO females (or their transplanted oocytes) can be restored in the absence of ovarian and/or extraovarian SR-BI expression by manipulations that modify the structure, composition and/or abundance of their abnormal plasma lipoproteins. These manipulations included inactivation of the apolipoprotein A-I gene and administration of the cholesterol-lowering drug PROBUCOL&#x2122;. In the absence of treatment, female animals which do not express SR-BI have dramatically reduced levels of offspring, even though they are otherwise healthy and the males normal. Studies demonstrate that they do not produce viable eggs and have a defect involving implantation of normal eggs.

Growing community of inventors

Helsinki, Finland

Helena E Miettinen